2. Academic Validation
  3. Pyrrolo and pyrrolopyrimidine sulfonamides act as cytotoxic agents in hypoxia via inhibition of transmembrane carbonic anhydrases

Pyrrolo and pyrrolopyrimidine sulfonamides act as cytotoxic agents in hypoxia via inhibition of transmembrane carbonic anhydrases

  • Eur J Med Chem. 2020 Feb 15;188:112021. doi: 10.1016/j.ejmech.2019.112021.
Omneya M Khalil 1,  Aliaa M Kamal 2,  Silvia Bua 3,  Heba El Sayed Teba 4,  Yassin M Nissan 5,  Claudiu T Supuran 6
Affiliations

Affiliations

  • 1 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt.
  • 2 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt; Organic Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 11787, Giza, Egypt. Electronic address: alkama@msa.eun.eg.
  • 3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 4 Organic Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 11787, Giza, Egypt. Electronic address: hteba@msa.eun.eg.
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 11787, Giza, Egypt.
  • 6 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.
PMID: 31901743 DOI: 10.1016/j.ejmech.2019.112021
Abstract

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as Carbonic Anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human Carbonic Anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical Cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound 11b potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX.

Keywords

Carbonic anhydrase inhibitor; Cytotoxic; Pyrrolopyrimidine; Sulfonamide.

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