A/C-Ring Colchicine Analogues: a Comparison of Molecular Conformations of the Minimized and Crystal Structures

Abstract

Molecular mechanics and molecular orbital calculations have been used to determine the low-energy conformations of six biaryl analogues of colchicine lacking the seven-membered B-ring. A comparison of the conformations resulting from the different minimizations has been made, and these conformations were also compared with those found in the solid state for the respective biaryl analogues and the A/C-ring systems of colchicine and isocolchicine. The barriers to rotation about the A/C-linkage of the analogues were estimated from rotational plots. The MM+ calculations were not satisfactory for estimating the barriers, whilst the MMX, MAXIMIN2 and AM1 values, although agreeing on average only to within 16 kJ mol^-1 , exhibited the expected trend in magnitude. This trend, however, did not correlate with the inhibition of tubulin polymerization to microtubules.