8co3
Three dimensional structure of human carbonic anhydrase XII in complex with sulfonamide
Structural highlights
DiseaseCAH12_HUMAN Defects in CA12 are the cause of hyperchlorhidrosis isolated (HCHLH) [MIM:143860. HCHLH is a disorder characterized by excessive sweating and increased sweat chloride levels. Affected individuals suffer from episodes of hyponatremic dehydration and report increased amounts of visible salt precipitates in sweat.[1] FunctionCAH12_HUMAN Reversible hydration of carbon dioxide. Publication Abstract from PubMedHere, we report for the first time a series of sulfonamide derivatives with scaffolds bearing flexible moieties, namely, rotamers or tropoisomers capable of adapting their geometry in the active center of enzymes thus being effective and selective carbonic anhydrase (CAs, EC 4.2.1.1) enzyme inhibitors. All compounds exhibited effective in vitro inhibition activity toward the main hCA isoforms related to cancer (i.e., hCA II, hCA IX, and hCA XII with K(I) values in the low nanomolar range). Three selected compounds showed a great cytotoxic effect on cancer cell lines ex vivo. X-ray crystallographic experiments assessed the binding modes of compound 35 with active centers of hCA IX and hCA XII. Atropo/Tropo Flexibility: A Tool for Design and Synthesis of Self-Adaptable Inhibitors of Carbonic Anhydrases and Their Antiproliferative Effect.,Ivanova JN, Nocentini A, Ta Rs K, Leita Ns JN, Dvinskis E, Kazaks A, Domraceva I, Supuran CT, Zalubovskis R J Med Chem. 2023 Apr 27;66(8):5703-5718. doi: 10.1021/acs.jmedchem.3c00007. Epub , 2023 Apr 6. PMID:37022308[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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