Synthesis and biological evaluation of nitric oxide-donating analogues of sulindac for prostate cancer treatment

Bioorg Med Chem. 2014 Jan 15;22(2):756-61. doi: 10.1016/j.bmc.2013.12.014. Epub 2013 Dec 12.

Abstract

A series of analogues of the non-steroidal anti-inflammatory drug (NSAID) sulindac 1 were synthesised tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliterative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate esters, furoxans and sydnonimines. To explore this approach further, a total of fifty-six sulindac-NO analogues were prepared and they were evaluated as NO-releasing cytotoxic agents against prostate cancer (PCa) cell lines. Compounds 1k and 1n exhibited significant cytotoxic with IC50 values of 6.1±4.1 and 12.1±3.2μM, respectively, coupled with observed nitric oxide release.

Keywords: Furoxan; Nitric oxide; Prostate cancer; Sulindac analogues; Sydnonimine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Male
  • Molecular Structure
  • Nitric Oxide / chemistry*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Structure-Activity Relationship
  • Sulindac / chemical synthesis
  • Sulindac / chemistry
  • Sulindac / pharmacology*

Substances

  • Antineoplastic Agents
  • Sulindac
  • Nitric Oxide