Pyrrolo and pyrrolopyrimidine sulfonamides act as cytotoxic agents in hypoxia via inhibition of transmembrane carbonic anhydrases
| Autor: | Heba El Sayed Teba, Aliaa M. Kamal, Claudiu T. Supuran, Silvia Bua, Omneya M. Khalil, Yassin M. Nissan |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Gene isoform
medicine.drug_class Antineoplastic Agents 01 natural sciences HeLa 03 medical and health sciences Antigens Neoplasm Carbonic anhydrase Catalytic Domain Drug Discovery medicine Potency Cytotoxic T cell Humans Carbonic anhydrase inhibitor Pyrroles Cytotoxicity Carbonic Anhydrase IX Carbonic Anhydrase Inhibitors 030304 developmental biology Pharmacology 0303 health sciences Sulfonamides biology 010405 organic chemistry Chemistry Organic Chemistry General Medicine biology.organism_classification 0104 chemical sciences Molecular Docking Simulation Pyrimidines Biochemistry biology.protein Drug Screening Assays Antitumor Acetazolamide medicine.drug HeLa Cells |
| Zdroj: | European journal of medicinal chemistry. 188 |
| ISSN: | 1768-3254 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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