STEREOCHEMISTRY OF COLCHICINOIDS - ENANTIOMERIC STABILITY AND BINDING TO TUBULIN OF DESACETAMIDOCOLCHICINE AND DESACETAMIDOISOCOLCHICINE

Desacetamidocolchicine (3) and desacetamidoisocolchicine (4) have been chromatographically resolved into enantiomers. Thermal racemization gives inversion barriers of 22.1 and 23.4 kcal mol-1, respectively, for rotation around the bond joining the two aromatic rings. Kinetic binding experiments show that the enantiomer of 3 with the same helicity as native colchicine binds approximately 62 times as fast as colchicine to tubulin whereas the other enantiomer and both enantiomers of 4 do not bind. With molecular mechanics computations both the structures and the rotational barriers are reproduced, provided that the MM2(1985) force field, which gives stiffer aromatic rings than earlier force fields, is used. © 1991.