Antitumor agents. 199. Three-dimensional quantitative structure-activity relationship study of the colchicine binding site ligands using comparative molecular field analysis

Inhibitors of tubulin polymerization interacting at the colchicine binding site are potential anticancer agents. We have been involved in the synthesi s of a number of colchicine site agents, such as thiocolchicinoids and allo colchicinoids, which are colchicine analogues, and 2-phenylquinolones and 2 -aryl-naphthyridinones, which are the amino analogue a of cytotoxic antimit otic flavonoids. The most cytotoxic of the latter compounds strongly inhibi t binding of radiolabeled colchicine to tubulin, and these agents therefore probably bind in the colchicine site of tubulin. We have applied conventio nal CoMFA and q(2)-GRS CoMFA to identify the essential structural requireme nts for increasing the ability of these compounds to form tubulin complexes . The CoMFA model for the training set of 51 compounds yielded cross-valida ted. R-2 (q(2)) values of 0.637 for conventional CoMFA and 0.692 for q(2)-G RS CoMFA. The predictive power of this model was confirmed by successful ac tivity prediction for a test set of 53 compounds with known potencies as in hibitors of tubulin polymerization. The activities of 88% of the compounds were predicted with absolute value of residuals of less than 0.5. The predi ctive q(2) values were 0.546 for conventional CoMFA and 0.426 for q(2)-GRS CoMFA. The conventional CoMFA model with the highest predictive q(2) (0.546 ) was analyzed in detail in terms of underlying structure-activity relation ships.