Carbonic anhydrase inhibitors based on sorafenib scaffold: Design, synthesis, crystallographic investigation and effects on primary breast cancer cells

Eur J Med Chem. 2019 Nov 15:182:111600. doi: 10.1016/j.ejmech.2019.111600. Epub 2019 Aug 7.

Abstract

Carbonic anhydrase inhibitors (CAIs) of the sulfonamide, sulfamate and coumarin classes bearing the phenylureido tail found in the clinically used drug Sorafenib, a multikinase inhibitor actually used for the management of hepatocellular carcinomas, are reported. All compounds were assayed on human (h) CA isoforms I, II, VII and IX, involved in various pathologies. Among the sulfonamides, several compounds were selective for inhibiting hCA IX, with KI values in the low nanomolar ranges (i.e. 0.7-30.2 nM). We explored the binding modes of such compounds by means of X-ray crystallographic studies on isoform hCA I in adduct with one sulfonamide and a sulfamate inhibitor. Antiproliferative properties of some sulfamates on breast tumor cell lines were also investigated.

Keywords: Carbonic anhydrase; Coumarin; Enzyme inhibitor; Sorafenib; Sulfamate; Sulfonamide.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Sorafenib / chemical synthesis
  • Sorafenib / chemistry
  • Sorafenib / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Carbonic Anhydrase Inhibitors
  • Sorafenib