A Synthetic Dolastatin 10 Analogue Suppresses Microtubule Dynamics, Inhibits Cell Proliferation, and Induces Apoptotic Cell Death

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• 作者：Praveen Kumar Gajula ; Jayant Asthana ; Dulal Panda ; Tushar Kanti Chakraborty
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2235-2245
• 全文大小：617K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

We have synthesized eight analogues (D1鈥?b>D8) of dolastatin 10 containing several unique amino acid subunits. Of these agents, D5 was found to be most effective in inhibiting both HeLa cell proliferation and microtubule assembly in vitro. At low nanomolar concentrations, D5 inhibited the proliferation of several types of cancer cells in culture. D5 bound to tubulin with a dissociation constant of 29.4 卤 6 渭M. D5 depolymerized microtubules in cultured cells and produced mulitpolar spindles. At its half-maximal inhibitory concentration (15 nM), D5 strongly suppressed the dynamics of individual microtubules in live MCF-7 cells. D5 increased the accumulation of checkpoint proteins BubR1 and Mad2 at the kinetochoric region and caused G2/M block in these cells. The blocked cells underwent apoptosis with the activation of Jun N-terminal kinase. The results suggested that D5 exerts its antiproliferative action by dampening microtubule dynamics.