Synthesis and structure-activity relationships of benzophenone-bearing diketopiperazine-type anti-microtubule agents |
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Authors: | Yamazaki Yuri Sumikura Makiko Masuda Yurika Hayashi Yoshiki Yasui Hiroyuki Kiso Yoshiaki Chinen Takumi Usui Takeo Yakushiji Fumika Potts Barbara Neuteboom Saskia Palladino Michael Lloyd George Kenneth Hayashi Yoshio |
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Institution: | Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan. |
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Abstract: | 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 IC(50) value against HT-29 cells (IC(50)=0.5 nM). Next, the effect of 16j on mitotic spindles was evaluated in HeLa cells. Treatment with 3nM 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. |
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