Antitubulin effects of aminobenzothiophene-substituted triethylated chromones

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2731-2735. doi: 10.1016/j.bmcl.2017.04.055. Epub 2017 Apr 19.

Abstract

In the course of our continuing studies on the 2-(benzo[b]thiophene-3'-yl)-6,8,8-triethyldesmosdumotin B (TEDB-TB) series, we designed and synthesized nine amino-TEDB-TB derivatives to improve pharmaceutical properties, identify structure activity relationships, and discover novel antitubulin agents. Among all newly synthesized amino-TEDB-TBs, the 5'- and 6'-amino derivatives, 6 and 7, exhibited significant antiproliferative activity against five human tumor cell lines, including an MDR subline overexpressing P-gp. The IC50 values of 0.50-1.01µM were 3-6 times better than those of previously reported hydroxy-TEDB-TBs. Compounds 6 and 7 inhibited tubulin polymerization, induced both depolymerization of interphase microtubules and multiple spindle formations, and caused cell arrest at prometaphase. Among all compounds, compound 7 scored best pharmaceutically with LogP 2.11 and biologically with greater antiproliferative activity and induction of cell cycle arrest at prometaphase.

Keywords: Aminobenzothiophene; Antiproliferative activity; Antitubulin; Triethylated chromones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromones / chemical synthesis
  • Chromones / chemistry
  • Chromones / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Flavonoids / chemical synthesis
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • Humans
  • Molecular Structure
  • Polymerization / drug effects
  • Prometaphase / drug effects
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Tubulin / metabolism*
  • Tubulin Modulators

Substances

  • 2-(6'-aminobenzo(b)thiophen-3'-yl)-6,8,8-triethyldesmosdumotin B
  • Antineoplastic Agents
  • Chromones
  • Flavonoids
  • Thiophenes
  • Tubulin
  • Tubulin Modulators