Synthesis of novel benzothiazole amides: Evaluation of PPAR activity and anti-proliferative effects in paraganglioma, pancreatic and colorectal cancer cell lines

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2302-2306. doi: 10.1016/j.bmcl.2019.06.020. Epub 2019 Jun 18.

Abstract

The reduced activation of PPARs has a positive impact on cancer cell growth and viability in multiple preclinical tumor models, suggesting a new therapeutic potential for PPAR antagonists. In the present study, the benzothiazole amides 2a-g were synthesized and their activities on PPARs were investigated. Transactivation assay showed a moderate activity of the novel compounds as PPARα antagonists. Notably, in cellular assays they exhibited cytotoxicity in pancreatic, colorectal and paraganglioma cancer cells overexpressing PPARα. In particular, compound 2b showed the most remarkable inhibition of viability (greater than 90%) in two paraganglioma cell lines, with IC50 values in the low micromolar range. In addition, 2b markedly impaired colony formation capacity in the same cells. Taken together, these results show a relevant anti-proliferative potential of compound 2b, which appears particularly effective in paraganglioma, a rare tumor poorly responsive to chemotherapy.

Keywords: Amides; Anti-proliferative; Benzothiazoles; Cytotoxicity; PPAR antagonists; Paraganglioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Peroxisome Proliferator-Activated Receptors / antagonists & inhibitors*
  • Peroxisome Proliferator-Activated Receptors / metabolism
  • Structure-Activity Relationship

Substances

  • Amides
  • Antineoplastic Agents
  • Benzothiazoles
  • Peroxisome Proliferator-Activated Receptors