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Synthesis of novel tellurides bearing benzensulfonamide moiety as carbonic anhydrase inhibitors with antitumor activity
Structural highlights
DiseaseCAH2_HUMAN Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5] FunctionCAH2_HUMAN Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.[6] [7] Publication Abstract from PubMedWe have synthetized a novel series of beta-hydroxy tellurides bearing the benzenesulfonamide group as potent inhibitors of carbonic anhydrase enzymes. In a one pot procedure, we discovered both the ring opening reaction of the three-membered ring and the cleavage of the sulfonamide protecting moiety at the same time. Moreover, the first X-ray co-crystallographic structure of a beta-hydroxy telluride derivative with hCA II is reported. The potent effects of these compounds against the tumor-associated hCA IX with low nanomolar constant inhibition values give the possibility to evaluate their activity in vitro using a breast cancer cell line (MDA-MB-231). Compounds 7e and 7g induced significant toxic effects against tumor cells after 48h incubation in normoxic conditions killing over 50% of tumor cells at 3muM, but their efficacy decreased in hypoxic conditions reaching the 50% of the tumor cell viability only at 30muM. These unusual features make them interesting lead compounds to act as antitumor agents, not only as Carbonic Anhydrase IX inhibitors, but reasonably in different pathways, where hCA IX is not overexpressed. Synthesis of novel tellurides bearing benzensulfonamide moiety as carbonic anhydrase inhibitors with antitumor activity.,Tanini D, Ricci L, Capperucci A, Di Cesare Mannelli L, Ghelardini C, Peat TS, Carta F, Angeli A, Supuran CT Eur J Med Chem. 2019 Aug 5;181:111586. doi: 10.1016/j.ejmech.2019.111586. PMID:31401537[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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