Synthesis and structure-activity relationships of benzophenone-bearing diketopiperazine-type anti-microtubule agents

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• 作者：Yuri Yamazaki ; Makiko Sumikura ; Yurika Masuda ; Yoshiki Hayashi ; Hiroyuki Yasui ; Yoshiaki Kiso ; Takumi Chinen ; Takeo Usui ; Fumika Yakushiji ; Barbara Potts ; Saskia Neuteboom ; Michael Palladino ; George Kenneth Lloyd ; Yoshio Hayashi
• 关键词：Anticancer drug ; Benzophenone ; Diketopiperazine ; Microtubule depolymerizing activity ; Vascular disrupting agent
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：15 July, 2012
• 年：2012
• 卷：20
• 期：14
• 页码：4279-4289
• 全文大小：1040 K

文摘

KPU-105 (4), a potent anti-microtubule agent that contains a benzophenone was derived from the diketopiperazine-type vascular disrupting agent (VDA) plinabulin 3, which displays colchicine-like tubulin depolymerization activity. To develop derivatives with more potent anti-microtubule and cytotoxic activities, we further modified the benzophenone moiety of 4. Accordingly, we obtained a 4-fluorobenzophenone derivative 16j that inhibited tumor cell growth in vitro with a subnanomolar IC₅₀ value against HT-29 cells (IC₅₀ = 0.5 nM). Next, the effect of 16j on mitotic spindles was evaluated in HeLa cells. Treatment with 3 nM of 16j partially disrupted the interphase microtubule network. By contrast, treatment with the same concentration of CA-4 barely affected the microtubule network, indicating that 16j exhibited more potent anti-mitotic effects than did CA-4.