A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20' urea derivatives.

Erick K Leggans, Katharine K Duncan, Timothy J Barker, Kristin D Schleicher, Dale L Boger

Journal of medicinal chemistry 2013 Feb 14

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A systematic series of previously inaccessible key C20' urea and thiourea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH(4)-mediated alkene functionalization reaction of anhydrovinblastine. Their examination defined key structural features of the urea-based analogues that contribute to their properties and provided derivatives that match or exceed the potency of vinblastine by as much as 10-fold in cell-based functional assays, which is directly related to their relative tubulin binding affinity. In contrast to expectations based on apparent steric constraints of the tubulin binding site surrounding the vinblastine C20' center depicted in an X-ray cocrystal structure, remarkably large C20' urea derivatives are accommodated.

Citation

Erick K Leggans, Katharine K Duncan, Timothy J Barker, Kristin D Schleicher, Dale L Boger. A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20' urea derivatives. Journal of medicinal chemistry. 2013 Feb 14;56(3):628-39