Structural analysis of the substoichiometric and stoichiometric microtuble-inhibiting biphenyl analogues 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 (TMB), were solved by X-ray diffraction. Their comparison with the structure of colchicine indicated the ability of both compounds to enter into a colchicine binding pocket. Comparison of TKB with 2,3,4-trimethoxy-4'-carbomethoxy-1,1'-biphenyl (TCB) showed that the methyl group of the carbomethoxy group in position 4' of TCB protrudes beyond the (C=O)-CH3 group in the same position in TKB. Superposition of both structures on the van der Waals surface of COL clearly demonstrates that TKB can fully fit within that domain, while the CH3 group of TCB protrudes beyond the COL contour. This is proposed to be the source of the inability of TCB to inhibit microtubule assembly substoichiometrically, while TKB is a very strong inhibitor. While the same steric hindrance to entering into the COL site on tubulin must exist in allocolchicine (ALLO), in its case, this is overcome by the rigidity of the three-ring structure which abolishes the loss on binding of the entropy of free rotation between the two rings of the biphenyl TCB.
Rossi
M
M
Graduate Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02254, USA.
Gorbunoff
M J
MJ
Caruso
F
F
Wing
B
B
Perez-Ramirez
B
B
Timasheff
S N
SN
D001713:Biphenyl Compounds / Q000737:chemistry*; D003078:Colchicine / Q000031:analogs & derivatives*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D008870:Microtubules / Q000187:drug effects; D008958:Models, Molecular
D001713:Biphenyl Compounds; C098547:2,3,4-trimethoxy-4'-acetyl-1,1'-biphenyl; C060033:2,3,4,4'-tetramethoxy-1,1'-biphenyl; D003078:Colchicine