CoChat
Sign Up
Cited by 37Drug Transport and Resistance MechanismsSynthesis and biological activityNatural product bioactivities and synthesis

Nitrogen-containing ecdysteroid derivatives vs. multi-drug resistance in cancer: Preparation and antitumor activity of oximes, oxime ethers and a lactam

Open access
Vágvölgyi, Máté, Martins, Ana, Kulmány, Ágnes, Zupkó, István, Gáti, Tamás, Simon, András, Tóth, Gábor, Hunyadi, Attila·2018·European Journal of Medicinal Chemistry
DOI 10.1016/j.ejmech.2017.12.032
Open this paper in CoChat — free accountOpen PDF

Abstract

Multidrug resistance is a widespread problem among various diseases and cancer is no exception. We had previously described the chemo-sensitizing activity of ecdysteroid derivatives with low polarity on drug susceptible and multi-drug resistant (MDR) cancer cells. We have also shown that these molecules have a marked selectivity towards the MDR cells. Recent studies on the oximation of various steroid derivatives indicated remarkable increase in their antitumor activity, but there is no related bioactivity data on ecdysteroid oximes. In our present study, 13 novel ecdysteroid derivatives (oximes, oxime ethers and a lactam) and one known compound were synthesized from 20-hydroxyecdysone 2,3;20,22-diacetonide and fully characterized by comprehensive NMR techniques revealing their complete 1 H and 13 C signal assignments. The compounds exerted moderate to strong in vitro antiproliferative activity on HeLa, SiHa, MCF-7 and MDA-MB-231 cell lines. Oxime and particularly oxime ether formation strongly increased their inhibitory activity on the efflux of rhodamine 123 by P-glycoprotein (P-gp), while the new ecdysteroid lactam did not interfere with the efflux function. All compounds exerted potent chemo-sensitizing activity towards doxorubicin on a mouse lymphoma cell line and on its MDR counterpart, and, on the latter, the lactam was found the most active. Because of its MDR-selective chemo-sensitizing activity with no functional effect on P-gp, this lactam is of high potential interest as a new lead for further antitumor studies.

AI snapshot

Written from the paper’s full text.

TL;DR

A series of 14 nitrogen-containing ecdysteroid derivatives (13 novel oximes, oxime ethers, and a lactam) was synthesized from 20-hydroxyecdysone 2,3;20,22-diacetonide and tested in vitro for antiproliferative, P-glycoprotein-inhibitory, and doxorubicin-chemosensitizing activities. The lactam 4 emerged as a promising MDR-selective chemosensitizer that sensitized MDR and non-MDR lymphoma cells to doxorubicin without inhibiting P-gp efflux.

Key findings

  • Thirteen novel derivatives plus one known compound were prepared; the t-butyl oxime ether 10 was stronger than cisplatin on HeLa and MDA-MB-231 cells (IC50 8.43 vs 14.02 on HeLa; 12.36 vs 18.65 on MDA-MB-231, units as reported). The paper notes parental compound 1 had IC50 values of 106.1 and 75.1 on MDA-MB-231 and MCF7, respectively, so certain oxime ether functions increased activity nearly an order of magnitude.
  • Oxime and especially oxime ether formation strongly increased inhibition of rhodamine 123 efflux by P-gp; the lactam 4 was the only compound completely inactive in this assay at as much as 20 mM concentration (Table 5 reports 4.27% ABCB1 inhibition at 20 mM).
  • All tested derivatives showed strong synergism with doxorubicin on the P-gp-expressing L5178 MDR cells (0.1 < CIavg < 0.3); lactam 4 gave the strongest MDR chemosensitization (CIavg 0.12) and also strong activity on non-MDR L5178 cells (CIavg 0.44) while not interfering with P-gp. Oximes 2 and 3 were the most cytotoxic on the lymphoma pair, with IC50 values ca. 4–5 times below compound 1, and E-oxime 2 was more cytotoxic than Z-oxime 3.

Methods

  • Synthesis: 20-hydroxyecdysone 2,3;20,22-diacetonide 1 was reacted with hydroxylamine or alkoxylamines in pyridine at 70 °C; Beckmann rearrangement of (6E)-oxime 2 with p-toluenesulfonyl chloride and Na2CO3 gave lactam 4. Products were characterized by comprehensive 1D/2D NMR, HR-HESI-MS, and RP-HPLC purity.
  • Bioassays: MTT antiproliferative assays on HeLa, SiHa, MCF-7, and MDA-MB-231 cells; MTT cytotoxicity on L5178 and L5178 MDR mouse lymphoma cells; rhodamine 123 accumulation by flow cytometry for ABCB1 inhibition; checkerboard microplate combination with doxorubicin, with combination indices calculated by CompuSyn.
  • Sample: 14 nitrogen-containing derivatives (compounds 2–15) plus parental compound 1; 13 were novel.

Limitations

  • The paper does not state a limitations section; evident from the text, all biological evaluation is in vitro (human gynecological cancer lines and a murine lymphoma pair), with no in vivo or clinical data.
  • Several compounds had IC50 >30 on multiple cell lines (e.g., 4 and 5 >30 on all four gynecological lines; 6 >30 on three), limiting conclusions about broad potency.
  • The paper itself notes that chemo-sensitizing activity had little if any correlation to P-gp inhibition, and that some SAR differences (e.g., Δ14,15 versus retained 14-OH on MDR sensitization) were small and hard to judge.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.ejmech.2017.12.032

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 16 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The values of δH-5 and δH-7 chemical shifts allow easy and unequivocal differentiation between the E and Z isomers.

    “Considering the data of Tables 2 and 3 it is clear that the values of dH-5 and dH-7 chemical shifts allow the easy and unequivocal differentiation between the E and Z isomers.”
    Quote in the paperNot a substantial claim
  • Findingown data

    A new t-butyl substituted ecdysteroid oxime ether (10) exerted a stronger antiproliferative effect on HeLa and MDA-MB-231 cells than cisplatin.

    “A new, t-butyl substituted ecdysteroid oxime ether (10) was found to exert stronger antiproliferative effect on HeLa and MDA-MB-231 cells than cisplatin.”
    Quote in the paperSubstantial claim
  • Findingown data

    Oxime ethers typically exerted weaker cytotoxic activities than non-substituted oximes, except compound 10.

    “The oxime ethers typically exerted weaker cytotoxic activities than the non-substituted oximes, with the exception of compound 10 where a bulky t-butyl substituent and a retained 14-OH group were present.”
    Quote in the paperNot a substantial claim
  • Findingown data

    14-OH elimination, forming a Δ14,15 double bond in the ecdysteroid D-ring, clearly increased ABCB1 inhibitory activity.

    “while the 14-OH elimination, forming a D 14,15 double bond in the ecdysteroid Dring, clearly increased this activity (compound 7 vs. 12, 9 vs. 13, and 10 vs. 15).”
    Quote in the paperSubstantial claim
  • Findingown data

    The retained 14-OH function is favorable over the Δ14,15 moiety for antiproliferative activity on the MCF-7 cell line.

    “It appears to be clear that the retained 14-OH function is favorable over the D 14,15 moiety in this regard on the MCF-7 cell line (compounds 7 vs. 12, 9 vs. 13, and 10 vs. 15)”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 18
  • May combine two claims. 20
  • The quote only partly states this claim. 4

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

    Findingown data

    Compound 8 was obtained in 15.5% yield with 98.3% RP-HPLC purity.

    “Compound 8: White solid; yield: 15.5% (34.05 mg); RP-HPLC purity: 98.3%; for 1 H and 13 C NMR data, see Tables 1 and 3, respectively; HR-HESI-MS: C 36 H 58 O 7 N, calcd.616.4208, found: 616.4201.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Compound 10 was obtained in 38.9% yield with 98.5% RP-HPLC purity.

    “Compound 10: White solid; yield: 38.9% (87.67 mg); RP-HPLC purity: 98.5%; for 1 H and 13 C NMR data, see Tables 1 and 3, respectively; HR-HESI-MS: C 37 H 62 O 7 N, calcd.632.4521, found: 632.4515.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Compound 9 was obtained in 1.6% yield with 99.6% RP-HPLC purity.

    “Compound 9: White solid; yield: 1.6% (3.5 mg); RP-HPLC purity: 99.6%; for 1 H and 13 C NMR data, see Tables 1 and 3, respectively; HR-HESI-MS: C 36 H 58 O 7 N, calcd.616.4208, found: 616.4200.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Compound 14 was obtained in 8.3% yield with 98.7% RP-HPLC purity.

    “White solid; yield: 8.3% (18.17 mg); RP-HPLC purity: 98.7%; for 1 H and 13 C NMR data, see Tables 2 and 3, respectively; HR-HESI-MS: C 37 H 60 O 6 N, calcd.614.4415, found: 614.4411.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Compound 6 was obtained in 15.2% yield with 99.6% RP-HPLC purity.

    “Compound 6: White solid; yield: 15.2% (32.75 mg); RP-HPLC purity: 99.6%; for 1 H and 13 C NMR data, see Tables 1 and 3, respectively; HR-HESI-MS: C 35 H 58 O 7 N, calcd.604.4208, found: 604.4198.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Compound 4 was obtained in 8% yield with 98.1% RP-HPLC purity.

    “Compound 4: White solid; yield: 8% (11.04 mg); RP-HPLC purity: 98.1%; for 1 H and 13 C NMR data, see Tables 2 and 3, respectively; HR-HESI-MS: C 33 H 52 O 6 N, calcd.558.3789, found: 558.3737.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Compound 12 was obtained in 33.3% yield with 97.5% RP-HPLC purity.

    “Compound 12: White solid; yield: 33.3% (69.59 mg); RP-HPLC purity: 97.5%; for 1 H and 13 C NMR data, see Tables 2 and 3, respectively; HR-HESI-MS: C 35 H 56 O 6 N, calcd.586.4102, found: 586.4099.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Compound 5 was obtained in 28.3% yield with 99.8% RP-HPLC purity.

    “Compound 5: White solid; yield: 28.3% (59.53 mg); RP-HPLC purity: 99.8%; for 1 H and 13 C NMR data, see Tables 1 and 3, respectively; HR-HESI-MS: C 34 H 56 O 7 N, calcd.590.4051, found: 590.4045.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Oximes 2 and 3 showed the strongest activity on either cell line with IC50 values about 4-5 times below that of compound 1.

    “The oximes 2 and 3 showed the strongest activity on either cell lines with IC 50 values ca.4e5 times below that of compound 1”
    Quote in the paperSubstantial claim

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

    Findingown data

    A complete 1H signal assignment was achieved for all compounds.

    “Thanks to the comprehensive one-and two-dimensional NMR techniques utilized in the structure elucidation process, a complete 1 H signal assignment could be achieved for all compounds.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Lactam derivative (4) was the only compound completely inactive in the rhodamine accumulation assay at as much as 20 μM concentration.

    “Evaluation of the results obtained from the rhodamine accumulation assay reveals that the lactam derivative (4) is the only one among the compounds that was completely inactive in this regard at as much as 20 mM concentration.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Compound 7 was obtained in 2.8% yield with 98.7% RP-HPLC purity.

    “Compound 7: White solid; yield: 2.8% (6.06 mg); RP-HPLC purity: 98.7%; for 1 H and 13 C NMR data, see Tables 1 and 3, respectively; HR-HESI-MS: C 35 H 58 O 7 N, calcd.604.4208, found: 604.4199.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among all derivatives, lactam 4 expressed the strongest chemosensitization on MDR cells, while being the only one to show no interference with P-gp function.

    “Most interestingly, among all derivatives obtained, the ecdysteroid lactam 4 was found to express the strongest chemosensitization on the MDR cells, while being the only one to show no interference with P-gp function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In compound 4, a significant paramagnetic shift on δC-5 proves the nitrogen atom is coupled to C-5, and the signal at 170.6 ppm supports formation of the lactam ring.

    “Indeed, the significant (13.1 ppm) paramagnetic shift on dC-5 proves that in 4 the nitrogen atom coupled to C-5, the appearance of the signal at 170.6 ppm supports the formation of the lactam ring.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Compound 13 was obtained in 2% yield with 98.3% RP-HPLC purity.

    “Compound 13: White solid; yield: 2% (4.25 mg); RP-HPLC purity: 98.3%; for 1 H and 13 C NMR data, see Tables 2 and 3, respectively; HR-HESI-MS: C 36 H 56 O 6 N, calcd.598.4102, found: 598.4094.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The synthesized compounds were fully characterized by comprehensive NMR techniques revealing complete 1H and 13C signal assignments.

    “and fully characterized by comprehensive NMR techniques revealing their complete 1 H and 13 C signal assignments.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Compound 11 was obtained in 43.3% yield with 97.7% RP-HPLC purity.

    “Compound 11: White solid; yield: 43.3% (88.32 mg); RP-HPLC purity: 97.7%; for 1 H and 13 C NMR data, see Tables 2 and 3, respectively; HR-HESI-MS: C 34 H 54 O 6 N, calcd.572.3946, found: 572.3937.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All oxime derivatives in Table 1 with δC-5 ~38.6 and δC-7 ~117.5 ppm are Z isomers, while δC-5 ~43.8 and δC-7 ~111.0 ppm assign E isomers.

    “On the basis of our data, all of the oxime derivatives in Table 1 with dC-5 ~38.6 and dC-7 ~117.5 ppm values, respectively, are Z isomers, while dC-5 ~43.8 and dC-7 ~111.0 ppm values assign the E isomers.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Oximation of ketones is accompanied by characteristic changes of several 13C and 1H chemical shifts.
    • Rests on an assumption: The Δδ syn-anti parameters on C-5 and =C-7 signals can be utilized for assignment of (Z/E) isomers.

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

    Findingown data

    Compound 15 was obtained in 2.5% yield with 95.8% RP-HPLC purity.

    “Compound 15: White solid; yield: 2.5% (5.48 mg); RP-HPLC purity: 95.8%; for 1 H and 13 C NMR data, see Tables 2 and 3, respectively; HR-HESI-MS: C 37 H 60 O 6 N, calcd.614.4415, found: 614.4407.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Doxorubicin had IC50 0.080 μM on L5178 and 4.49 μM on L5178 MDR.

    “Dox | e | e | 0.080 [0.053e0.12] | 4.49 [3.43e5.89] | e | e”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Compound 13 at 20 μM inhibited ABCB1 by 102.7%.

    “13 | (Z); R ¼ Allyl | D 14,15 | 55.28 [46.21e66.13] | 52.72 [39.97e65.53] | 61.13 | 102.7”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Compound 12 at 20 μM inhibited ABCB1 by 107.7%.

    “12 | (Z); R ¼ Et | D 14,15 | 53.20 [38.64e73.26] | 58.94 [45.86e75.74] | 56.41 | 107.7”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The structure and NMR signals of the products were assigned by comprehensive one- and two-dimensional NMR methods.

    “The structure and NMR signals of the products were assigned by comprehensive one-and two-dimensional NMR methods, such as 1 H, 13 C, DEPTQ, gradient-selected COSY, edited HSQC, HMBC, ROESY (Rotating frame Overhauser Enchancement Spectroscopy) spectra and 1D-selective variants thereof.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Ecdysteroids are a,b-unsaturated 6-ketosteroids that occur in a wide range of plant species and are analogs of the insect molting hormone ecdysone.

    “Ecdysteroids are a,b-unsaturated 6-ketosteroids that occur in a wide range of plant species; as analogs of the insect molting hormone ecdysone, these compounds possess several biological functions in the flora and the fauna [11,12].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Dinan, 2001, Phytochemistry source

      Not checked in the free run.

    • cites [12] Dinan, 2009, Arch. Insect Biochem. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxidative side-chain cleavage of ecdysteroids knocks out inhibitory activity on efflux function of ABCB1 (P-gp) while maintaining MDR-selective sensitizing activity towards doxorubicin.

    “2) an oxidative side-chain cleavage knocks out the inhibitory activity on the efflux function of the ABCB1 transporter (P-glycoprotein; P-gp) while maintaining MDR selective sensitizing activity towards doxorubicin [20].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Hunyadi, 2017, Molecules source

      Not checked in the free run.

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

    Premisecitation

    Galyautdinov et al. previously reported successful preparation of several (E/Z)-isomeric ecdysteroid 6-oxime and some lactam derivatives.

    “Galyautdinov et al. have previously reported the successful preparation of several (E/Z)-isomeric ecdysteroid 6-oxime and some lactam derivatives [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Galyautdinov, 2006, Russ. J. Org. Chem. source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premiseown data

    Ecdysteroid derivatives with low polarity have marked selectivity towards MDR cancer cells.

    “We have also shown that these molecules have a marked selectivity towards the MDR cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The novel Δ14,15 δ-lactam ecdysteroid derivative (4) is a most promising new lead compound with low intrinsic cytotoxicity and strong ability to sensitize MDR and non-MDR cancer cells towards doxorubicin without interfering with P-gp efflux.

    “In particularly, a novel D 14,15 d-lactam ecdysteroid derivative (4) was revealed as a most promising new lead compound with low intrinsic cytotoxicity, and strong ability to sensitize MDR and also non-MDR cancer cells towards doxorubicin without interfering with the efflux function of P-gp.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To avoid solvent ambiguity, NMR experiments were performed exclusively in methanol-d4.

    “To avoid this ambiguity, we have performed our NMR experiments exclusively in methanol-d 4 .”
    Quote in the paperSubstantial claim
29 of 29

  • The paper relies on this without support.

    No studies are available on the bioactivity of ecdysteroid oximes or lactams.

    “there is no related bioactivity data on ecdysteroid oximes.”
    “Considering the above mentioned antitumor potential of steroidal oximes and the fact that no studies are available on the bioactivity of ecdysteroid oximes or lactams, the aim of the present work was to prepare a series of such compounds, and study their in vitro antitumor potential with a focus on their chemo-sensitizing activity.”

  • The paper relies on this without support.

    Oximation of ketones is accompanied by characteristic changes of several 13C and 1H chemical shifts.

    “It is well known that oximation of ketones is accompanied with characteristic changes of several 13 C and 1 H chemical shifts.”

  • The paper relies on this without support.

    The Δδ syn-anti parameters on C-5 and =C-7 signals can be utilized for assignment of (Z/E) isomers.

    “The significant (Dd syn-anti) parameters on C-5 and ¼C-7 signals successfully can be utilized for the assignment of (Z/E) isomers.”
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.

  • The stated replacement of H2-16 conflicts with the NMR tables

    Minor

    The text says the H-15 olefinic signal appears instead of H2-16 signals. Both Table 2 and Table 3 list two H-16 signals; it is the two H-15 signals in Table 3 that are replaced by one H-15 signal in Table 2.

  • Compound descriptions cite the wrong carbon-NMR table

    Minor

    The descriptions of compounds 4 and 11-15 direct readers to Tables 2 and 3 for proton and carbon NMR data, respectively. Table 3 contains proton data for compounds 5-10; their carbon data are in Table 1.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Martins, 2015, BioMed Res. Int.

Cited by

Sorted by citations

Related

Authors
Vágvölgyi, M., Martins, A., Kulmány, Á., Zupkó, I., Gáti, T., Simon, A., Tóth, G., & Hunyadi, A.
Affiliations
  • University of Szeged (HU)
  • Budapest University of Technology and Economics (HU)
Corresponding author
Hunyadi, Attila
ORCID
Venue
European Journal of Medicinal Chemistry
Publisher
Elsevier BV
Published
2018-01
Volume
144
Pages
730-739
ISSN
0223-5234 (ISSN-L)
DOI
10.1016/j.ejmech.2017.12.032
OpenAlex
W2773543372
Cited by
37
References
32
Citations by year
2025: 3 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 3
FWCI
1.33
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • European Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion, other-oa)
  • Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
Funders
  • National Research, Development and Innovation Office, Hungary (K119770, K109293)
  • Hungarian Academy of Sciences
  • Kálmán Szász Prize
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
Keywords
multidrug resistance, oximes, oxime ethers, lactams, 20-hydroxyecdysone, P-glycoprotein, chemosensitization, doxorubicin, anticancer activity, antiproliferative activity, rhodamine 123 efflux
MeSH terms
Antineoplastic Agents, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Ethers, Humans, Lactams, Neoplasms, Nitrogen, Oximes, Structure-Activity Relationship, Tumor Cells, Cultured, Molecular Structure, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Ecdysteroids, Cell Proliferation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review