Krymov Stepan K, Scherbakov Alexander M, Dezhenkova Lyubov G, Salnikova Diana I, Solov'eva Svetlana E, Sorokin Danila V, Vullo Daniela, De Luca Viviana, Capasso Clemente, Supuran Claudiu T, Shchekotikhin Andrey E
Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, 119021 Moscow, Russia.
Department of Experimental Tumor Biology, Blokhin N.N. National Medical Research Center of Oncology, 115522 Moscow, Russia.
Pharmaceuticals (Basel). 2022 Nov 23;15(12):1453. doi: 10.3390/ph15121453.
The overexpression and activity of carbonic anhydrase (CA, EC 4.2.1.1) isoforms CA IX and CA XII promote the accumulation of exceeding protons and acidosis in the extracellular tumor environment. Sulfonamides are effective inhibitors of most families of CAs. In this study, using scaffold-hopping, indoline-5-sulfonamide analogs of the CA IX-selective inhibitor were designed and synthesized to evaluate their biological properties. 1-Acylated indoline-5-sulfonamides demonstrated inhibitory activity against tumor-associated CA IX and XII with K values up to 132.8 nM and 41.3 nM. Compound as one of the most potent inhibitors of CA IX and XII, exhibits hypoxic selectivity, suppressing the growth of MCF7 cells at 12.9 µM, and causes partial inhibition of hypoxia-induced CA IX expression in A431 skin cancer cells. and reverse chemoresistance to doxorubicin of K562/4 with overexpression of P-gp.
碳酸酐酶（CA，EC 4.2.1.1）同工型CA IX和CA XII的过表达及活性会促使细胞外肿瘤环境中过量质子积累和酸中毒。磺胺类药物是大多数碳酸酐酶家族的有效抑制剂。在本研究中，通过骨架跃迁设计并合成了CA IX选择性抑制剂的吲哚啉-5-磺酰胺类似物，以评估其生物学特性。1-酰化吲哚啉-5-磺酰胺对肿瘤相关的CA IX和CA XII表现出抑制活性，K值分别高达132.8 nM和41.3 nM。化合物作为CA IX和CA XII最有效的抑制剂之一，具有缺氧选择性，在12.9 µM时抑制MCF7细胞生长，并部分抑制A431皮肤癌细胞中缺氧诱导的CA IX表达。并且逆转了P-糖蛋白过表达的K562/4对阿霉素的耐药性。
