A Remarkable Series of Vinblastine Analogues Displaying Enhanced Activity and an Unprecedented Tubulin Binding Steric Tolerance: C20鈥?Urea Derivatives

详细信息    查看全文

• 作者：Erick K. Leggans ; Katharine K. Duncan ; Timothy J. Barker ; Kristin D. Schleicher ; Dale L. Boger
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：628-639
• 全文大小：554K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

A systematic series of previously inaccessible key C20鈥?urea and thiourea derivatives of vinblastine were prepared from 20鈥?aminovinblastine that was made accessible through a unique Fe(III)/NaBH₄-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鈥?center depicted in an X-ray cocrystal structure, remarkably large C20鈥?urea derivatives are accommodated.