STRUCTURAL-ANALYSIS OF THE SUBSTOICHIOMETRIC AND STOICHIOMETRIC MICROTUBULE-INHIBITING BIPHENYL ANALOGS OF COLCHICINE

The structures of the colchicine (COL) analogues, 2,3,4-trimethoxy-4'- acetyl-1,1'-biphenyl (TKB) and 2,3,4,4'-tetramethoxy-1,1'-biphenyl (TM B), were solved by X-ray diffraction. Their comparison with the struct ure of colchicine indicated the ability of both compounds to enter int o a colchicine binding pocket. Comparison of TKB with 2,3,4-trimethoxy -4'-carbomethoxy-1,1'-biphenyl (TCB) showed that the methyl group of t he carbomethoxy group in position 4' of TCB protrudes beyond the (C=O) -CH3 group in the same position in TKB. Superposition of both structur es on the van der Waals surface of COL clearly demonstrates that TKB c an fully fit within that domain, while the CH3 group of TCB provides b eyond the COL contour. This is proposed to be the source of the inabil ity of TCB to inhibit microtubule assembly substoichiometrically, whil e TKB is a very strong inhibitor, While the same steric hindrance to e ntering into the COL site on tubulin must exist in allocolchicine (ALL O), in its case, this is overcome by the rigidity of the three-ring st ructure which abolishes the loss on binding of the entropy of free rot ation between the two rings of the biphenyl TCB.