Aryl Derivatives of 3H-1,2-Benzoxaphosphepine 2-Oxides as Inhibitors of Cancer-Related Carbonic Anhydrase Isoforms IX and XII

Journal of Enzyme Inhibition and Medicinal Chemistry 2023
Anastasija Balašova, Aleksandrs Pustenko, Alessio Nocentini, Daniela Vullo, Claudiu T. Supuran, Raivis Žalubovskis

A range of 3H-1,2-benzoxaphosphepine 2-oxide aryl derivatives with various substitution patterns at positions 7, 8, or 9 of the scaffold was synthesised in five steps from the commercially available salicylaldehydes. All of the newly obtained compounds were studied for their inhibition potency against carbonic anhydrase (CA) isoforms I, II, IX, and XII. Delightfully, these compounds showed a striking selectivity for the cancer-associated CA IX and XII over the cytosolic CA I and II, whose inhibition may lead to side-effects. Overall, a structure–activity relationship (SAR) revealed that 7- and 8-substituted aryl derivatives were more effective inhibitors of CA IX and XII than 9-substituted derivatives. In addition, the fluorine-containing analogues emerged as the most potent CA IX/XII inhibitors in this series.

Keywords
anticancer | benzoxaphosphepine 2-oxide | Carbonic anhydrase | isoform-selective inhibitors | Suzuki reaction
DOI
10.1080/14756366.2023.2249267
Hyperlink
https://www.tandfonline.com/doi/full/10.1080/14756366.2023.2249267

Balašova, A., Pustenko, A., Nocentini, A., Vullo, D., Supuran, C., Žalubovskis, R. Aryl Derivatives of 3H-1,2-Benzoxaphosphepine 2-Oxides as Inhibitors of Cancer-Related Carbonic Anhydrase Isoforms IX and XII. Journal of Enzyme Inhibition and Medicinal Chemistry, 2023, Vol. 38, No. 1, Article number 2249267. ISSN 1475-6366. Available from: doi:10.1080/14756366.2023.2249267

Publication language
English (en)