Design, synthesis and evaluation of 4-substituted anthra[2,1-c][1,2,5]thiadiazole-6,11-dione derivatives as novel non-camptothecin topoisomerase I inhibitors

Bioorg Med Chem Lett. 2017 May 1;27(9):1929-1933. doi: 10.1016/j.bmcl.2017.03.039. Epub 2017 Mar 18.

Abstract

Previously, 4-tosylanthra[1,2-c][1,2,5]thiadiazole-6,11-dione (1) was identified as a novel non-camptothecin topoisomerase I (Top1) inhibitor by structure-based virtual screening. Herein, a series of 4-substituted derivatives were designed and synthesized. Most of them showed potent Top1 inhibitory activity. Their in vitro antiproliferative activity was also evaluated in A549, HCT-116 and ZR-75-30 human cancer cell lines. Compound 8s showed good antiproliferative activity with IC50 of 0.52μM and 0.42μM against HCT-116 and ZR-75-30 cell line, respectively. Top1 unwinding assay and molecular modeling studies rationalized the mode of action of this new class of inhibitors.

Keywords: Anthrathiadiazole; Antiproliferative activity; Structure-activity relationship; Topoisomerase I inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthraquinones / chemical synthesis
  • Anthraquinones / chemistry*
  • Anthraquinones / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Topoisomerases, Type I / metabolism
  • Drug Design
  • Humans
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / chemistry*
  • Thiadiazoles / pharmacology*
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / chemistry*
  • Topoisomerase I Inhibitors / pharmacology*

Substances

  • Anthraquinones
  • Antineoplastic Agents
  • Thiadiazoles
  • Topoisomerase I Inhibitors
  • anthra(2,1-c)(1,2,5)thiadiazole-6,11-dione
  • DNA Topoisomerases, Type I
  • TOP1 protein, human