7-Acylamino-3H-1,2-benzoxathiepine 2,2-Dioxides as New Isoform-Selective Carbonic Anhydrase IX and XII Inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry 2020
Aleksandrs Pustenko, Alessio Nocentini, Anastasija Balašova, Mikhail Krasavin, Raivis Žalubovskis, Claudiu T. Supuran

A series of 3H-1,2-benzoxathiepine 2,2-dioxides incorporating 7-acylamino moieties were obtained by an original procedure starting from 5-nitrosalicylaldehyde, which was treated with propenylsulfonyl chloride followed by Wittig reaction of the bis-olefin intermediate. The new derivatives, belonging to the homosulfocoumarin chemotype, were assayed as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Four pharmacologically relevant human (h) isoforms were investigated, the cytosolic hCA I and II and the transmembrane, tumour-associated hCA IX and XII. No relevant inhibition of hCA I and II was observed, whereas some of the new derivatives were effective, low nanomolar hCA IX/XII inhibitors, making them of interest for investigations in situations in which the activity of these isoforms is overexpressed, such as hypoxic tumours, arthritis or cerebral ischaemia.

Keywords
Carbonic anhydrase, homosulfocoumarin, isoform-selective inhibitor, sulfocoumarin, transmembrane isoforms
DOI
10.1080/14756366.2020.1722658
Hyperlink
https://www.tandfonline.com/doi/full/10.1080/14756366.2020.1722658

Pustenko, A., Nocentini, A., Balašova, A., Krasavin, M., Žalubovskis, R., Supuran, C. 7-Acylamino-3H-1,2-benzoxathiepine 2,2-Dioxides as New Isoform-Selective Carbonic Anhydrase IX and XII Inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 2020, Vol. 35, No. 1, pp.650-656. ISSN 1475-6366. e-ISSN 1475-6374. Available from: doi:10.1080/14756366.2020.1722658

Publication language
English (en)