A C-RING COLCHICINE ANALOGS - A COMPARISON OF MOLECULAR-CONFORMATIONSOF THE MINIMIZED AND CRYSTAL-STRUCTURES/

Molecular mechanics and molecular orbital calculations have been used to determine the low-energy conformations of six biaryl analogues of c olchicine lacking the seven-membered B-ring. A comparison of the confo rmations 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-l inkage of the analogues were estimated from rotational plots. The MMcalculations were not satisfactory for estimating the barriers, whilst the MMX, MAXIMIN2 and AM1 values, although agreeing on average only t o within 16 kJ mol(-1), exhibited the expected trend in magnitude. Thi s trend, however, did not correlate with the inhibition of tubulin pol ymerization to microtubules.