Organoruthenium(II) complexes of acetazolamide potently inhibit human carbonic anhydrase isoforms I, II, IX and XII

J Enzyme Inhib Med Chem. 2019 Dec;34(1):388-393. doi: 10.1080/14756366.2018.1547288.

Abstract

Two acetazolamide (AAZ) complexes with ruthenium(II) η6-p-cymene chloride were synthesised, characterised and tested for their inhibitory effects on several carbonic anhydrase (CA, EC 4.2.1.1) isoforms with pharmacological applications. Against human (h) isoform hCA I, the two complexes showed inhibition constants in the range of 8.5-23.4 nM (AAZ has a KI of 250 nM), against hCA II of 0.48-4.2 nM, whereas against hCA IX of 0.63-3.8 nM and against hCA XII of 0.04-0.52 nM, respectively. These highly effective ruthenium acetazolamide derivatives against the tumour-associated CA isoforms IX and XII warrant further in vivo studies, in hypoxic tumours overexpressing these enzymes.

Keywords: Carbonic anhydrase; Ru(II); acetazolamide; human isoforms; metal complex.

MeSH terms

  • Acetazolamide / chemistry
  • Acetazolamide / pharmacology*
  • Antigens, Neoplasm
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase I / metabolism
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase IX / antagonists & inhibitors
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Organometallic Compounds / chemical synthesis
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology*
  • Ruthenium / chemistry
  • Ruthenium / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antigens, Neoplasm
  • Carbonic Anhydrase Inhibitors
  • Organometallic Compounds
  • Ruthenium
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • carbonic anhydrase XII
  • Acetazolamide

Grants and funding

This work was supported by the Slovenian Research Agency [P-0175].