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

  • Bioorg Med Chem. 2012 Jul 15;20(14):4279-89. doi: 10.1016/j.bmc.2012.05.059.
Yuri Yamazaki  1 ,  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
Affiliations
  • 1. Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
PMID: 22727370 DOI: 10.1016/j.bmc.2012.05.059
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.