Pyrrolo and pyrrolopyrimidine sulfonamides act as cytotoxic agents in hypoxia via inhibition of transmembrane carbonic anhydrases.
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.
['Khalil|Omneya M|OM|', 'Kamal|Aliaa M|AM|', 'Bua|Silvia|S|', 'El Sayed Teba|Heba|H|', 'Nissan|Yassin M|YM|', 'Supuran|Claudiu T|CT|']
D000951:Antigens, Neoplasm D000970:Antineoplastic Agents D000071231:Carbonic Anhydrase IX D002257:Carbonic Anhydrase Inhibitors D020134:Catalytic Domain D004354:Drug Screening Assays, Antitumor D006367:HeLa Cells D006801:Humans D062105:Molecular Docking Simulation D011743:Pyrimidines D011758:Pyrroles D013449:Sulfonamides
Pyrrolopyrimidine Sulfonamide Cytotoxic Carbonic anhydrase inhibitor