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. Epub 2012 Jun 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / toxicity
  • Benzophenones / chemical synthesis
  • Benzophenones / chemistry*
  • Cell Proliferation / drug effects
  • Colchicine / chemistry
  • Crystallography, X-Ray
  • Diketopiperazines / chemical synthesis
  • Diketopiperazines / chemistry*
  • Diketopiperazines / toxicity
  • HT29 Cells
  • HeLa Cells
  • Humans
  • Microtubules / chemistry*
  • Microtubules / metabolism
  • Molecular Conformation
  • Structure-Activity Relationship
  • Tubulin Modulators / chemical synthesis*
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / toxicity

Substances

  • Antineoplastic Agents
  • Benzophenones
  • Diketopiperazines
  • Tubulin Modulators
  • benzophenone
  • Colchicine