A Remarkable Series of
Vinblastine Analogues Displaying Enhanced Activity and an Unprecedented
Tubulin Binding Steric Tolerance: C20′ Urea Derivatives
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Abstract
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<sub>4</sub>-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