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Cited by 366Plant biochemistry and biosynthesisSesquiterpenes and Asteraceae StudiesPhytochemical compounds biological activities

The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao)

Open access
Brown, Geoffrey D.·2010·Molecules
DOI 10.3390/molecules15117603PMC PMC6259225
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Abstract

The Chinese medicinal plant Artemisia annua L. (Qinghao) is the only known source of the sesquiterpene artemisinin (Qinghaosu), which is used in the treatment of malaria. Artemisinin is a highly oxygenated sesquiterpene, containing a unique 1,2,4-trioxane ring structure, which is responsible for the antimalarial activity of this natural product. The phytochemistry of A. annua is dominated by both sesquiterpenoids and flavonoids, as is the case for many other plants in the Asteraceae family. However, A. annua is distinguished from the other members of the family both by the very large number of natural products which have been characterised to date (almost six hundred in total, including around fifty amorphane and cadinane sesquiterpenes), and by the highly oxygenated nature of many of the terpenoidal secondary metabolites. In addition, this species also contains an unusually large number of terpene allylic hydroperoxides and endoperoxides. This observation forms the basis of a proposal that the biogenesis of many of the highly oxygenated terpene metabolites from A. annua – including artemisinin itself – may proceed by spontaneous oxidation reactions of terpene precursors, which involve these highly reactive allyllic hydroperoxides as intermediates. Although several studies of the biosynthesis of artemisinin have been reported in the literature from the 1980s and early 1990s, the collective results from these studies were rather confusing because they implied that an unfeasibly large number of different sesquiterpenes could all function as direct precursors to artemisinin (and some of the experiments also appeared to contradict one another). As a result, the complete biosynthetic pathway to artemisinin could not be stated conclusively at the time. Fortunately, studies which have been published in the last decade are now providing a clearer picture of the biosynthetic pathways in A. annua. By synthesising some of the sesquiterpene natural products which have been proposed as biogenetic precursors to artemisinin in such a way that they incorporate a stable isotopic label, and then feeding these precursors to intact A. annua plants, it has now been possible to demonstrate that dihydroartemisinic acid is a late-stage precursor to artemisinin and that the closely related secondary metabolite, artemisinic acid, is not (this approach differs from all the previous studies, which used radio-isotopically labelled precursors that were fed to a plant homogenate or a cell-free preparation). Quite remarkably, feeding experiments with labeled dihydroartemisinic acid and artemisinic acid have resulted in incorporation of label into roughly half of all the amorphane and cadinane sesquiterpenes which were already known from phytochemical studies of A. annua. These findings strongly support the hypothesis that many of the highly oxygenated sesquiterpenoids from this species arise by oxidation reactions involving allylic hydroperoxides, which seem to be such a defining feature of the chemistry of A. annua. In the particular case of artemisinin, these in vivo results are also supported by in vitro studies, demonstrating explicitly that the biosynthesis of artemisinin proceeds via the tertiary allylic hydroperoxide, which is derived from oxidation of dihydroartemisinic acid. There is some evidence that the autoxidation of dihydroartemisinic acid to this tertiary allylic hydroperoxide is a non-enzymatic process within the plant, requiring only the presence of light; and, furthermore, that the series of spontaneous rearrangement reactions which then convert this allylic hydroperoxide to the 1,2,4-trioxane ring of artemisinin are also non-enzymatic in nature.

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Written from the paper’s full text.

TL;DR

This review compiles the phytochemistry of *Artemisia annua* and argues that many highly oxygenated terpenes, including artemisinin, arise via spontaneous autoxidation of terpene precursors through allylic hydroperoxides. It concludes that dihydroartemisinic acid, not artemisinic acid, is the late-stage precursor to artemisinin, with the final steps likely non-enzymatic.

Key findings

  • Nearly 600 secondary metabolites have been characterized from *A. annua*, including around 50 amorphane and cadinane sesquiterpenes; artemisinin content varies from 0.01% to 1%, and can reach 1.4% in some cultivated strains.
  • Stable-isotope feeding to intact plants showed dihydroartemisinic acid is a late-stage precursor to artemisinin, whereas artemisinic acid is not; labeled dihydroartemisinic acid yielded sixteen labeled amorphane/cadinane sesquiterpenes, while labeled artemisinic acid yielded seven metabolites.
  • Artemisinin biosynthesis is proposed to proceed via the tertiary allylic hydroperoxide derived from dihydroartemisinic acid; in vitro evidence supports a four-step spontaneous autoxidation mechanism, and autoxidation to the hydroperoxide may require only light and be non-enzymatic.
  • Many highly oxygenated terpenes from *A. annua* are proposed to arise by oxidation reactions involving allylic hydroperoxides and endoperoxides, which the review treats as a defining feature of this species’ chemistry.

Methods

  • Comprehensive review of original phytochemical literature on *A. annua* up to 2009, organizing almost 600 secondary metabolites into eight sections and more than forty tables using a largely biogenetic classification.
  • Synthesizes biosynthetic studies including older radiolabeled cell-free/homogenate experiments and more recent stable-isotope feeding to intact plants, alongside in vitro autoxidation experiments.
  • Evaluates three phases of artemisinin biosynthesis and production strategies: plant breeding, plant tissue culture, endophytic fungi, and genetic engineering.

Limitations

  • The paper states that the proposed biosynthetic route is still not universally accepted and that older literature contains results that may appear to contradict it; many phase 3 intermediates have been proposed, and not all can be correct.
  • No enzymes have yet been described for phase 3 reactions, and there is no direct in vivo evidence for steps ii–iv of the proposed autoxidation mechanism; evidence for those steps comes solely from in vitro studies.
  • The text notes that understanding of spontaneous autoxidation without a photosensitizer remains incomplete; as a review, conclusions depend on synthesis of prior literature rather than a single new experimental dataset (evident from the text).

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Integrity signals

Registry

Crossref · 10.3390/molecules15117603

Cites

303 of 303 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 360 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The largest group of monocyclic monoterpenes in A. annua is the p-menthane series, which incorporates a single six-membered ring.

    “The largest group of such monocyclic monoterpenes in A. annua is the p-menthane series (Table 25), which incorporate a single six-membered ring.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Studies with 14C-labeled LPP have shown that in A. annua LPP is converted to cyclised monoterpenes such as 1,8-cineole and α-pinene with greater efficiency than the alternative precursors NPP and GPP.

    “Studies with 14C-labeled LPP have shown that in A. annua this precursor is converted to cyclised monoterpenes such as 1,8-cineole (326) and α-pinene (347) with greater efficiency than the alternative precusors, NPP and GPP [109].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Banthorpe, 1983, Metabolism of linaloyl, neryl and geranyl pyrophosphates in Artemisia annua, Phytochemistry source

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  • Findingcitation

    Myrcene is the most abundant regular acyclic monoterpene from A. annua.

    “Myrcene (254) is the most abundant regular acyclic monoterpene from A. annua, and can account for up to 5% of the essential oil [22,33,43].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Liu, 1988, Preliminary analysis on chemical constituents of essential oil from inflorescence of of Artemisia annua L., Acta Botanica Sinica (Zhiwu Xuebao)

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    • cites [33] Libbey, 1989, Unusual essential oils grown on Oregon II, Artemisia annua L. J. Essent. Oil Res. source

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    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

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  • Findingcitation

    Artemisia ketone can account for up to 50% of the total essential oil in some varieties of A. annua.

    “which is the major constituent of the essential oil in some varieties of A. annua [29,37,42,73], and can account for up to 50% of the total [22,25,33,43,45,53].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [22] Liu, 1988, Preliminary analysis on chemical constituents of essential oil from inflorescence of of Artemisia annua L., Acta Botanica Sinica (Zhiwu Xuebao)

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    • cites [25] Chalchat, 1991, A contribution to chemotaxonomy of Artemisia annua L., Asteraceae, Acta Pharm. Jugosl.

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    • cites [33] Libbey, 1989, Unusual essential oils grown on Oregon II, Artemisia annua L. J. Essent. Oil Res. source

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    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

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    • cites [45] Jain, 2002, Essential oil composition of Artemisia annua L. "Asha" from the plains of Northern India, J. Essent. Oil Res. source

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    • cites [53] Charles, 1991, Characterization of the essential oil of Artemisia annua L., J. Essent. Oil Res. source

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  • Findingnone given

    The vast majority of monocyclic monoterpenes from A. annua are p-menthanes, incorporating a six-membered ring formed directly by cyclization of an LPP/NPP precursor.

    “The vast majority of monocyclic monoterpenes from A. annua, however, are p-menthanes (Table 25), incorporating a six-membered ring, which is formed directly by cyclization of an LPP/NPP precursor.”
    Quote in the paperNot a substantial claim
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    Findingnone given

    The simple aromatic compounds described in Tables 12, 13 and 14 form a relatively small group of natural products from A. annua.

    “The simple aromatic compounds described in Table 12, Table 13 and Table 14 form a relatively small group of natural products from A. annua.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Myrcene can account for up to 5% of the essential oil of A. annua.

    “Myrcene (254) is the most abundant regular acyclic monoterpene from A. annua, and can account for up to 5% of the essential oil [22,33,43].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Liu, 1988, Preliminary analysis on chemical constituents of essential oil from inflorescence of of Artemisia annua L., Acta Botanica Sinica (Zhiwu Xuebao)

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    • cites [33] Libbey, 1989, Unusual essential oils grown on Oregon II, Artemisia annua L. J. Essent. Oil Res. source

      Not checked in the free run.

    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

      Not checked in the free run.

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    Findingnone given

    Most of the simple phenylpropanoids reported in Table 15 were described from GC-MS studies.

    “Most of the simple phenylpropanoids reported in Table 15 were described from GC-MS studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    A biomimetic synthesis supported the derivation of 279 and 280 from lavandulol by spontaneous autoxidation: photooxygenation of racemic lavandulol yielded both hydroperoxide intermediates expected from reaction of singlet oxygen with the tri-substituted double bond in lavandulol.

    “This suggestion was supported by a biomimetic synthesis, in which photooxygenation of racemic lavandulol yielded both of the hydroperoxide intermediates expected from the reaction of singlet oxygen with the tri-substituted double bond in this precursor.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Sy, 2001, Deoxyarteannuin B, dihydro-deoxyarteannuin B and trans-5-hydroxy-2-isopropenyl-5-methylhex-3-en-1-ol from Artemisia annua, Phytochemistry source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Artemisia ketone is the major constituent of the essential oil in some varieties of A. annua.

    “which is the major constituent of the essential oil in some varieties of A. annua [29,37,42,73], and can account for up to 50% of the total [22,25,33,43,45,53].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [29] Genov, 1983, Gas-Chromatographic study of the essential oil of Artemisia annua L., Naunchi Trudove - Vissh Institut po Khranitelna i Vkusova Promishlenost, Plodiv

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    • cites [37] Holm, 1997, Variation in the essential oil composition of Artemisia annua L. of different origin cutivated in Finland, Flavour Frag. J. source

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    • cites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi

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    • cites [73] Georgiev, 1978, On the distillation of annual wormwood (Artemisia annua Linnaeus), Rivista Italiana Essenze, Profumi, Piante Officinali, Arromatizanti, Syndets, Saponi, Cosmaetici, Aerosols

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Nine of the structures reported in Table 36 and Table 38 occur in both their 11,13-dihydro and 11,13-dehydro forms, and these nine pairs are listed in Table 37.

    “It is interesting to note that nine of the structures reported in Table 36 and Table 38 occur in both their 11,13-dihydro and 11,13-dehydro forms. These nine pairs are listed in Table 37.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In the most recent experiments, artemisinic acid (473) failed to show detectable incorporation into artemisinin but showed significant conversion into arteannuin B (462) and six other highly oxygenated sesquiterpene natural products retaining the 11,13-double bond.

    “Although the most recent experiments with artemisinic acid (473) failed to observe any detectable incorporation into artemisinin, a very significant conversion was observed into arteannuin B (462), as well as six other highly oxygenated sesquiterpene natural products, all of which retained the 11,13- double bond, as shown in Scheme 7 in Section 2.6.3 [155]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Brown, 2007, In vivo transformations of artemisinic acid in Artemisia annua plants, Tetrahedron source

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    Findingcitation

    Stable isotope-labeled metabolites detected by NMR represented at least 1% (very often 5-30%) of the label supplied, providing a picture only of the most significant and direct transformations undergone by the precursor.

    “By contrast, the stable isotope-labeled metabolites which have been detected by NMR [155] represented at least 1% (very often between 5-30%) of the label that had been supplied and therefore provide a picture only of the most significant and direct transformations which have been undergone by the precursor.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Brown, 2007, In vivo transformations of artemisinic acid in Artemisia annua plants, Tetrahedron source

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  • May combine two claims.

    Findingcitation

    Artemisinin can be obtained in reasonable quantities from differentiated shoot cultures of A. annua, but is produced in only small or undetectable amounts by callus or suspension cell cultures.

    “Although artemisinin can be obtained in reasonable quantities from differentiated shoot cultures [343,344,345], it is produced in only small or undetectable amounts [346,347,348] by callus or suspension cell cultures of A. annua.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [343] Chen, 1993, Enhanced synthesis of the natural phytotoxin artemisinin in tissue culture, PGRSA Q.

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    • cites [344] Zhang, 2004, Related factors of artemisinin biosynthesis in clone strain of Artemisia annua L., Yingyong Yu Huanjung Shengwu Xuebao

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    • cites [345] Nair, 1986, Production of artemisinin in tissue cultures of Artemisia annua, J. Nat. Prod. source

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    • cites [346] Elhag, 1992, Selection and micropropagation of high artemisinin producing clones of Artemisia annua L., Phytother. Res. source

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    • cites [347] Li, 1999, Artificial regulation of artemisinin biosynthesis metabolite in cultured cells of Artemisia annua, Zhongguo Shengwu Huaxue Yu Fenzi Shengwu Xuebao

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    • cites [348] Xie, 2001, Isolation and production of artemisinin and stigmasterol in hairy root cultures of Artemisia annua, Plant Cell Tissue Org. Cult. source

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  • May combine two claims.

    Findingcitation

    In the most recent study of artemisinic acid metabolism, arteannuin B (462) was obtained as the major metabolite of artemisinic acid (473), without evidence for accompanying formation of artemisinin (495).

    “As noted above, in the most recent study of the metabolism of artemisinic acid, arteannuin B (462) was obtained as the major metabolite of artemisinic acid (473), without any evidence for the accompanying formation of artemisinin (495) [155].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Brown, 2007, In vivo transformations of artemisinic acid in Artemisia annua plants, Tetrahedron source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Several authors have reported that the artemisinin content is highest just before flowering.

    “Several authors have reported that the artemisinin content is highest just before flowering [326,327,328]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [326] Singh, 1988, Evaluation of Artemisia annua strains for higher artemisinin production, Planta Med. source

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    • cites [327] Wang, 2004, Studies on the effects of fpf1 gene on Artemisia annua flowering time and on the linkage between flowering and artemisinin biosynthesis, Planta Med. source

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    • cites [328] Ferreira, 1995, Developmental studies of Artemisia annua: Flowering and artemisinin production under greenhouse and field conditions, Planta Med. source

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  • May combine two claims.

    Findingcitation

    More recent experiments using stable isotope-labeled dihydro-epi-deoxyarteannuin B (485) fed to an intact plant system showed no detectable incorporation into artemisinin (495), although three novel hydroxylated metabolites were obtained in significant quantities.

    “However, once again, more recent experiments using dihydro-epi-deoxyarteannuin B (485) which had been labelled with a stable isotope [169] and fed to an intact plant system have shown no detectable incorporation into artemisinin (495); although three novel hydroxylated metabolites were obtained in significant quantities from this feeding experiment [190].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [169] Sy, 2001, Synthesis of dihydroartemisinic acid and dihydro-epi-deoxyarteannuin B incorporating a stable isotope label at the 15-position for studies into the biosynthesis of artemisinin, Tetrahedron source

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    • cites [190] Brown, 2007, In vivo transformations of dihydro-epi-deoxyarteannuin B in Artemisia annua plants, Tetrahedron source

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  • May combine two claims.

    Findingcitation

    The most successful strategy to date has been plant breeding, resulting in the cultivar Artemis, registered in Switzerland in 1999, which contains up to 1.4% artemisinin, whereas wild varieties typically range between 0.01-0.5% artemisinin.

    “The most successful strategy to date has been plant breeding, resulting in the cultivar “Artemis”, which was registered in Switzerland in 1999, and contains up to 1.4% artemisinin (by comparison, the extremely variable yields obtained from wild varieties of A. annua typically range between 0.01-0.5% artemisinin [321]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [321] Pereira, 1999, New hybrid lines of the antimalarial species Artemisia annua L., Acta Hortic.

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  • Classified as probably not a substantial claim. May combine two claims.

    Findingcitation

    Correlated variations in artemisinin, dihydroartemisinic acid, and artemisinic acid prove the existence of chemotypes of A. annua: high artemisinin plants also have high dihydroartemisinic acid but low artemisinic acid, while low artemisinin and low dihydroartemisinic acid chemotypes have high artemisinic acid.

    “One particularly interesting study has concluded that correlated variations in all three natural products prove the existence of chemotypes of A. annua. Thus, plants with a high artemisinin (495) level were found also to have a high dihydroartemisinic acid (480) level, but a relatively low concentration of artemisinic acid (473); while chemotypes with low levels of artemisinin (495) and dihydroart”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [338] Yang, 2008, Quantitative transcript profiling reveals down-regulation of a sterol pathway relevant gene and overexpression of artemisinin biogenetic genes in transgenic Artemisia annua plants, Planta Med. source

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    Findingcitation

    Several endophytes have now been described from A. annua.

    “Several endophytes have now been described from A. annua [357].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [357] Simanjuntak, 2004, Studies on endophytic microbes of Artemisia spp (3). Isolation and identification of artemisinin from product of endophyte microbe cultivation from Artemisia annua, Majalah Farmasi Indonesia

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    Findingcitation

    Understanding of how the spontaneous autoxidation of natural products such as 480 occurs in the absence of a photosensitizer or other additional chemical reagents, leading to highly oxidized products such as 495, is still incomplete.

    “It should be noted that our understanding of how the spontaneous autoxidation of natural products such as 480 occurs in the absence of a photosensitizer [388] (or, indeed, any other additional chemical reagents [218]), leading to highly oxidized products such as 495, is still incomplete.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [388]

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    • cites [218] Sy, 2002, The role of the 12-carboxylic acid group in the spontaneous autoxidation of dihydroartemisinc acid, Tetrahedron source

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    Findingcitation

    The approach outlined in Scheme 13 has succeeded in producing high levels of amorpha-4,11-diene from E. coli and artemisinic acid from S. cerevisiae in quantities exceeding those from A. annua itself (100 mg-1 g L-1).

    “The approach outlined in Scheme 13 has succeded in producing high levels of amorpha-4,11-diene (451) from E. coli [384] and artemisinic acid (473) from S. cerevisiae in quantities which exceed those from A. annua itself (100 mg–1·g·L-1) [385,386].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [384] Ro, 2006, Production of the antimalarial drug precursor artemisinic acid in engineered yeast, Nature source

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    • cites [385] Ro, D.-K., Ouellet, M., Paradise, E.M., Burd, H., Eng, D., Paddon, C.J., Newman, J.D., and Keasling, J.D. (2008). Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid. BMC Biotechnol. source

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    • cites [386] Dietrich, 2009, A novel semi-biosynthetic route for artemisinin production using engineered substrate-promiscuous P450BM3, ACS Chem. Biol. source

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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The 1,2,4-trioxane ring structure of artemisinin is responsible for its antimalarial activity.

    “Artemisinin is a highly oxygenated sesquiterpene, containing a unique 1,2,4-trioxane ring structure, which is responsible for the antimalarial activity of this natural product.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Compounds 166-182 are esters formed by various combinations of ferulic and cinnamic acid with the four hydroxyl groups of quinic acid and were isolated from a single HPLC-MS study.

    “Compounds 166-182 (Table 16), which are esters formed by various combinations of ferulic and cinnamic acid with the four hydroxyl groups of quinic acid, were isolated from a single HPLC-MS study [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Han, 2008, Characterization of phenolic compounds in the Chinese herbal drug Artemisia annua by liquid chromatography coupled to electrospray ionization mass spectrometry, J. Pharm. Biomed. Anal. source

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    Premisenone given

    The regular acyclic monoterpenes described in Section 2.5.1 consist of an eight-carbon chain, often functionalized at the 1-position, with methyl substituents at the 3- and 7-positions.

    “The regular acyclic monoterpenes which are described in Section 2.5.1 consist of an eight-carbon chain, which is often functionalized at the 1-position, with methyl substituents at the 3- and 7-positions (Table 23).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The essential oil of the Chinese variety of A. annua contained predominantly artemisia ketone, while the Vietnamese oil was dominated by camphor and germacrene D.

    “A detailed study of the essential oils from Chinese and Vietnamese varieties of A. annua demonstrated that the Chinese variety contained predominantly artemisia ketone, while the Vietnamese oil was dominated by camphor and germacrene D [21]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Woerdenbag, 1993, Volatile constituents of Artemisia annua L. (Asteraceae), Flavour Frag. J. source

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    Interpretationreasoning

    The structures of both of the 2,2-dihydroxychromene natural products 190 and 191 are questionable on thermodynamic grounds, because one might expect both to lose a molecule of water thereby forming a more highly conjugated coumarin.

    “The structures of both of the 2,2-dihydroxychromene natural products 190 and 191, which appear in Table 17, are questionable on thermodynamic grounds - one might expect both to lose a molecule of water thereby forming a more highly conjugated coumarin.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The flavonoids are produced from the cyclization of a C15 chalcone precursor, which is in turn derived from malonyl coenzyme A and p-coumaryl coenzyme A.

    “The flavonoids are produced from the cyclization of a C15 chalcone precursor, which is in turn derived from malonyl coenzyme A and p-coumaryl coenzyme A (see Section 2.3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    A. annua is distinguished from other Asteraceae by the very large number of natural products characterised to date, almost six hundred in total, including around fifty amorphane and cadinane sesquiterpenes.

    “However, A. annua is distinguished from the other members of the family both by the very large number of natural products which have been characterised to date (almost six hundred in total, including around fifty amorphane and cadinane sesquiterpenes), and by the highly oxygenated nature of many of the terpenoidal secondary metabolites.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Differences in the essential oil composition between varieties of A. annua should be ascribed to the existence of chemotypes (or chemical races) in this species.

    “Others have reported a similar variation in essential oil content between varieties of A. annua [53,54] and have concurred that differences in the essential oil composition should be ascribed to the existence of chemotypes (or chemical races) in this species [43]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

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  • May combine two claims.

    Premisenone given

    The artemisinin content of Chinese and Vietnamese plants was 0.17% and 1.0% dry weight, respectively.

    “Interestingly, this difference was also reflected in the artemisinin content of Chinese and Vietnamese plants at 0.17% and 1.0% dry weight, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Monoterpenoids generally contain ten carbons (C10) and are the principal components of the essential oil of A. annua obtained by steam distillation or other techniques selective for more volatile natural products.

    “Monoterpenoids generally contain ten carbons (C10) and are the principal components of the essential oil of A. annua obtained by steam distillation (or other techniques that are selective for more volatile natural products).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The only two polyacetylenes reported to date from A. annua are ponticaepoxide (121) and annuadiepoxide (122).

    “The only two such compounds to be reported to date are ponticaepoxide (121) and annuadiepoxide (122)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Artemisinin is a highly oxygenated sesquiterpene containing a unique 1,2,4-trioxane ring structure.

    “Artemisinin is a highly oxygenated sesquiterpene, containing a unique 1,2,4-trioxane ring structure, which is responsible for the antimalarial activity of this natural product.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Allylic hydroperoxides are found for monoterpenes (264 and 265), sesquiterpenes (414 and 481) and diterpenes (553), all of which might be derived from abundant hydrocarbon precursors.

    “Thus, allylic hydroperoxides are found for monoterpenes (264 and 265; Section 2.5.1), sesquiterpenes (414 and 481; Section 2.6.3) and diterpenes (553; Section 2.7.1), all of which might be derived from abundant hydrocarbon precursors”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Some of the coumarins reported in Table 17 have also been obtained from undifferentiated tissue cultures (callus and suspension) of A. annua.

    “Some of the coumarins reported in Table 17 have also been obtained from undifferentiated tissue cultures (callus and suspension) of A. annua (see Section 4.2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The artemisinin content from A. annua is highly variable, ranging between 0.01% and 1% depending on variety, and can be as high as 1.4% in some cultivated strains.

    “The artemisinin content from A. annua is highly variable, ranging anywhere between 0.01% and 1%, depending on variety, and can even be as high as 1.4% in some cultivated strains.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    A. annua L. is a rich source of flavonoids, as are many other members of the Asteraceae family.

    “A. annua L. is a rich source of flavonoids, as are many other members of the Asteraceae family.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    A. annua contains one monoterpene endoperoxide (329) and three sesquiterpene endoperoxides (465, 495 and 497).

    “in addition to one monoterpene endoperoxide (329; Section 2.5.3) and three sesquiterpene endoperoxides (465, 495 and 497; Section 2.6.3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    A. annua is also a rich source of irregular acyclic monoterpenoids, which are derived from the head-to-middle condensation of two C5 precursors.

    “A. annua is also a rich source of irregular acyclic monoterpenoids (Section 2.5.2), which are derived from the “head-to-middle” condensation of two C5 precursors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    A. annua contains relatively few polyacetylenes by comparison with other members of the genus Artemisia and other members of the Asteraceae family.

    “Artemisia annua contains relatively few polyacetylenes by comparison with other members of the genus Artemisia (and also as compared to other members of the Asteraceae family).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Artemisinin (Qinghaosu) is used in the treatment of malaria.

    “The Chinese medicinal plant Artemisia annua L. (Qinghao) is the only known source of the sesquiterpene artemisinin (Qinghaosu), which is used in the treatment of malaria.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Regular acyclic monoterpenes are formed by ionization of the pyrophosphate group in one of the C10 precursors: geranyl pyrophosphate (GPP), neryl pyrophosphate (NPP) or linalyl pyrophosphate (LPP).

    “They are formed by ionization of the pyrophosphate group in one of the C10 precursors: geranyl pyrophosphate (GPP), neryl pyrophosphate (NPP) or linalyl pyrophosphate (LPP) (Figure 2)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Phytochemical studies have sometimes sought to determine the distribution of bioactive flavonoids such as chrysoplenetin, casticin, eupatin and artemetin in conjunction with that of artemisinin.

    “Perhaps for this reason, phytochemical studies have sometimes sought to determine the distribution of bioactive flavonoids (such as chrysoplenetin (226), casticin (227), eupatin (232) and artemetin (228)) in conjunction with that of artemisinin [93].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Baraldi, 2008, Distribution of artemisinin and bioactive flavonoids from Artemisia annua L. during plant growth, Biochemical Syst. Ecol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Metabolites in the simple aromatic section are probably biosynthesised by both the polyketide and shikimate pathways.

    “Metabolites in this section are probably biosynthesised by both the polyketide and shikimate pathways (some simple aromatics which are derived from the terpenoid pathway are discussed separately in Section 2.5.3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The phytochemistry of A. annua is dominated by sesquiterpenoids and flavonoids.

    “The phytochemistry of A. annua is dominated by both sesquiterpenoids and flavonoids, as is the case for many other plants in the Asteraceae family.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ponticaepoxide (121) and annuadiepoxide (122) have been isolated from both leaves and seeds of A. annua.

    “which have been isolated from both leaves [67] and seeds [9] of A. annua.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Manns, 1992, Annuadiepoxide, a new polyacetylene from the aerial parts of Artemisia annua, J. Nat. Prod. source

      Not checked in the free run.

    • cites [9] Brown, 2003, Terpenoids from the seeds of Artemisia annua, Phytochemistry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The polycyclic aromatic natural product acenaphthylene, 1,2,4,5-tetrahydro- (241) is reported from A. annua.

    “The miscellaneous polycyclic aromatic natural product acenaphthylene, 1,2,4,5-tetrahydro- ([54271-92-0]) (241) is also reported from A. annua [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Ali, 2000, Volatile oil constituents of Artemisia annua leaves, J. Med. Aromat. Plant Sci.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    1,8-Cineole accounts for as much as 10-30% of the essential oil of A. annua.

    “accounting for as much as 10-30% of the essential oil [25,28,33,34,41,53]”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [25] Chalchat, 1991, A contribution to chemotaxonomy of Artemisia annua L., Asteraceae, Acta Pharm. Jugosl.

      Not checked in the free run.

    • cites [28] Mukhtar, 2007, GC-MS analysis of volatile oil of aerial parts of Artemisia annua L., J. Essent. Oil-Bearing Plants source

      Not checked in the free run.

    • cites [33] Libbey, 1989, Unusual essential oils grown on Oregon II, Artemisia annua L. J. Essent. Oil Res. source

      Not checked in the free run.

    • cites [34] Ali, 2000, Volatile oil constituents of Artemisia annua leaves, J. Med. Aromat. Plant Sci.

      Not checked in the free run.

    • cites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi

      Not checked in the free run.

    • cites [53] Charles, 1991, Characterization of the essential oil of Artemisia annua L., J. Essent. Oil Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    α-Campholenal (284) and cyclopentene, 4-ethenyl-1,5,5-trimethyl- (285) are reported from A. annua.

    “Two unusual cyclopentane monoterpeneoids, α-campholenal ([4501-58-0]) (284) [19] and cyclopentene, 4-ethenyl-1,5,5-trimethyl- ([1727-69-1]) (285) [23] are reported from A. annua.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Billa, 2008, GC-MS analysis of the volatile constituents of essential oil and aromatic waters of Artemisia annua L. at different developmental stages, Nat. Prod. Comm.

      Not checked in the free run.

    • cites [23] Tian, 2007, Study on volatile constituents of herba Artemisia annua and its preparation by GC-MS, Shizen Guoyi Guoyao

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Two other classes of irregular cyclic monoterpenoids, the lavandulanes 279-281 and the santolinanes 282 and 283, are known from A. annua.

    “Two other classes of irregular cyclic monoterpenoids, the lavandulanes 279)–281 and the santolinanes 282 and 283, are also known from A. annua.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A. annua is a rich source of unusual irregular acyclic monoterpenoids, such as artemisia ketone.

    “Phytochemists were interested in A. annua before the discovery of artemisinin because it is a rich source of unusual irregular acyclic monoterpenoids, such as artemisia ketone (276) [115,116,117,118,119,120]”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [115] Asahina, Y., and Takagi, S. (1920). Report on the essential oil of Artemisia annua L. II. Constitution of artemisia ketone. Yakugaku Zasshi, 837–864.

      Not checked in the free run.

    • cites [116] Ruzicka, 1936, Synthesis of tetrahydroartemisia ketone, Helv. Chim. Acta source

      Not checked in the free run.

    • cites [117] Takemoto, 1957, Essential oil of Artemisia annua. I. Isolation of a new ester compound, Yakugaku Zasshi source

      Not checked in the free run.

    • cites [118] Takemoto, 1957, Essential oil of Artemisia annua. II. Structure of 1-β-artemisia alcohol, Yakugaku Zasshi source

      Not checked in the free run.

    • cites [119] Takemoto, 1957, Essential oil of Artemisia annua. III. Structure of artemisia ketone, Yakugaku Zasshi source

      Not checked in the free run.

    • cites [120] Takemoto, 1957, Essential oil of Artemisia annua. IV. Dihydroartemisia ketone, Yakugaku Zasshi source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    α- and β-myrcene hydroperoxide are possibly formed by an ene-type reaction of molecular oxygen with the tri-substituted double bond in myrcene, occurring in the presence of light and a photosensitizer such as singlet oxygen.

    “and are possibly formed by an “ene”-type reaction of molecular oxygen with the tri-substituted double bond in myrcene (254), occurring in the presence of light and a photosensitizer (i.e. singlet oxygen, 1O2), as is shown in Scheme 1.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The lavandulane tertiary allylic alcohol 279 and its secondary allylic alcohol analogue 280 are proposed to be derived from lavandulol by spontaneous autoxidation reactions yielding allylic hydroperoxide intermediates.

    “Both the lavandulane tertiary allylic alcohol 279 and its secondary allylic alcohol analogue 280 have been proposed to be derived from the precursor, lavandulol, by spontaneous autoxidation reactions which yield allylic hydroperoxide intermediates as shown in Scheme 3 [129].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Sy, 2001, Deoxyarteannuin B, dihydro-deoxyarteannuin B and trans-5-hydroxy-2-isopropenyl-5-methylhex-3-en-1-ol from Artemisia annua, Phytochemistry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Artemisia ketone is formed by a non-standard head-to-middle condensation of DMAPP, which is thought to proceed via chrysanthemyl pyrophosphate, an intermediate containing a three-membered ring.

    “Artemisia ketone (276) is formed by a non-standard “head-to-middle” condensation of DMAPP [104,122,123,124,125,126], which is thought to proceed as shown in Scheme 2 via chrysanthemyl pyrophosphate, an intermediate containing a three-membered ring.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [104] Olsson, 2009, Localization of enzymes of artemisinin biosynthesis to the apical cells of glandular secretory trichomes of Artemisia annua L., Phytochemistry source

      Not checked in the free run.

    • cites [122] Suga, 1972, Biosynthesis of a non-head-to-tail monoterpene, artemisia ketone, Chem. Lett. source

      Not checked in the free run.

    • cites [123] Simpson, J.B. (1979). On the Biosynthesis of Artemisia Ketone in Artemisia annua, Louisiana State Univ.

      Not checked in the free run.

    • cites [124] Banthorpe, 1977, Terpene biosynthesis. Part 20. Role of geraniol and nerol in the biosynthesis of artemisia ketone, Phytochemistry source

      Not checked in the free run.

    • cites [125] Risinger, 1978, On the biosynthesis of artemisia ketone and bakuchiol, Experientia source

      Not checked in the free run.

    • cites [126] Allen, 1977, Terpene biosynthesis. Part 17. Biosynthesis of irregular monoterpenes in extracts from higher plants, Phytochemistry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationcitation

    p-Cymene and α-terpineol could be derived from opening of the ether linkage in 1,8-cineole.

    “which could be derived from opening of the ether linkage in 1,8-cineole (326).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    1,8-Cineole is sometimes accompanied by significant quantities of p-cymene and α-terpineol.

    “1,8-Cineole is sometimes accompanied by significant quantities of p-cymene (295) [28,34] and α-terpineol (322) [28]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Mukhtar, 2007, GC-MS analysis of volatile oil of aerial parts of Artemisia annua L., J. Essent. Oil-Bearing Plants source

      Not checked in the free run.

    • cites [34] Ali, 2000, Volatile oil constituents of Artemisia annua leaves, J. Med. Aromat. Plant Sci.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Only two o-menthanes and one m-menthane are reported from A. annua.

    “Only two o-menthanes: o-cymene (1-isopropyl-2-methylbenzene [527-84-4] [25155-15-1]) (331) [41] and o-mentha-1(7),8-dien-3-ol ([15358-81-3]) (332) [23]; and one m-menthane: m-cymene (β-cymene; 1-methyl-3-(1-methylethyl)benzene [535-77-3]) (333) [31] are reported from A. annua.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi

      Not checked in the free run.

    • cites [23] Tian, 2007, Study on volatile constituents of herba Artemisia annua and its preparation by GC-MS, Shizen Guoyi Guoyao

      Not checked in the free run.

    • cites [31] Ma, 2007, Analysis of Artemisia annua L. volatile oil by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry, J. Chromatogr. A. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    α-Pinene sometimes co-occurs with significant amounts of either β-pinene or pinocarvone.

    “and sometimes co-occurrs with significant amounts of either β-pinene (356) [101] or pinocarvone (360) [42].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [101] Bhardwaj, 1985, Constituents of Artemisia annua, Proc. Indian Nat. Sci. Acad.

      Not checked in the free run.

    • cites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Borneol and bornyl acetate are sometimes reported together with camphor as significant constituents of the essential oil.

    “Borneol (334) [46,73] and bornyl acetate (335) [29] are sometimes reported together with camphor (351) as significant constituents of the essential oil.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Yang, 2008, Investigation of essential oil from leaves of Artemisia annua L. in Guizhou, Shizen Guoyi Guoyao

      Not checked in the free run.

    • cites [73] Georgiev, 1978, On the distillation of annual wormwood (Artemisia annua Linnaeus), Rivista Italiana Essenze, Profumi, Piante Officinali, Arromatizanti, Syndets, Saponi, Cosmaetici, Aerosols

      Not checked in the free run.

    • cites [29] Genov, 1983, Gas-Chromatographic study of the essential oil of Artemisia annua L., Naunchi Trudove - Vissh Institut po Khranitelna i Vkusova Promishlenost, Plodiv

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Sabinene hydrate and sabinol are two of the most abundant thujanes, both can be present at around 7% of the total essential oil.

    “Two of the most abundant thujanes are sabinene hydrate (373) [34] and sabinol (371) [43], both of which can be present at around levels of 7% of the total essential oil.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Ali, 2000, Volatile oil constituents of Artemisia annua leaves, J. Med. Aromat. Plant Sci.

      Not checked in the free run.

    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The majority of monoterpenes which incorporate an additional three-membered ring belong to the thujane class.

    “the majority of monoterpenes which incorporate an additional three-membered ring belong to the thujane class (Table 28).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Camphene has been obtained as both its (+)- and (-)-enantiomeric forms from A. annua.

    “Camphene (343) has been obtained as both its (+)- and (-)-enantiomeric forms [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Holm, 1997, Variation in the essential oil composition of Artemisia annua L. of different origin cutivated in Finland, Flavour Frag. J. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The acyclic farnesanes are produced by ionization of the pyrophosphate group in FPP followed by quenching with water or loss of a proton.

    “This acyclic group of natural products is produced by ionization of the pyrophosphate group in the 15-carbon precursor, FPP (378), followed either by quenching with water or loss of a proton”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tricyclene is the only tricyclic monoterpenoid known from A. annua.

    “Tricyclene ([508-32-7] [160339-05-9]) (375) [25,32,41,43,45] is the only tricyclic monoterpenoid known from A. annua.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [25] Chalchat, 1991, A contribution to chemotaxonomy of Artemisia annua L., Asteraceae, Acta Pharm. Jugosl.

      Not checked in the free run.

    • cites [32] Goel, 2007, Essential oils of petal, leaf and stem of the antimalarial plant Artemisia annua, J. Nat. Med. source

      Not checked in the free run.

    • cites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi

      Not checked in the free run.

    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

      Not checked in the free run.

    • cites [45] Jain, 2002, Essential oil composition of Artemisia annua L. "Asha" from the plains of Northern India, J. Essent. Oil Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    α-Pinene is the most abundant pinane monoterpene from A. annua, up to 10%.

    “α-Pinene (347) [40,42,43] is the most abundant pinane monoterpene from A. annua (up to 10%) [33]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [40] Dembitskii, A.D., Krotova, G.I., Kuchukhidze, N.M., and Yakobashvili, N.Z. (1983). Essential Oil of Artemisia annua L.. Maslozhirovaya Promyshlennost, 31–34.

      Not checked in the free run.

    • cites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi

      Not checked in the free run.

    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

      Not checked in the free run.

    • cites [33] Libbey, 1989, Unusual essential oils grown on Oregon II, Artemisia annua L. J. Essent. Oil Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Camphor can account for up to 10-30% of the essential oil of A. annua.

    “which can account for up to 10-30% of the essential oil [19,22,41,42]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [19] Billa, 2008, GC-MS analysis of the volatile constituents of essential oil and aromatic waters of Artemisia annua L. at different developmental stages, Nat. Prod. Comm.

      Not checked in the free run.

    • cites [22] Liu, 1988, Preliminary analysis on chemical constituents of essential oil from inflorescence of of Artemisia annua L., Acta Botanica Sinica (Zhiwu Xuebao)

      Not checked in the free run.

    • cites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi

      Not checked in the free run.

    • cites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Only two caranes are known from A. annua.

    “Only two caranes (3,7,7-trimethylbicyclo[4.1.0]heptane, 9CI): α-carene ([13466-78-9]) (364) [32,41] and 2-acetyl-3-carene ([40824-36-0]) (365) [23] are known from A. annua”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [32] Goel, 2007, Essential oils of petal, leaf and stem of the antimalarial plant Artemisia annua, J. Nat. Med. source

      Not checked in the free run.

    • cites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi

      Not checked in the free run.

    • cites [23] Tian, 2007, Study on volatile constituents of herba Artemisia annua and its preparation by GC-MS, Shizen Guoyi Guoyao

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    α-Pinene is known in both its (+)- and (-)-enantiomeric forms from A. annua.

    “α-Pinene (347) is known in both its (+)- and (-)-enantiomeric forms from this species [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Holm, 1997, Variation in the essential oil composition of Artemisia annua L. of different origin cutivated in Finland, Flavour Frag. J. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    FPP is the product of a "head-to-tail" condensation of three C5 units (IPP and DMAPP).

    “which is the product of a “head-to-tail” condensation of three C5 units (IPP and DMAPP; see Figure 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    FPP can undergo further cyclization to mono-, bi-, or tricyclic sesquiterpenes according to enzymatically-catalysed mechanisms analogous to cyclized monoterpenoid biosynthesis.

    “Alternatively, FPP can undergo further cyclization to mono-cyclic sesquiterpenes (Section 2.6.2), bicyclic sesquiterpenes (Section 2.6.3) or tricyclic sesquiterpenes (Section 2.6.4), according to enzymatically-catalysed mechanisms which bear close analogies with the biosynthesis of the cyclized monoterpenoids”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Further cyclization of the carbocation which produces the p-menthane skeleton results in bicyclic monoterpenes.

    “Further cyclization of the carbocation which produces the p-menthane skeleton results in bicyclic monoterpenes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    β-Farnesene constitutes up to 10% of the essential oil of A. annua.

    “constituting up to 10% of the essential oil [19,27]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Billa, 2008, GC-MS analysis of the volatile constituents of essential oil and aromatic waters of Artemisia annua L. at different developmental stages, Nat. Prod. Comm.

      Not checked in the free run.

    • cites [27] Goel, 2007, Composition of the essential oil from the root of Artemisia annua, J. Nat. Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    These unusual o- and m-menthane skeletons presumably arise by migration of a methyl group in the corresponding p-menthane precursor.

    “These unusual skeletons presumably arise by migration of a methyl group in the corresponding p-menthane precursor”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A β-pinene synthase, which converts GPP to both (-)-α-pinene and (-)-β-pinene, has recently been described from A. annua.

    “A β-pinene synthase, which converts GPP to both (-)-α-pinene (347) and (-)-β-pinene (356), has recently been described from A. annua [131].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Lu, 2002, Cloning and functional characterization of a β-pinene synthase from Artemisia annua that shows a circadian pattern of expression, Plant Physiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Sesquiterpenoids constitute the most abundant and most diverse group of natural products from A. annua.

    “Sesquiterpenoids (C15) constitute the most abundant and most diverse group of natural products from A. annua.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    β-Farnesene is the most abundant member of the farnesane class of sesquiterpenes from A. annua.

    “β-Farnesene (382) is the most abundant member of this class of sesquiterpenes [22,43]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Liu, 1988, Preliminary analysis on chemical constituents of essential oil from inflorescence of of Artemisia annua L., Acta Botanica Sinica (Zhiwu Xuebao)

      Not checked in the free run.

    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Reduction of the hydroperoxide in 414 would result in the allylic alcohol group observed in 5α-hydroxy-eudesma-4(15),11-diene (413).

    “It has been suggested that reduction of the hydroperoxide in 414 would then result in the allylic alcohol group observed in the natural product 5α-hydroxy-eudesma-4(15),11-diene (413), as shown in Scheme 4 [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Brown, 2003, Terpenoids from the seeds of Artemisia annua, Phytochemistry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Compound (395) is the only example of a bicyclogermacrane sesquiterpene so far described from A. annua.

    “Compound (395) ([24703-35-3]) is the only example of a bicyclogermacrane sesquiterpene so far described from A. annua [19,32,43,45,74].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [19] Billa, 2008, GC-MS analysis of the volatile constituents of essential oil and aromatic waters of Artemisia annua L. at different developmental stages, Nat. Prod. Comm.

      Not checked in the free run.

    • cites [32] Goel, 2007, Essential oils of petal, leaf and stem of the antimalarial plant Artemisia annua, J. Nat. Med. source

      Not checked in the free run.

    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

      Not checked in the free run.

    • cites [45] Jain, 2002, Essential oil composition of Artemisia annua L. "Asha" from the plains of Northern India, J. Essent. Oil Res. source

      Not checked in the free run.

    • cites [74] Perazzo, 2003, Central properties of the essential oil and the crude ethanol extract from aerial parts of Artemisia annua L., Pharmacol. Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Germacrene D can constitute between 5-20% of the essential oil of A. annua.

    “and can constitute between 5-20% of the essential oil [19,42,43]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Billa, 2008, GC-MS analysis of the volatile constituents of essential oil and aromatic waters of Artemisia annua L. at different developmental stages, Nat. Prod. Comm.

      Not checked in the free run.

    • cites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi

      Not checked in the free run.

    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Amorpha-4,11-diene synthase produces small amounts of γ-humulene as well as the expected bicyclic product.

    “The enzyme amorpha-4,11-diene synthase from A. annua has been observed to produce small amounts of γ-humulene (isomeric with α-humulene (401) in Table 33 – see also Figure 3, Section 3.1), as well as the expected bicyclic product [134].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Picaud, 2005, Expression, purification and characterization of recombinant amorpha-4,11-diene synthase from Artemisia annua L., Arch. Biochem. Biophys. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    β-Caryophyllene is the most abundant member of the humulane/caryophyllane group of sesquiterpenes from A. annua.

    “β-Caryophyllene (405) is the most abundant member of this group of sesquiterpenes [26,37,40,43,46]”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [26] Zhong, 1983, Studies of volatile constituents from Artemisia annua, Zhongyao Tongbao

      Not checked in the free run.

    • cites [37] Holm, 1997, Variation in the essential oil composition of Artemisia annua L. of different origin cutivated in Finland, Flavour Frag. J. source

      Not checked in the free run.

    • cites [40] Dembitskii, A.D., Krotova, G.I., Kuchukhidze, N.M., and Yakobashvili, N.Z. (1983). Essential Oil of Artemisia annua L.. Maslozhirovaya Promyshlennost, 31–34.

      Not checked in the free run.

    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

      Not checked in the free run.

    • cites [46] Yang, 2008, Investigation of essential oil from leaves of Artemisia annua L. in Guizhou, Shizen Guoyi Guoyao

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Alternative cyclizations of FPP can lead to ten-membered germacrane and eleven-membered humulane sesquiterpenes.

    “Alternative cyclizations of FPP can lead to the ten-membered germacrane sesquiterpenes, which are described in Table 31, and the eleven-membered humulane sesquiterpenes in Table 33.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    β-Caryophyllene might play a role in plant defense.

    “This was interpreted as evidence that β-caryophyllene (405) might play a role in plant defense [139].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Cai, 2002, A cDNA clone for β-caryophyllene synthase from Artermisia annua, Phytochemistry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    α-Bisabolol has been found as a minor product from the enzyme amorpha-4,11-diene synthase from A. annua.

    “The bisabolane sesquiterpene, α-bisabolol (385), has been found as a minor product from the enzyme amorpha-4,11-diene synthase from A. annua (Section 2.6.3) [136].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Picaud, 2006, Amorpha-4,11-diene synthase: mechanism and stereochemistry of the enzymatic cycization of farnesyl diphosphate, Arch. Biochem. Biophys. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    β-Caryophyllene can be found at levels of up to 5-10% of the total essential oil of A. annua.

    “and can be found at levels of up to 5-10% of the total essential oil [19,22,42]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Billa, 2008, GC-MS analysis of the volatile constituents of essential oil and aromatic waters of Artemisia annua L. at different developmental stages, Nat. Prod. Comm.

      Not checked in the free run.

    • cites [22] Liu, 1988, Preliminary analysis on chemical constituents of essential oil from inflorescence of of Artemisia annua L., Acta Botanica Sinica (Zhiwu Xuebao)

      Not checked in the free run.

    • cites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The six-membered ring in elemane sesquiterpenes is thought to be formed by Cope rearrangement of 1(10),4-germacradienes.

    “The six-membered ring in the elemane sesquiterpenes (Table 32) is thought to be formed by Cope rearrangement of such 1(10),4-germacradienes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    trans-Nerolidol and (E)-1,3(15),6,10-farnesatetraene are reported as natural products from A. annua.

    “both of which are reported as natural products from A. annua [134] (Table 29).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Picaud, 2005, Expression, purification and characterization of recombinant amorpha-4,11-diene synthase from Artemisia annua L., Arch. Biochem. Biophys. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    α- and β-Bisabolene constitute up to 5% of the essential oil of A. annua.

    “constituting up to 5% of the essential oil [28,46]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Mukhtar, 2007, GC-MS analysis of volatile oil of aerial parts of Artemisia annua L., J. Essent. Oil-Bearing Plants source

      Not checked in the free run.

    • cites [46] Yang, 2008, Investigation of essential oil from leaves of Artemisia annua L. in Guizhou, Shizen Guoyi Guoyao

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The eremophilane skeleton is thought to be derived from the eudesmane skeleton by migration of the C-10 methyl group to C-5.

    “The eremophilane skeleton (decahydro-1,8a-dimethyl-7-(1-methylethyl)naphthalene, 9CI) is thought to be derived from the eudesmane skeleton by migration of the C-10 methyl group to C-5 [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Buckingham, 2004, Introduction to the Type of Compound Index, Dictionary of Natural Products

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The bicyclic eudesmane sesquiterpenes are thought to be derived from further cyclization of monocyclic germacranes.

    “The bicyclic eudesmane sesquiterpenes (Table 34) are thought to be derived from further cyclization of the monocyclic germacranes (Table 31, Section 2.6.2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Bicyclic caryophyllanes are formed by further cyclization of a humulane precursor.

    “The bicyclic caryophyllanes, which are formed by a further cyclization of a humulane precursor, have also been included in Table 33.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    All seven metabolites from the artemisinic acid (473) feeding experiment are also known as natural products from A. annua, and six of the seven feature in the pairs of metabolites in Table 37.

    “However, all seven metabolites from this experiment are also known as natural products from A. annua and six of the seven feature in the pairs of metabolites discussed in Table 37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Brown, 2007, In vivo transformations of artemisinic acid in Artemisia annua plants, Tetrahedron source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Artemisinin (495) is believed to be localized primarily within the glandular trichomes of A. annua, which are loosely attached to the leaf surface.

    “Artemisinin (495) is believed to be localized primarily within the glandular trichomes of A. annua, which are loosely attached to the leaf surface [244].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [244] Duke, 1994, Localization of artemisinin and artemisitene in foliar tissues of glanded and glandless biotypes of Artemisia annua L., Int. J. Plant Sci. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Artemisinic acid, arteannuin B, and artemisinin were amongst the first sesquiterpenes to be reported from A. annua.

    “and were amongst the first sesquiterpenes to be reported from A. annua.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [105] Zheng, 1994, Cytotoxic terpenoids and flavonoids from Artemisia annua, Planta Med. source

      Not checked in the free run.

    • cites [147] Tu, 1982, Studies on the constituents of Artemisia annua: 2, Planta Med. source

      Not checked in the free run.

    • cites [148] Misra, 1993, Crystal structure of artemisinic acid: A possible biogenetic precursor of antimalarial artemisinin from Artemisia annua, J. Nat. Prod. source

      Not checked in the free run.

    • cites [149] Jeremic, D., Jokic, A., Behbud, A., and Stefanovic, M. (1973). New type of sesquiterpene lactone isolated from Artemisia annua. Arteannuin B. Tetrahedron Lett., 3039–42. source

      Not checked in the free run.

    • cites [150] Liu, 1979, Structure and reaction of arteannuin, Huaxue Xuebao

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Artemisitene (497) is present in A. annua at much lower levels than artemisinin, typically around 0.01% compared with 1%.

    “Artemisitene (497), the 11,13-dehydro analogue of artemisinin, is present in A. annua at much lower levels than artemisinin (typically concentrations in the order of 0.01%, as compared with 1%) [240]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [240] Woerdenbag, 1994, Artemisinin related sesquiterpenes, and essential oil in Artemisia annua during a vegetation period in Vietnam, Planta Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    No representative of the bulgarane sesquiterpenes is known from A. annua.

    “(No representative of the bulgarane sesquiterpenes (1α,6β,7α), the fourth possible skeleton allowed by this classification scheme, is known from A. annua).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Artemisitene can be obtained readily by chemical transformations of artemisinin, and a partial synthesis of artemisitene from artemisinic acid (473) has been reported.

    “although artemisitene can be obtained readily by chemical transformations of artemisinin [165,213,241,242]; and a partial synthesis of artemisitene from artemisinic acid (473) has also been reported [243].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [165] Sy, L.-K., and Brown, G.D. (2002). Synthesis of 6,7-dehydroartemisinic acid. J. Chem. Soc. Perkin Trans. 1, 2421–2429. source

      Not checked in the free run.

    • cites [213] Ayalp, 1990, Conversion of artemisinin to artemisitene, J. Nat. Prod. source

      Not checked in the free run.

    • cites [241] Ekthawatchai, 2003, An environmentally friendly, low cost, one-pot synthesis of artemisitene, Synth. Commun. source

      Not checked in the free run.

    • cites [242] Zhang, 1988, Structure and synthesis of arteannuin and related compounds. XXIV. Conversion of arteannuin into artemisitene, Youji Huaxue

      Not checked in the free run.

    • cites [243] Haynes, R.K., and Vonwiller, S.C. (1990). Catalyzed oxygenation of allylic hydroperoxides derived from qinghao (artemisinic) acid. Conversion of qinghao acid into dehydroqinghaosu (artemisitene) and qinghaosu (artemisinin). J. Chem. Soc., Chem. Commun., 451–453. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Artemisinin (495) is a seco-cadinane sesquiterpene.

    “Artemisinin (495) is a seco-cadinane sesquiterpene, which was first isolated from A. annua in 1972.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The unusual endoperoxide group in artemisinin has been confirmed by a variety of means, and the absolute stereochemistry of artemisinin has been established by X-ray crystallography.

    “The unusual endoperoxide group in artemisinin has been confirmed by a variety of means [219,220,221,222,223,224,225,226] and the absolute stereochemistry of artemisinin has been established by X-ray crystallography [227].”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [219] Anonymous (1977). Co-ordinating group of research on the structure of Qing Hao Su. A new type of lactone - Qing Hau Sau. K’O Hsueh Tung Pao, 22, 142. (CA 1977, 87, 98788).

      Not checked in the free run.

    • cites [220] Blasko, 1988, Definitive 1H and 13C NMR assignments of artemisinin (qinghaosu), J. Nat. Prod. source

      Not checked in the free run.

    • cites [221] Huang, 1988, Two-dimensional NMR studies of arteannuin, Huaxue Xuebao

      Not checked in the free run.

    • cites [222] Leban, 1988, Crystal and molecular structure of Qinghaosu: A redetermination, Acta Pharmaceutica Jugoslavica

      Not checked in the free run.

    • cites [223] Madhusudanan, 1989, Mass spectral studies on artemisinin, dihydroartemisinin and artether, Indian J. Chem. Sect. B, Organic Chemistry including Medicinal Chemistry

      Not checked in the free run.

    • cites [224] Mi, 1987, Circular dichroism of some synthetic intermeidates of qinghaosu, Yaowu Fenxi Zazhi

      Not checked in the free run.

    • cites [225] Wang, 1985, Qinghaosu: proton and carbon-13 nuclear magnetic resonance spectral assignments and luminescence, Can. J. Chem. source

      Not checked in the free run.

    • cites [226] Wang, 1986, The 13C NMR spectroscopy of arteannuin analogues, Huaxue Xuebao

      Not checked in the free run.

    • cites [227] Lisgarten, 1998, Structure, absolute configuration and conformation of the antimalarial compound, artemisinin, J. Chem. Crystallogr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The most abundant metabolite from feeding artemisinic acid (473) was arteannuin B (462), followed by epi-deoxyarteannuin B (478) and the seco-cadinane (494).

    “The most abundant metabolite from feeding artemisinic acid (473) was arteannuin B (462), followed by epi-deoxyarteannuin B (478) and the seco-cadinane (494) as shown in Scheme 7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Brown, 2007, In vivo transformations of artemisinic acid in Artemisia annua plants, Tetrahedron source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Feeding labelled dihydroartemisinic acid (480) to A. annua resulted in sixteen labelled amorphane and cadinane sesquiterpenes, including all nine of the 11,13-dihydro forms in the pairs in Table 37.

    “Feeding labelled dihydroartemisinic acid (480) to A. annua resulted in sixteen labelled amorphane and cadinane sesquiterpenes [185], which included all nine of the 11,13-dihydro forms in the “pairs” in Table 37”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Brown, 2004, In vivo transformations of dihydroartemisinic acid in Artemisia annua plants, Tetrahedron source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nootkatone and valencene are currently reported from A. annua.

    “Two eremophilanes: nootkatone (1(10),11-eremophiladiene-2-one [4674-50-4]) (430) [22,43] and valencene (1(10),11-eremophiladiene (4α,5α,7β) [4630-07-3]) (431) [28] are currently reported from A. annua.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Liu, 1988, Preliminary analysis on chemical constituents of essential oil from inflorescence of of Artemisia annua L., Acta Botanica Sinica (Zhiwu Xuebao)

      Not checked in the free run.

    • cites [43] Goel, 2007, Volatile metabolite composition of the essential oil from aerial parts of ornamanetal and artemisinin-rich cultivars of Artemisia annua, J. Essent. Oil Res. source

      Not checked in the free run.

    • cites [28] Mukhtar, 2007, GC-MS analysis of volatile oil of aerial parts of Artemisia annua L., J. Essent. Oil-Bearing Plants source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The biological transformations of (473)/(480) have been proposed to involve spontaneous autoxidation of the Δ4,5 double bond and subsequent rearrangements of the resultant allylic hydroperoxides.

    “These biological transformations have been proposed to involve spontaneous autoxidation of the Δ4,5 double bond in (473)/(480) and subsequent rearrangements of the resultant allylic hydroperoxides [155,185].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Brown, 2007, In vivo transformations of artemisinic acid in Artemisia annua plants, Tetrahedron source

      Not checked in the free run.

    • cites [185] Brown, 2004, In vivo transformations of dihydroartemisinic acid in Artemisia annua plants, Tetrahedron source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The formyl ester in nor-amorphane 502 is thought to have been derived from the carbon at the 12-position of an amorphane precursor by oxidative rearrangements.

    “The formyl ester in nor-amorphane 502 is thought to have been derived from the carbon at the 12-position of an amorphane precursor by oxidative rearrangements.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both phytol (550) and an authentic sample of phytene-1,2-diol (552) were subsequently obtained as natural products from the seeds of A. annua.

    “Both phytol (550) itself and an authentic sample of phytene-1,2-diol (552) were subsequently obtained as natural products from the seeds of A. annua [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Brown, 2003, Terpenoids from the seeds of Artemisia annua, Phytochemistry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The related seco-cadinane natural product 504 has been reported from the in vitro autoxidation of dihydroartemisinic acid in organic solution.

    “(the related seco-cadinane natural product 504 has also been reported from the in vitro autoxidation of dihydroartemisinic acid in organic solution) [193].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Sy, 2002, The mechanism of the spontaneous autoxidation of dihydroartemisinic acid, Tetrahedron source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The structure of 3α,15-dihydroxycedrane (534) from A. annua has been rigorously determined both by 2D-NMR and by synthesis from (+)-β-cedrene.

    “The structure of 3α,15-dihydroxycedrane (534) from A. annua has been rigorously determined both by 2D-NMR and by synthesis from (+)-β-cedrene [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Brown, 2003, Terpenoids from the seeds of Artemisia annua, Phytochemistry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Terpene biosynthesis and its regulation in A. annua have been well reviewed, including the central role of amorpha-4,11-diene (451) in artemisinin biosynthesis and the likelihood that glandular trichomes are the location of artemisinin biosynthesis.

    “Terpene biosynthesis [271,272,273,274,275,276] and its regulation [277,278] in A. annua have been well reviewed, including the central role of amorpha-4,11-diene (451) in the biosynthesis of artemisinin (495) [279] and the likelihood that glandular trichomes are the location wherein artemisinin biosynthesis actually occurs [244,280]”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [271] Haynes, 2006, From artemisinin to new antimalarials: biosynthesis, extraction, old and new derivatives and medicinal chemistry requirements, Curr. Top. Med. Chem. source

      Not checked in the free run.

    • cites [272] Ryden, 2007, Chemistry, biosynthesis and biological activity of artemisinin and related natural peroxides, Top. Heterocycl. Chem. source

      Not checked in the free run.

    • cites [273] Bharel, 1996, Structure, biosynthesis and functions of artemisinin, Fitoterapia

      Not checked in the free run.

    • cites [274] Liu, 2000, Advance in artemisinin biosynthesis research, Tianran Chanwu Yanjiu Yu Kaifa

      Not checked in the free run.

    • cites [275] Chen, 2000, Advances in molecular biology of plant isoprenoid metabolic pathway, Zhiwu Xuebao

      Not checked in the free run.

    • cites [276] Wang, 2003, Advances in molecular regulation of artemisinin biosynthesis, Shengwu Gongcheng Xuebao

      Not checked in the free run.

    • cites [277] Weathers, 2006, Artemisinin: the biosynthetic pathway and its regulation in Artemisia annua, a terpenoid-rich species, In Vitro Cell. Dev. Biol.: Plant source

      Not checked in the free run.

    • cites [278] Covello, P., Teoh, K., Polichuk, D.R., Reed, D.W., and Nowak, G. (2007, January August). How the antimalarial artemisinin is made in plants. Abstracts of Papers; In Prceedings of 234th ACS national Meeting, Boston, MA, USA.

      Not checked in the free run.

    • cites [279] Covello, 2007, Functional genomics and the biosynthesis of artemisinin, Phytochemistry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Squalene synthase (SQS) catalyses the first committed step in the pathway leading from FPP (378) to triterpenes and phytosterols.

    “Squalene synthase (SQS) is the enzyme which catalyses the first committed step in the pathway leading from FPP (378) to triterpenes and phytosterols, such as these (Table 43).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    α-Guaiane (506) is the most abundant guaiane sesquiterpene in A. annua, and spathulenol (515) is the most common aromadendrane; both can reach levels up to 5% of the essential oil.

    “α-Guaiane (506) is the most abundant guaiane sesquiterpene in A. annua [22], whilst spathulenol (515) is the most common aromadendrane [41] (both can reach levels up to 5% of the essential oil).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Liu, 1988, Preliminary analysis on chemical constituents of essential oil from inflorescence of of Artemisia annua L., Acta Botanica Sinica (Zhiwu Xuebao)

      Not checked in the free run.

    • cites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The ethyl substituent in artemisinin G (496) might be derived from the 4- and 15-positions of a conventional amorphane precursor.

    “It seems likely that the ethyl substituent in artemisinin G (496) might be derived from the 4- and 15-positions of a conventional amorphane precursor.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The most abundant sterols from A. annua are stigmasterol (570) and sitosterol (568), which are ubiquitous components of plant cell membranes.

    “The most abundant sterols from A. annua are stigmasterol (570) and sitosterol (568) [96], which are ubiquitous components of plant cell membranes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Tang, 2000, Terpenoids and flavonoids from Artemisia species, Planta Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The mechanism of ADS-catalysed cyclization of FPP involves isomerization to nerolidyl diphosphate, C-1,C-6-ring closure to a bisabolyl cation, a 1,3-hydride shift, second ring closure between 1- and 10-positions to generate the amorphane skeleton, and deprotonation at C-12 or C-13 to afford amorpha-4,11-diene.

    “It is proposed that FPP is first isomerized to nerolidyl diphosphate; ionization of nerolidyl pyrophosphate is followed by C-1,C-6-ring closure to generate a bisabolyl cation; next, this cation undergoes a 1,3-hydride shift [295] permitting a second ring closure between the 1- and 10-positions to generate the amorphane skeleton; and, finally, deprotonation at either C-12 or C-13 affords amorpha-4,”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [295] Mercke, 2000, Molecular cloning, expression, and characterization of amorpha-4,11-diene synthase, a key enzyme of artemisinin biosynthesis in Artemisia annua L., Arch. Biochem. Biophys. source

      Not checked in the free run.

    • cites [136] Picaud, 2006, Amorpha-4,11-diene synthase: mechanism and stereochemistry of the enzymatic cycization of farnesyl diphosphate, Arch. Biochem. Biophys. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recombinant DBR2 enzyme purified to approximately 90% from E. coli is capable of reducing the Δ11(13) double bond in artemisinic aldehyde (460), but not in artemisinic alcohol (458), artemisinic acid (473), arteannuin B (462) or artemisitene (497).

    “A recombinant DBR2 enzyme has been purified to approximately 90% from E. coli and found to be capable of reducing the Δ11(13) double bond in artemisinic aldehyde (460) [but not in artemisinic alcohol (458), artemisinic acid (473), arteannuin B (462) or artemisitene (497)] [298].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [298] Zhang, 2004, Molecular cloning of a classical plant peroxidase from Artemisia annua and its effect on the biosynthesis of artemisinin in vitro, Acta Bot. Sin.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    FPP sits at a branch point in terpenoid metabolism.

    “FPP sits at a branch point in terpenoid metabolism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    DBR2 appears to be a member of the enoate reductase family, with similarities to 12-oxophytodienoate reductases.

    “This enzyme appears to be a member of the enoate reductase family of enzymes, with similarities to 12-oxophytodienoate reductases [298]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [298] Zhang, 2004, Molecular cloning of a classical plant peroxidase from Artemisia annua and its effect on the biosynthesis of artemisinin in vitro, Acta Bot. Sin.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Further elaboration to triterpenes and plant sterols requires head-to-head coupling of two FPP molecules, catalysed by squalene synthase.

    “Further elaboration to triterpenes and plant sterols (Table 43) requires the “head-to-head” coupling of two molecules of FPP, which is catalysed by the enzyme squalene synthase (SQS), as discussed in Section 2.7.2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    This first phase in artemisinin biosynthesis is the least controversial, and most of the enzymes involved in conversion of IPP and DMAPP to amorpha-4,11-diene (451) have now been isolated and characterized from A. annua.

    “This first phase in the biosynthesis of artemisinin is the least controversial, and most of the enzymes involved in the conversion of isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP) to amorpha-4,11-diene (451) have now been isolated and characterized from A. annua.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    None of compounds 462, 478, 479, 485, 494 or 497 feature in the most likely biogenetic route to artemisinin (495), although many have been implicated as side-products in reactions diverging from this main route.

    “In fact, none of 462, 478, 479, 485, 494 or 497 feature in the most likely biogenetic route to artemisinin (495) which is discussed first in Section 3.3, although many of these compounds have been implicated as side-products, in reactions which diverge away from this main biosynthetic route to (495)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Isomerization of the Δ11,13 bond to the Δ11,12 position in artemisinic alcohol (458) would produce an enol that would spontaneously tautomerize to the carbonyl group in dihydroartemisinic aldehyde (483), without reduction at C-11/13 or oxidation at C-12.

    “Thus, isomerization of the Δ11,13 bond to the Δ11,12 position in (458) would produce an enol, which would spontaneously tautomerize to the carbonyl group in (483), without any necessity for either reduction at C-11/13 or oxidation at C-12.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These three sequential oxidations of amorpha-4,11-diene (451) produce artemisinic acid (473) via artemisinic alcohol (458) and artemisinic aldehyde (460), with the exocyclic 11,13-double bond remaining intact.

    “These three sequential oxidations of amorpha-4,11-diene (451) produce artemisinic acid (473) via artemisinic alcohol (458) and artemisinic aldehyde (460) [196] (note that the exocyclic 11,13-double bond remains intact in this route).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [196] Teoh, 2006, Artemisia annua L. (Asteraceae) trichome-specific cDNAs reveal CYP71AV1, a cytochrome P450 with a key role in the biosynthesis of the antimalarial sesquiterpene lactone artemisinin, FEBS Lett. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    13C labeling studies have characterized the photosynthetic mechanism of A. annua as C3.

    “and 13C labeling studies have also been used to characterize the photosynthetic mechanism of A. annua as C3 [289].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [289] Matsushita, 1996, Cloning and anaysis of a cDNA encoding farnesyl diphosphate synthase from Artemisia annua, Gene source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Phase 2 of artemisinin biosynthesis has only recently been the subject of experimental investigation and is less well understood than phase 1.

    “Phase 2 of the biosynthesis has only recently been the subject of experimental investigation and is therefore less well understood than phase 1.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Artemisinin biosynthesis has recently been correlated with increased levels of singlet oxygen, although this has been explained by upregulation of genes involved in artemisinin biosynthesis rather than non-enzymatic processes.

    “In this regard, it is interesting to note that artemisinin biosynthesis has recently been correlated with increased levels of singlet oxygen -although this has been explained in terms of the upregulation of genes involved in artemisinin biosynthesis, rather than the operation of non-enzymatic processes [256].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [256] Yang, 2010, Senescent leaves of Artemisia annua are one of the most active organs for overexpression of artemisinin biosynthesis responsible genes upon burst of singlet oxygen, Planta Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The committed intermediate in artemisinin biosynthesis is amorpha-4,11-diene (451), formed from FPP by amorpha-4,11-diene synthase (ADS).

    “The comitted intermediate in the biosynthesis of artemisinin (495) is the bicyclic sesquiterpene-amorpha-4,11-diene (451) [291], which is formed from FPP (378) by the action of the sesquiterpene cyclase, amorpha-4,11-diene synthase (ADS) [138,292].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [291] Shen, 2007, Advances in sesquiterpene synthase cyclases of Artemisia annua, Shengwu Gongcheng Xuebao

      Not checked in the free run.

    • cites [138] Kong, 2009, Recent advances in the study of amorpha-4,11-diene synthase and its metabolic engineering, Yaoxue Xuebao

      Not checked in the free run.

    • cites [292] Jang, Y.-J., Kim, S.-U., Park, S.-H., and Song, S.-H. (2001). Amorpha-4,11-diene synthase of Artemisia annua, its coding gene, expression vector containing the gene and E. coli and plant transformants transformed with the vector. Repub. Korean Kongkae Taeho Kongbo.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    cDNAs encoding ADS from A. annua have been isolated, sequenced, and expressed.

    “cDNAs encoding ADS from A. annua have been isolated, sequenced, and expressed [293,294].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [293] Wallaart, 2001, Amorpha-4,11-diene synthase: cloning and functional expression of a key enzyme in the biosynthetic pathway of the novel antimalarial drug artemisinin, Planta source

      Not checked in the free run.

    • cites [294] Kim, 2006, Cyclization mechanism of amorpha-4,11-diene synthase, a key enzyme in artemisinin biosynthesis, J. Nat. Prod. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Artemisinin is a seco-cadinane, and carbon-carbon cleavage at C-4/C-5 in artemisinin accompanies formation of the 1,2,4-trioxane ring in the final phase of biosynthesis.

    “Artemisinin is a seco-cadinane (Table 38), and carbon-carbon cleavage at C-4/C-5 in (495) therefore accompanies formation of the 1,2,4-trioxane ring in this final phase of the biosynthesis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    α-Epoxyartemisinic acid (487) has been stated not to be a biosynthetic intermediate to artemisinin.

    “(in addition, α-epoxyartemisinic acid (487) has been stated not to be a biosynthetic intermediate to artemisinin [194]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] Wu, 1984, Structure and synthesis of arteannuin and related compounds. XI, Identification of epoxyarteannuic acid, Huaxue Xuebao

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The IPP used in artemisinin biosynthesis comes from both the mevalonate and the mevalonate-independent pathways.

    “It has been proposed that the IPP used in the biosynthesis of artemisinin comes from both the mevalonate and the mevalonate-independent pathways [287]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [287] Kudaksseril, 1987, Effect of sterol inhibitors on the incorporation of carbon-14 isopentenyl pyrophosphate into artemisinin by a cell-free system from Artemisia annua tissue cultures and plants, Planta Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Not all of the many different proposals for phase 3 of artemisinin biosynthesis can be correct.

    “However, as the length of the foregoing list shows, there have been so many different proposals for phase 3 of the biosynthesis, that not all of them can be correct.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The step iii reaction most probably proceeds via an ene-type mechanism similar to the conversion of 480 to 481, apparently without requirement for light, with 3O2 rather than 1O2 as the active species.

    “This reaction most probably proceeds via an “ene-type” mechanism similar to that for the conversion of 480 to 481, although apparently without the requirement for light (i.e. 3O2 rather than 1O2 is perhaps the active species) [193,236,304,305].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [193] Sy, 2002, The mechanism of the spontaneous autoxidation of dihydroartemisinic acid, Tetrahedron source

      Not checked in the free run.

    • cites [236] Ye, B., and Wu, Y.-L. (1990). An efficient synthesis of qinghaosu and deoxoqinghaosu from arteannuin acid. J. Chem. Soc., Chem. Commun., 726–727. source

      Not checked in the free run.

    • cites [304] Adam, 1988, Preparative visible-laser photochemistry: Qinghaosu-type 1,2,4-trioxanes by molecular oxygen trapping of Paterno-Buchi triplet 1,4-diradicals derived from 3,4-dihydro-4,4-dimethyl-2H-pyran-2-one and quinones, J. Org. Chem. source

      Not checked in the free run.

    • cites [305] Cumming, 1998, Design, synthesis, derivatization, and structure-activity relationships of simplified, tricyclic, 1,2,4-trioxane alcohol analogues of the antimalarial artemisinin, J. Med. Chem. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    A non-enzymatic mechanism involving molecular oxygen is particularly attractive in view of the variety of spontaneous autoxidation reactions already suggested for the biogenesis of many other highly oxygenated terpenes from A. annua.

    “A non-enzymatic mechanism involving molecular oxygen is particularly attractive in view of the variety of spontaneous autoxidation reactions which have already been suggested for the biogenesis of many other highly oxygenated terpenes from A. annua.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The formation of regular acyclic monoterpenes 263-265, 267, 271 and 272; irregular acyclic monoterpenes 279 and 280; eudesmane sesquiterpenes 413 and 414; amorphane sesquiterpenes 457, 465-467, 477, 478, 481, 484, 485 and 490; 479, 481, 485 and 493; 462, 478 and 494; and diterpenes 552 and 553 have all been proposed to proceed by spontaneous autoxidation chemistry.

    “For example, the formation of regular acyclic monoterpenes 263-265, 267, 271 and 272 in Scheme 1 (Section 2.5.1); irregular acyclic monoterpenes 279 and 280 in Scheme 3 (Section 2.5.2); eudesmane sesquiterpenes 413 and 414 in Scheme 4 (Section 2.6.3); amorphane sesquiterpenes 457, 465-467, 477, 478, 481, 484, 485 and 490 in Scheme 5; 479, 481, 485 and 493 in Scheme 6; 462, 478 and 494 in Scheme 7”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A microbial system capable of converting arteannuin B (462) to artemisinin (495) has been described, and an enzyme with the appropriate activity has been purified.

    “A microbial system which is capable of converting arteannuin B (462) to artemisinin (495) has recently been described [309] and an enzyme with the appropriate activity has also been purified [310,311].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [309] Dhingra, 2001, Purification and Characterization of an enzyme involved in biochemical transformation of arteannuin B to artemisinin from Artemisia annua, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

    • cites [310] Dhingra, 2000, Partial purification of proteins involved in the bioconversion of arteannuin B to artemisinin, Bioresource Technol. source

      Not checked in the free run.

    • cites [311] Abdin, 2004, Molecular approaches to enhance artemisinin content in Artemisia annua L., Recent Prog. Med. Plants

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dihydroarteannuin B (479) can be converted into artemisinin by cell-free extracts of A. annua.

    “It has also been claimed that the 11,13-dihydro analogue of arteannuin B (462), dihydroarteannuin B (479), can be converted into artemisinin by cell free extracts of A. annua [249,312].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [249] Bharel, 1998, Enzymic synthesis of artemisinin from natural and synthetic precursors, J. Nat. Prod. source

      Not checked in the free run.

    • cites [312] Brown, 1993, Production of anti-malarial and anti-migraine drugs in tissue culture of Artemisia annua and Tanacetum parthenium, Acta Hortic. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Epoxyartemisinic acid (487) can be converted to arteannuin B (462) but cannot be transformed into artemisinin (495), implying that arteannuin B cannot be a precursor to artemisinin.

    “a study which found that epoxyartemisinic acid (487) could be converted to arteannuin B (462) also stated that epoxyartemisinic acid (487) could not be transformed into artemisinin (495) and therefore – by implication – arteannuin B cannot be a precursor to artemisinin [284].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [284] Nair, 1992, Use of cell-free systems in the production of the potent antimalarial, artemisinin, Indian J. Chem., Sect. B

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both artemisinin from A. annua and taxol from Taxus brevifolium are available in only limited quantities from the natural source and are difficult to synthesize chemically.

    “Both artemisnin from A. annua and taxol from Taxus brevifolium are attractive targets for this emerging science of synthetic biology since both drugs are available in only limited quantities from the natural source and are also difficult to synthesize chemically [364].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [364] Huang, 2006, Genetic manipulation on biosynthesis of terpenoids, Zhongguo Shengwu

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Keasling has observed that production of drugs via heterologous pathways in microbial hosts is frequently hindered by insufficient knowledge of the native metabolic pathway and its cognate enzymes.

    “Keasling has observed that “the production of drugs via heterologous pathways in microbial hosts is frequently hindered by insufficient knowledge of the native metabolic pathway and its cognate enzymes; often the pathway is unresolved, and the enzymes lack detailed characterization” [387].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [387] Sy, 1999, Novel seco-cycloartanes from Kadsura coccinea and the assisted autoxidation of a tri-substituted alkene, Tetrahedron source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dodecane has been incorporated into culture medium to provide a separate hydrophobic layer in which volatile amorpha-4,11-diene produced by microbial fermentation can be trapped.

    “Previously, dodecane has been incorporated into the culture medium, in order to provide a separate hydrophobic layer in which volatile amorpha-4,11-diene (451) produced by microbial fermentation can be trapped [382, 385].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [382] Picaud, 2007, Improved conditions for production of recombinant plant sesquiterpene synthases in Escherichia coli, Prot. Expr. Purif. source

      Not checked in the free run.

    • cites [385] Ro, D.-K., Ouellet, M., Paradise, E.M., Burd, H., Eng, D., Paddon, C.J., Newman, J.D., and Keasling, J.D. (2008). Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid. BMC Biotechnol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lateral transfer of genes involved in taxol biosynthesis from Taxus brevifolium to an endophytic symbiont has been observed.

    “Interest in endophytic fungi as a novel source of plant-derived drugs was first sparked by the observation of the lateral transfer of genes which are involved in the biosynthesis of taxol (paclitaxel) from Taxus brevifolium L. [356] - the plant which produces this important anti-cancer compound - to an endophytic symbiont.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [356] Liu, 2001, Antifungal activity of Artemisia annua endophyte cultures against phytopathenogenic fungi, J. Biotechnol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The prerequisite for reconstruction of the complete biosynthetic pathway to artemisinin in a transgenic yeast or bacterium is elucidation of the full details of phase 2 and a better understanding of phase 3.

    “The author would argue that the prerequisite for the reconstruction of the complete biosynthetic pathway to artemisinin (495) in a transgenic yeast or bacterium is the elucidation of the full details of phase 2 of the biosynthesis in A. annua, in which amorpha-4,11-diene (451) is converted to dihydroartemisinic acid (480); as well as a better understanding of phase 3, in which 480 is then”
    Quote in the paperSubstantial claim
137 of 137

  • The authors state this as an assumption.

    The final steps in the biosynthetic pathway to artemisinin proceed from dihydroartemisinic acid (480), rather than artemisinic acid (473) or other proposed late-stage intermediates.

    “In this review, it is assumed that the final steps in the biosynthetic pathway to artemisinin (495) proceed from dihydroartemisinic acid (480), rather than artemisinic acid (473) (or, indeed, any of the other late stage intermediates: 462, 478, 479, 485, 494 or 497 which have been proposed in the past).”

  • The authors state this as an assumption.

    The configuration at the 7- and 11-positions of phytene-1,2-diol (552) remained fixed, as in phytol.

    “on the assumption that the configuration at the 7- and 11- positions of (552) remained fixed, as in phytol.”

  • The authors state this as an assumption.

    Artemisinic acid (473) is a “dead end” metabolite, leading away from artemisinin (495) in phase 2 of the biosynthetic route.

    “the existence of these two chemotypes might instead be explained on the assumption that artemisinic acid (473) is a “dead end” metabolite, leading “away” from artemisinin (495) in phase 2 of the biosynthetic route, as is implied in Scheme 11.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Complete metabolite list contains 14, not 16, entries

    Minor

    The feeding experiment is said to yield sixteen labelled sesquiterpenes, but the purported complete list names only fourteen.

  • Phase 3 mechanism points to the wrong scheme

    Minor

    The text places Hock cleavage in step ii) of Scheme 11, although the four-step conversion and its Hock-cleavage step are explicitly assigned to Scheme 12.

  • Artemisinic and dihydroartemisinic acid identifiers are reversed

    Minor

    The phase 2 discussion assigns (473) to dihydroartemisinic acid and (480) to artemisinic acid, reversing the identities used in Table 36 and elsewhere.

  • Claimed continuous C16-C26 hydrocarbon series omits C22

    Minor

    The text says all saturated unbranched hydrocarbons from C16 through C26 are reported, but Table 1 jumps from heneicosane (C21) to tricosane (C23), omitting docosane (C22).

  • Camphor is assigned myrtenol's compound number

    Minor

    The prose calls camphor compound 351, whereas Table 26 identifies camphor as 341; Table 27 assigns 351 to myrtenol.

5 of 5

Cites

Flagged first, then by citations

25 of the 328 references couldn’t be matched to a known paper.

Research works printed but not linked: 81

  1. (1992). Pharmacopoeia of the People’s Republic of China, English edition ed., Guangdong Science and Technology Press.
  2. Balachandran, 1987, Chemical investigation of some Artemisia species: Search for artemisinin or other related sesquiterpene lactones with a peroxide bridge, Indian J. Pharm. Sci., 49, 152
  3. Bhakuni, 2001, Secondary metabolites of Artemisia annua and their biological activity, Curr. Sci., 80, 35
  4. Buckingham, 2004, Introduction to the Type of Compound Index, Dictionary of Natural Products, Volume 1, xi
  5. Tian, 2007, Study on volatile constituents of herba Artemisia annua and its preparation by GC-MS, Shizen Guoyi Guoyao, 18, 1840
  6. Zou, 1999, Analysis of volatile components from Artemisia annua Linn, Fenxi Ceshi Xuebao, 18, 55
  7. Zhong, 1983, Studies of volatile constituents from Artemisia annua, Zhongyao Tongbao, 8, 31
  8. Genov, 1983, Gas-Chromatographic study of the essential oil of Artemisia annua L., Naunchi Trudove - Vissh Institut po Khranitelna i Vkusova Promishlenost, Plodiv, 30, 141
  9. Tsankova, 1976, On the composition of the essential oil from Artemisia annua Linnaeus, Italiana Essenze, Profumi, Piante Officinale, Aromi, Saponi, Cosmetici, Aerosol, 58, 502
  10. Biougne, 1993, Essential oil of Artemisia annua: Seasonal variations in chemical composition, Rivista Italiania EPPOS, 4, 622
  11. Popescu, 1980, Artemisia annua: An indigenous source of volatile oil, Clujul Med., 53, 331
  12. He, 2008, Analysis of chemical composition of voatile oil in Youyang Artemisia annua by GC-MS, Huaxi Yaoxue Zazhi, 23, 30
  13. Zhang, 2004, Studies on the chemical composition of the essential oil of Artemisia annua L. from Xinjiang, Xibei Shifan Daxue Xuebao, Ziran Kexueban, 40, 67
  14. Tian, 1982, Studies on the chemical constituents of Qinghao (Artemisia annua), a traditional chinese herb, Zhongcaoyao, 13, 9
  15. Zhang, 2004, Studies on the composition of the fatty acids of five species of Artemisia in Xinjiang, Xibei Shifan Daxue Xuebao, Ziran Kexueban, 40, 64
  16. Deng, 2008, Alleochemicals isolation and structure identification of Artemisia annua, Huanan Nongye Daxue Xuebao, 29, 42
  17. Chen, 2001, Isolation and identification of arteannuin and its precursor, Zhongcaoyao, 32, 302
  18. Georgiev, 1983, Changes in the essential oil of Artemisia annua L. during storage, Nauchni Trudove - Vissh Institut po Khranitelna i Vkusova Promishlenost, 30, 149
  19. Georgiev, 1978, On the distillation of annual wormwood (Artemisia annua Linnaeus), Rivista Italiana Essenze, Profumi, Piante Officinali, Arromatizanti, Syndets, Saponi, Cosmaetici, Aerosols, 60, 302
  20. Tu, 1985, Chemical constituents of sweet wormwood (Artemisia annua) (III), Zhongcaoyao, 16, 200
  21. Liu, 1980, Studies on the constituents of Artemisia annua, Yaoxue Tongbao, 15, 39
  22. Djermanovic, 1997, Some new constituents from domestic plant species of Artemisia monogyna W and K and Artemisia annua L., J. Serb. Chem. Soc., 62, 113
  23. Yang, 2006, Determination of scopoletin in Artemisia annua by HPLC, Zhongguo Shiyan Fangjixue Zazhi, 12, 10
  24. Nguyen, 1998, Research on the extraction of a coumarin derivative from the leaves of Artemisia annua L. growing in Vietnam, Tap Chi Duoc Hoc, 36, 58
  25. Yang, 1989, Methoxylated flavones and coumarins from Artemisia annua, Phytochemistry, 28, 1509, 10.1016/s0031-9422(00)97776-8 · DOI
  26. Jeremic, 1979, Flavonols from Artemisia annua, Glas. Khem. Drush. Beograd., 44, 615
  27. Bhardwaj, 1985, Constituents of Artemisia annua, Proc. Indian Nat. Sci. Acad., 51A, 741
  28. Liu, 1981, Studies on the chemical constituents of Artemisia annua L., Yaoxue Xuebao (Acta Pharmaceutica Sinica), 16, 65
  29. Georgiev, 1981, Changes in yield and quality of essential oil in annual wormwood (Artemisia annua L.) during growth, Rastenievundi Nauki, 18, 95
  30. Hethelyl, 1994, Capillary gas chromatographic investigation of Artemisia annua essential oils, Olaj, Szappan, Kozmetika, 43, 103
  31. Youann, 1955, Essential oil of Artemisia annua, Perfumery and Essential Oil Rec., 46, 75
  32. Tu, 1981, Studies on the constituents of Artemisia annua, Yaoxue Xuebao (Acta Pharmaceutica Sinica), 16, 366
  33. Liu, 2007, Determination of camphor and caryophyllene in Artemisia annua L. and Herba artemisiae annuae oil by capillary GC, Huaxue Yaoxue Zashi, 22, 218
  34. Zhu, 1982, Study on antibacterial constituents of Qing Hao (Artemisia annua L.), Zhongcaoyao, 13, 6
  35. Zhou, 1987, Synthesis of arteannuin and related compounds, Yiyao Gongye, 18, 470
  36. Agrawal, 1996, NMR spectral investigations. Part 41. Sesquiterpenoids from Artemisia annua: 13C NMR shielding behavior, J. Sci. Ind. Res., 55, 17
  37. Tu, 1981, Chemical constituents in Artemisia annua L. and the derivatives of artemisinin, Chung Yao Tong Pao, 6, 31
  38. Pang, 1997, Study on the absolute configuration of artemisinic acid isolated from chinese antimalaria herb Artemisia annua L., Shenyang Yaoke Daxue Xuebao, 14, 189
  39. Zhou, 1989, Studies on the structure and synthesis of arteannuin and related compounds, Huaxue Xuebao, 47, 710
  40. Xu, 1982, Stereoselective synthesis of arteannuin B, Kexue Tongbao, 27, 1022
  41. Zhou, 1986, Studies on the structure and syntheses of arteannuin and related compounds XVIII. Synthesis of arteannuin A, Huaxue Xuebao, 44, 968
  42. Stefanovic, 1977, Chemical transformations of arteannuin B - cadinane sesquiterpenic lactone - isolated from Artemisia annua L., Glas. Khem. Drus., Beograd, 42, 227
  43. Pajarin, 1987, The total synthesis of (+/-)-arteannuin B, Diss. Abstr. Int., 48, 444
  44. Barriault, L., and Deon, D.H. (2001, January April). Recent progress towards the total synthesis of arteannuin M. Abstracts of Papers; In Proceedings of 221st ACS national Meeting, San Diego, CA, USA.
  45. Engel, D.A., Lam, H.T.C., Singletary, J.A., Poon, K.W.C., and Dudley, G.B. (2006, January March). Synthetic approaches to artemisinin-related natural products, dihydroartemisinic acid and arteannuin M. Abstracts of Papers; In Proceedings of 231st ACS national Meeting, Atlanta, GA, USA.
  46. Engel, D.A., Lam, H.T.C., Singletary, J.A., Poon, K.-W.C., and Dudley, G.B. (2008, January April). Synthetic approaches to artemisinin-related natural products, didesmethylartemisinin and dihydro-epi-deoxyarteannuin B. Abstracts of Papers; In Proceedings of 235th ACS national Meeting, New Orleans, LA, USA.
  47. Wu, 1984, Structure and synthesis of arteannuin and related compounds. XI, Identification of epoxyarteannuic acid, Huaxue Xuebao, 42, 596
  48. Kasymov, 1986, Lactones of Artemisia annua, Khim. Prir. Soedin., 5, 636
  49. Deng, 1981, Studies on the structure of the artemisic acid, Kexue Tongbao, 26, 1209
  50. Zhu, 1982, Studies on the antibacterial artemisinin, Zhongcaoyao (Chinese Traditional and Herbal Drugs), 13, 6
  51. Huang, 1987, Constituents of Artemisia annua L. I. Isolation and identification of 11R-(-)-dihydroarteannuic acid, Huaxue Xuebao, 45, 609
  52. Anonymous (1977). Co-ordinating group of research on the structure of Qing Hao Su. A new type of lactone - Qing Hau Sau. K’O Hsueh Tung Pao, 22, 142. (CA 1977, 87, 98788).
  53. Huang, 1988, Two-dimensional NMR studies of arteannuin, Huaxue Xuebao, 45, 305
  54. Leban, 1988, Crystal and molecular structure of Qinghaosu: A redetermination, Acta Pharmaceutica Jugoslavica, 38, 71
  55. Madhusudanan, 1989, Mass spectral studies on artemisinin, dihydroartemisinin and artether, Indian J. Chem. Sect. B, Organic Chemistry including Medicinal Chemistry, 28, 751
  56. Mi, 1987, Circular dichroism of some synthetic intermeidates of qinghaosu, Yaowu Fenxi Zazhi, 7, 262
  57. Wang, 1986, The 13C NMR spectroscopy of arteannuin analogues, Huaxue Xuebao, 44, 834
  58. Zhang, 1988, Structure and synthesis of arteannuin and related compounds. XXIV. Conversion of arteannuin into artemisitene, Youji Huaxue, 8, 329
  59. Gu, 1987, Pharmacological studies on artemisinin and its derivatives as antimalarial, Int. Congr. Ser. - Excerpta Med., 750, 657
  60. Shukla, 1991, Growth inhibitors from Artemisia annua, Indian Drugs, 28, 376
  61. Feng, 2004, Cloning and sequencing of Artemisia annua squalene synthase gene and its cDNA, Guangzhou Zhongyiyao Daxue Xuebao, 21, 387
  62. Liu, 2003, Molecuar cloning, Escherichia coli expression and genomic organization of squalene synthase gene from Artemisia annua, Acta Bot. Sin., 45, 608
  63. Lu, 2005, Terpenoid metabolism in cotton (Gossypium spp.) and qinghao, Adv. Plant Physiol., 8, 265
  64. Bharel, 1996, Structure, biosynthesis and functions of artemisinin, Fitoterapia, 67, 387
  65. Li, 1994, Synthesis of [15-14C] labeled artemisinin, Yaoxue Xuebao (Acta Pharmaceutica Sinica), 29, 713
  66. Nair, 1992, Use of cell-free systems in the production of the potent antimalarial, artemisinin, Indian J. Chem., Sect. B, 31B, 880
  67. Zhang, 2003, Effect of horseradish peroxidase on the biosynthesis of artemisinin in Artemisia annua in vitro, Yingyong Yu Huanjung Shengwu Xuebao, 9, 616
  68. Huang, 1990, Biosynthesis of arteannuin. I. In vivo biosynthesis of arteannuic acid of Artemisia annua, Huaxue Xuebao, 48, 275
  69. Abdin, 2004, Molecular approaches to enhance artemisinin content in Artemisia annua L., Recent Prog. Med. Plants, 4, 145
  70. Liu, 1999, Advances in artemisinin research, Huaxue Jinzhan, 11, 41
  71. Gulati, 1996, Experimental studies on Artemisia, a herbal remedy to malaria, Fitoterapia, 67, 403
  72. Chen, 1986, Factors affecting the content of artemisinin in Artemisia annua, Zhongyao Tongbao, 11, 393
  73. Chen, 1987, Studies of several physiological factors on artemisinin synthesis in Artemisia annua, Zhiwu Shenglixue Tongxun, 5, 26
  74. Chen, 1993, Enhanced synthesis of the natural phytotoxin artemisinin in tissue culture, PGRSA Q., 21, 151
  75. Zhang, 2004, Related factors of artemisinin biosynthesis in clone strain of Artemisia annua L., Yingyong Yu Huanjung Shengwu Xuebao, 10, 277
  76. Li, 1999, Artificial regulation of artemisinin biosynthesis metabolite in cultured cells of Artemisia annua, Zhongguo Shengwu Huaxue Yu Fenzi Shengwu Xuebao, 15, 479
  77. Wang, 2006, Preparation of an elicitor from a fungal endophyte to enhance artemisinin production in hairy root culture of Artemisia annua L., Shengwu Gongcheng Xuebao, 22, 829
  78. Liu, 2002, Leptosphaerone, a metabolite with a novel skeleton from Leptosphaeria sp. IV403, an endophytic fungus in Artemisia annua, Helv. Chim. Acta, 85, 2664, 10.1002/1522-2675(200209)85:9<2664::aid-hlca2664>3.0.co;2-r · DOI
  79. Huang, 2006, Genetic manipulation on biosynthesis of terpenoids, Zhongguo Shengwu, 26, 60
  80. Huang, 2008, Cloning and expression of Artemisia annua L. amorpha-4,11-diene synthase gene, Guangzhou Zhongyiyao Daxue Xuebao, 25, 68
  81. Keasling, J.D. (2005, January March). Engineering microbes for anti-malarial production. Abstracts of Papers; In Proceedings of 229th ACS National Meeting, San Diego, CA, USA.

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Authors
Brown, G. D.
Affiliations
University of Reading (GB)
Corresponding author
Brown, Geoffrey D.
ORCID
Brown, Geoffrey D.
Venue
Molecules
Publisher
MDPI AG
Published
2010-10-28
Volume
15
Issue
11
Pages
7603-7698
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules15117603
PMC
PMC6259225
OpenAlex
W1981404580
Semantic Scholar
bab630601f2f4ad0568f26b578ad5ff6c4077517
Cited by
363
References
328
Citations by year
2026: 16 · 2025: 25 · 2024: 25 · 2023: 29 · 2022: 21 · 2021: 23 · 2020: 27 · 2019: 22 · 2018: 24 · 2017: 18 · 2016: 26 · 2015: 27 · 2014: 28 · 2013: 23 · 2012: 22
FWCI
1.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CentAUR (University of Reading) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Biotechnology and Biological Sciences Research Council (BB/G008744/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Sesquiterpenes and Asteraceae Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phytochemical compounds biological activities
Keywords
Artemisia annua, sesquiterpenes, dihydroartemisinic acid, allylic hydroperoxides, endoperoxides, terpene oxidation, cadinane sesquiterpenes, flavonoids, stable isotope labeling, feeding experiments, antimalarial natural products, phytochemistry
MeSH terms
Antimalarials, Plants, Medicinal, Sesquiterpenes, Artemisia annua, Artemisinins

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