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Antitumor Agents. 183. Syntheses, Conformational Analyses, and Antitubulin Activity of Allothiocolchicinoids

Publication ,  Journal Article
Shi, Q; Chen, K; Chen, X; Brossi, A; Verdier-Pinard, P; Hamel, E; McPhail, AT; Tropsha, A; Lee, KH
Published in: Journal of Organic Chemistry
June 12, 1998

7-O-Substituted analogues of allothiocochicine were synthesized and evaluated for their inhibitory effects on tubulin polymerization in vitro. Ketone 6, a key compound in this study, was derived from thiocolchicone 5 by ring contraction. The structure of 6 was determined from spectral data. Optically active alcohols 7a and 7b were obtained by reduction of ketone 6 followed by chemical resolution including a separation of the camphanate diastereomers 8a and 8b and basic hydrolysis. The aR,7R configuration of 8b was verified by X-ray crystallographic analysis. Almost all compounds had strong inhibitory effects on the tubulin polymerization reaction, with IC50 values from 1.7 to 9.0 μM. The camphanates, cyclohexanates, and, most notably, the 7S-benzoate ester (10a), were inactive with IC50 values >40 μM. Compounds 6 and 7a also showed potent antitumor activity with GI50 values at nM concentration range for most cell lines in NCI's in vitro screening. Generally, the 7S enantiomers of colchicinoids with a troplone C-ring showed greater activity than the 7R enantiomers. In the current allothiocolchicinoid (with a benzenoid C-ring) study, only small differences occurred between the two active enantiomers of each pair. The acyl esters with a 7S configuration were slightly more active than the 7R isomers. However, the aroyl ester with a 7S configuration was less active than the 7R isomer. NMR, optical rotation, and molecular modeling studies revealed two conformers in a solvent-dependent equilibrium for both 7S and 7R isomers. In polar solvents, the molecular chirality in esters with a 7-O-aroyl substituent was reversed from aS to aR or from aR to aS at an intensified rate.

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Published In

Journal of Organic Chemistry

DOI

ISSN

0022-3263

Publication Date

June 12, 1998

Volume

63

Issue

12

Start / End Page

4018 / 4025

Related Subject Headings

  • Organic Chemistry
  • 3405 Organic chemistry
  • 3404 Medicinal and biomolecular chemistry
  • 0305 Organic Chemistry
  • 0304 Medicinal and Biomolecular Chemistry
 

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Shi, Q., Chen, K., Chen, X., Brossi, A., Verdier-Pinard, P., Hamel, E., … Lee, K. H. (1998). Antitumor Agents. 183. Syntheses, Conformational Analyses, and Antitubulin Activity of Allothiocolchicinoids. Journal of Organic Chemistry, 63(12), 4018–4025. https://doi.org/10.1021/jo980073p
Shi, Q., K. Chen, X. Chen, A. Brossi, P. Verdier-Pinard, E. Hamel, A. T. McPhail, A. Tropsha, and K. H. Lee. “Antitumor Agents. 183. Syntheses, Conformational Analyses, and Antitubulin Activity of Allothiocolchicinoids.” Journal of Organic Chemistry 63, no. 12 (June 12, 1998): 4018–25. https://doi.org/10.1021/jo980073p.
Shi Q, Chen K, Chen X, Brossi A, Verdier-Pinard P, Hamel E, et al. Antitumor Agents. 183. Syntheses, Conformational Analyses, and Antitubulin Activity of Allothiocolchicinoids. Journal of Organic Chemistry. 1998 Jun 12;63(12):4018–25.
Shi, Q., et al. “Antitumor Agents. 183. Syntheses, Conformational Analyses, and Antitubulin Activity of Allothiocolchicinoids.” Journal of Organic Chemistry, vol. 63, no. 12, June 1998, pp. 4018–25. Scopus, doi:10.1021/jo980073p.
Shi Q, Chen K, Chen X, Brossi A, Verdier-Pinard P, Hamel E, McPhail AT, Tropsha A, Lee KH. Antitumor Agents. 183. Syntheses, Conformational Analyses, and Antitubulin Activity of Allothiocolchicinoids. Journal of Organic Chemistry. 1998 Jun 12;63(12):4018–4025.
Journal cover image

Published In

Journal of Organic Chemistry

DOI

ISSN

0022-3263

Publication Date

June 12, 1998

Volume

63

Issue

12

Start / End Page

4018 / 4025

Related Subject Headings

  • Organic Chemistry
  • 3405 Organic chemistry
  • 3404 Medicinal and biomolecular chemistry
  • 0305 Organic Chemistry
  • 0304 Medicinal and Biomolecular Chemistry