ANTITUMOR AGENTS - 183 - SYNTHESES, CONFORMATIONAL-ANALYSES, AND ANTITUBULIN ACTIVITY OF ALLOTHIOCOLCHICINOIDS

7-O-Substituted analogues of allothiocochicine were synthesized and ev aluated for their inhibitory effects on tubulin polymerization in vitr o. Ketone 6, a key compound in this study, was derived from thiocolchi cone 5 by ring contraction. The structure of 6 was determined from spe ctral data. Optically active alcohols 7a and 7b were obtained by reduc tion of ketone 6 followed by chemical resolution including a separatio n of the camphanate diastereomers 8a and 8b and basic hydrolysis. The aR,7R configuration of 8b was verified by X-ray crystallographic analy sis. Almost all compounds had strong inhibitory effects on the tubulin polymerization reaction, with IC50 values from 1.7 to 9.0 mu M. The c amphanates, cyclohexanates, and, most notably, the 7S-benzoate ester ( 10a), were inactive with IC50 values >40 mu M. Compounds 6 and 7a also showed potent antitumor activity with GI(50) values at nM concentrati on range for most cell lines in NCI's in vitro screening. Generally, t he 7S enantiomers of colchicinoids with a troplone C-ring showed great er activity than the 7R enantiomers. In the current allothiocolchicino id (with a benzenoid C-ring) study, only small differences occurred be tween the two active enantiomers of each pair. The acyl esters with a 7S configuration were slightly more active than the 7R isomers. Howeve r, the aroyl ester with a 7S configuration was less active than the 7R isomer. NMR, optical rotation, and molecular modeling studies reveale d 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 a n intensified rate.