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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [33] Libbey, 1989, Unusual essential oils grown on Oregon II, Artemisia annua L. J. Essent. Oil Res. source
• Not checked yetcites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi
• Not checked yetcites [73] Georgiev, 1978, On the distillation of annual wormwood (Artemisia annua Linnaeus), Rivista Italiana Essenze, Profumi, Piante Officinali, Arromatizanti, Syndets, Saponi, Cosmaetici, Aerosols

In the paper

“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.”

In the paper

“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]”

What the sources say

• Not checked yetcites [155] Brown, 2007, In vivo transformations of artemisinic acid in Artemisia annua plants, Tetrahedron source

In the paper

“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.”

What the sources say

• Not checked yetcites [155] Brown, 2007, In vivo transformations of artemisinic acid in Artemisia annua plants, Tetrahedron source

In the paper

“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.”

What the sources say

• Not checked yetcites [343] Chen, 1993, Enhanced synthesis of the natural phytotoxin artemisinin in tissue culture, PGRSA Q.
• Not checked yetcites [344] Zhang, 2004, Related factors of artemisinin biosynthesis in clone strain of Artemisia annua L., Yingyong Yu Huanjung Shengwu Xuebao
• Not checked yetcites [345] Nair, 1986, Production of artemisinin in tissue cultures of Artemisia annua, J. Nat. Prod. source
• Not checked yetcites [346] Elhag, 1992, Selection and micropropagation of high artemisinin producing clones of Artemisia annua L., Phytother. Res. source
• Not checked yetcites [347] Li, 1999, Artificial regulation of artemisinin biosynthesis metabolite in cultured cells of Artemisia annua, Zhongguo Shengwu Huaxue Yu Fenzi Shengwu Xuebao
• Not checked yetcites [348] Xie, 2001, Isolation and production of artemisinin and stigmasterol in hairy root cultures of Artemisia annua, Plant Cell Tissue Org. Cult. source

In the paper

“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].”

What the sources say

• Not checked yetcites [155] Brown, 2007, In vivo transformations of artemisinic acid in Artemisia annua plants, Tetrahedron source

In the paper

“Several authors have reported that the artemisinin content is highest just before flowering [326,327,328]”

What the sources say

• Not checked yetcites [326] Singh, 1988, Evaluation of Artemisia annua strains for higher artemisinin production, Planta Med. source
• Not checked yetcites [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
• Not checked yetcites [328] Ferreira, 1995, Developmental studies of Artemisia annua: Flowering and artemisinin production under greenhouse and field conditions, Planta Med. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [190] Brown, 2007, In vivo transformations of dihydro-epi-deoxyarteannuin B in Artemisia annua plants, Tetrahedron source

In the paper

“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]).”

What the sources say

• Not checked yetcites [321] Pereira, 1999, New hybrid lines of the antimalarial species Artemisia annua L., Acta Hortic.

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“Several endophytes have now been described from A. annua [357].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [388]
• Not checked yetcites [218] Sy, 2002, The role of the 12-carboxylic acid group in the spontaneous autoxidation of dihydroartemisinc acid, Tetrahedron source

In the paper

“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].”

What the sources say

• Not checked yetcites [384] Ro, 2006, Production of the antimalarial drug precursor artemisinic acid in engineered yeast, Nature source
• Not checked yetcites [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 yetcites [386] Dietrich, 2009, A novel semi-biosynthetic route for artemisinin production using engineered substrate-promiscuous P450BM3, ACS Chem. Biol. source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

In the paper

“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]”

What the sources say

• Not checked yetcites [21] Woerdenbag, 1993, Volatile constituents of Artemisia annua L. (Asteraceae), Flavour Frag. J. source

In the paper

“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.”

In the paper

“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).”

In the paper

“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 the paper

“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]”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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).”

In the paper

“The only two such compounds to be reported to date are ponticaepoxide (121) and annuadiepoxide (122)”

In the paper

“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.”

In the paper

“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”

In the paper

“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).”

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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).”

In the paper

“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.”

In the paper

“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)”

In the paper

“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].”

What the sources say

• Not checked yetcites [93] Baraldi, 2008, Distribution of artemisinin and bioactive flavonoids from Artemisia annua L. during plant growth, Biochemical Syst. Ecol. source

In the paper

“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).”

In the paper

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

In the paper

“which have been isolated from both leaves [67] and seeds [9] of A. annua.”

What the sources say

• Not checked yetcites [67] Manns, 1992, Annuadiepoxide, a new polyacetylene from the aerial parts of Artemisia annua, J. Nat. Prod. source
• Not checked yetcites [9] Brown, 2003, Terpenoids from the seeds of Artemisia annua, Phytochemistry source

In the paper

“The miscellaneous polycyclic aromatic natural product acenaphthylene, 1,2,4,5-tetrahydro- ([54271-92-0]) (241) is also reported from A. annua [34].”

What the sources say

• Not checked yetcites [34] Ali, 2000, Volatile oil constituents of Artemisia annua leaves, J. Med. Aromat. Plant Sci.

In the paper

“accounting for as much as 10-30% of the essential oil [25,28,33,34,41,53]”

What the sources say

• Not checked yetcites [25] Chalchat, 1991, A contribution to chemotaxonomy of Artemisia annua L., Asteraceae, Acta Pharm. Jugosl.
• Not checked yetcites [28] Mukhtar, 2007, GC-MS analysis of volatile oil of aerial parts of Artemisia annua L., J. Essent. Oil-Bearing Plants source
• Not checked yetcites [33] Libbey, 1989, Unusual essential oils grown on Oregon II, Artemisia annua L. J. Essent. Oil Res. source
• Not checked yetcites [34] Ali, 2000, Volatile oil constituents of Artemisia annua leaves, J. Med. Aromat. Plant Sci.
• Not checked yetcites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi
• Not checked yetcites [53] Charles, 1991, Characterization of the essential oil of Artemisia annua L., J. Essent. Oil Res. source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [23] Tian, 2007, Study on volatile constituents of herba Artemisia annua and its preparation by GC-MS, Shizen Guoyi Guoyao

In the paper

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

In the paper

“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]”

What the sources say

• Not checked yetcites [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 yetcites [116] Ruzicka, 1936, Synthesis of tetrahydroartemisia ketone, Helv. Chim. Acta source
• Not checked yetcites [117] Takemoto, 1957, Essential oil of Artemisia annua. I. Isolation of a new ester compound, Yakugaku Zasshi source
• Not checked yetcites [118] Takemoto, 1957, Essential oil of Artemisia annua. II. Structure of 1-β-artemisia alcohol, Yakugaku Zasshi source
• Not checked yetcites [119] Takemoto, 1957, Essential oil of Artemisia annua. III. Structure of artemisia ketone, Yakugaku Zasshi source
• Not checked yetcites [120] Takemoto, 1957, Essential oil of Artemisia annua. IV. Dihydroartemisia ketone, Yakugaku Zasshi source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [122] Suga, 1972, Biosynthesis of a non-head-to-tail monoterpene, artemisia ketone, Chem. Lett. source
• Not checked yetcites [123] Simpson, J.B. (1979). On the Biosynthesis of Artemisia Ketone in Artemisia annua, Louisiana State Univ.
• Not checked yetcites [124] Banthorpe, 1977, Terpene biosynthesis. Part 20. Role of geraniol and nerol in the biosynthesis of artemisia ketone, Phytochemistry source
• Not checked yetcites [125] Risinger, 1978, On the biosynthesis of artemisia ketone and bakuchiol, Experientia source
• Not checked yetcites [126] Allen, 1977, Terpene biosynthesis. Part 17. Biosynthesis of irregular monoterpenes in extracts from higher plants, Phytochemistry source

In the paper

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

In the paper

“1,8-Cineole is sometimes accompanied by significant quantities of p-cymene (295) [28,34] and α-terpineol (322) [28]”

What the sources say

• Not checked yetcites [28] Mukhtar, 2007, GC-MS analysis of volatile oil of aerial parts of Artemisia annua L., J. Essent. Oil-Bearing Plants source
• Not checked yetcites [34] Ali, 2000, Volatile oil constituents of Artemisia annua leaves, J. Med. Aromat. Plant Sci.

In the paper

“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.”

What the sources say

• Not checked yetcites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi
• Not checked yetcites [23] Tian, 2007, Study on volatile constituents of herba Artemisia annua and its preparation by GC-MS, Shizen Guoyi Guoyao
• Not checked yetcites [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

In the paper

“and sometimes co-occurrs with significant amounts of either β-pinene (356) [101] or pinocarvone (360) [42].”

What the sources say

• Not checked yetcites [101] Bhardwaj, 1985, Constituents of Artemisia annua, Proc. Indian Nat. Sci. Acad.
• Not checked yetcites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi

In the paper

“Borneol (334) [46,73] and bornyl acetate (335) [29] are sometimes reported together with camphor (351) as significant constituents of the essential oil.”

What the sources say

• Not checked yetcites [46] Yang, 2008, Investigation of essential oil from leaves of Artemisia annua L. in Guizhou, Shizen Guoyi Guoyao
• Not checked yetcites [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 yetcites [29] Genov, 1983, Gas-Chromatographic study of the essential oil of Artemisia annua L., Naunchi Trudove - Vissh Institut po Khranitelna i Vkusova Promishlenost, Plodiv

In the paper

“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.”

What the sources say

• Not checked yetcites [34] Ali, 2000, Volatile oil constituents of Artemisia annua leaves, J. Med. Aromat. Plant Sci.
• Not checked yetcites [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

In the paper

“the majority of monoterpenes which incorporate an additional three-membered ring belong to the thujane class (Table 28).”

In the paper

“Camphene (343) has been obtained as both its (+)- and (-)-enantiomeric forms [37].”

What the sources say

• Not checked yetcites [37] Holm, 1997, Variation in the essential oil composition of Artemisia annua L. of different origin cutivated in Finland, Flavour Frag. J. source

In the paper

“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”

In the paper

“Tricyclene ([508-32-7] [160339-05-9]) (375) [25,32,41,43,45] is the only tricyclic monoterpenoid known from A. annua.”

What the sources say

• Not checked yetcites [25] Chalchat, 1991, A contribution to chemotaxonomy of Artemisia annua L., Asteraceae, Acta Pharm. Jugosl.
• Not checked yetcites [32] Goel, 2007, Essential oils of petal, leaf and stem of the antimalarial plant Artemisia annua, J. Nat. Med. source
• Not checked yetcites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi
• Not checked yetcites [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 yetcites [45] Jain, 2002, Essential oil composition of Artemisia annua L. "Asha" from the plains of Northern India, J. Essent. Oil Res. source

In the paper

“α-Pinene (347) [40,42,43] is the most abundant pinane monoterpene from A. annua (up to 10%) [33]”

What the sources say

• Not checked yetcites [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 yetcites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi
• Not checked yetcites [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 yetcites [33] Libbey, 1989, Unusual essential oils grown on Oregon II, Artemisia annua L. J. Essent. Oil Res. source

In the paper

“which can account for up to 10-30% of the essential oil [19,22,41,42]”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi
• Not checked yetcites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi

In the paper

“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”

What the sources say

• Not checked yetcites [32] Goel, 2007, Essential oils of petal, leaf and stem of the antimalarial plant Artemisia annua, J. Nat. Med. source
• Not checked yetcites [41] Hadjakhoondi, 2008, Chemical composition and antimicrobial activity of Artemisia annua L. essential oil from Iran, Fasinmah-i Giyahan-i-Daruyi
• Not checked yetcites [23] Tian, 2007, Study on volatile constituents of herba Artemisia annua and its preparation by GC-MS, Shizen Guoyi Guoyao

In the paper

“α-Pinene (347) is known in both its (+)- and (-)-enantiomeric forms from this species [37].”

What the sources say

• Not checked yetcites [37] Holm, 1997, Variation in the essential oil composition of Artemisia annua L. of different origin cutivated in Finland, Flavour Frag. J. source

In the paper

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

In the paper

“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”

In the paper

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

In the paper

“constituting up to 10% of the essential oil [19,27]”

What the sources say

• Not checked yetcites [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 yetcites [27] Goel, 2007, Composition of the essential oil from the root of Artemisia annua, J. Nat. Med. source

In the paper

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

In the paper

“A β-pinene synthase, which converts GPP to both (-)-α-pinene (347) and (-)-β-pinene (356), has recently been described from A. annua [131].”

What the sources say

• Not checked yetcites [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

In the paper

“Sesquiterpenoids (C15) constitute the most abundant and most diverse group of natural products from A. annua.”

In the paper

“β-Farnesene (382) is the most abundant member of this class of sesquiterpenes [22,43]”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [9] Brown, 2003, Terpenoids from the seeds of Artemisia annua, Phytochemistry source

In the paper

“Compound (395) ([24703-35-3]) is the only example of a bicyclogermacrane sesquiterpene so far described from A. annua [19,32,43,45,74].”

What the sources say

• Not checked yetcites [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 yetcites [32] Goel, 2007, Essential oils of petal, leaf and stem of the antimalarial plant Artemisia annua, J. Nat. Med. source
• Not checked yetcites [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 yetcites [45] Jain, 2002, Essential oil composition of Artemisia annua L. "Asha" from the plains of Northern India, J. Essent. Oil Res. source
• Not checked yetcites [74] Perazzo, 2003, Central properties of the essential oil and the crude ethanol extract from aerial parts of Artemisia annua L., Pharmacol. Res. source

In the paper

“and can constitute between 5-20% of the essential oil [19,42,43]”

What the sources say

• Not checked yetcites [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 yetcites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [134] Picaud, 2005, Expression, purification and characterization of recombinant amorpha-4,11-diene synthase from Artemisia annua L., Arch. Biochem. Biophys. source

In the paper

“β-Caryophyllene (405) is the most abundant member of this group of sesquiterpenes [26,37,40,43,46]”

What the sources say

• Not checked yetcites [26] Zhong, 1983, Studies of volatile constituents from Artemisia annua, Zhongyao Tongbao
• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [46] Yang, 2008, Investigation of essential oil from leaves of Artemisia annua L. in Guizhou, Shizen Guoyi Guoyao

In the paper

“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.”

In the paper

“This was interpreted as evidence that β-caryophyllene (405) might play a role in plant defense [139].”

What the sources say

• Not checked yetcites [139] Cai, 2002, A cDNA clone for β-caryophyllene synthase from Artermisia annua, Phytochemistry source

In the paper

“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].”

What the sources say

• Not checked yetcites [136] Picaud, 2006, Amorpha-4,11-diene synthase: mechanism and stereochemistry of the enzymatic cycization of farnesyl diphosphate, Arch. Biochem. Biophys. source

In the paper

“and can be found at levels of up to 5-10% of the total essential oil [19,22,42]”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [42] Lari, 2002, The composition of essential oil from Artemisia annua L. growing wild in Iran, Falsnamah-i-Giyahan-i Daruyi

In the paper

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

In the paper

“both of which are reported as natural products from A. annua [134] (Table 29).”

What the sources say

• Not checked yetcites [134] Picaud, 2005, Expression, purification and characterization of recombinant amorpha-4,11-diene synthase from Artemisia annua L., Arch. Biochem. Biophys. source

In the paper

“constituting up to 5% of the essential oil [28,46]”

What the sources say

• Not checked yetcites [28] Mukhtar, 2007, GC-MS analysis of volatile oil of aerial parts of Artemisia annua L., J. Essent. Oil-Bearing Plants source
• Not checked yetcites [46] Yang, 2008, Investigation of essential oil from leaves of Artemisia annua L. in Guizhou, Shizen Guoyi Guoyao

In the paper

“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].”

What the sources say

• Not checked yetcites [16] Buckingham, 2004, Introduction to the Type of Compound Index, Dictionary of Natural Products

In the paper

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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [155] Brown, 2007, In vivo transformations of artemisinic acid in Artemisia annua plants, Tetrahedron source

In the paper

“Artemisinin (495) is believed to be localized primarily within the glandular trichomes of A. annua, which are loosely attached to the leaf surface [244].”

What the sources say

• Not checked yetcites [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

In the paper

“and were amongst the first sesquiterpenes to be reported from A. annua.”

What the sources say

• Not checked yetcites [105] Zheng, 1994, Cytotoxic terpenoids and flavonoids from Artemisia annua, Planta Med. source
• Not checked yetcites [147] Tu, 1982, Studies on the constituents of Artemisia annua: 2, Planta Med. source
• Not checked yetcites [148] Misra, 1993, Crystal structure of artemisinic acid: A possible biogenetic precursor of antimalarial artemisinin from Artemisia annua, J. Nat. Prod. source
• Not checked yetcites [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 yetcites [150] Liu, 1979, Structure and reaction of arteannuin, Huaxue Xuebao

In the paper

“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]”

What the sources say

• Not checked yetcites [240] Woerdenbag, 1994, Artemisinin related sesquiterpenes, and essential oil in Artemisia annua during a vegetation period in Vietnam, Planta Med. source

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [213] Ayalp, 1990, Conversion of artemisinin to artemisitene, J. Nat. Prod. source
• Not checked yetcites [241] Ekthawatchai, 2003, An environmentally friendly, low cost, one-pot synthesis of artemisitene, Synth. Commun. source
• Not checked yetcites [242] Zhang, 1988, Structure and synthesis of arteannuin and related compounds. XXIV. Conversion of arteannuin into artemisitene, Youji Huaxue
• Not checked yetcites [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

In the paper

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