3H-1,2-Benzoxathiepine 2,2-Dioxides: a New Class of Isoform-Selective Carbonic Anhydrase Inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry 2017
Aleksandrs Pustenko, Dmitrijs Stepanovs, Raivis Žalubovskis, Daniela Vullo, Andris Kazaks, Janis Leitans, Kaspars Tārs, Claudiu Supuran

A new chemotype with carbonic anhydrase (CA, EC 4.2.1.1) inhibitory action has been discovered, the homo-sulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) which have been designed considering the (sulfo)coumarins as lead molecules. An original synthetic strategy of a panel of such derivatives led to compounds with a unique inhibitory profile and very high selectivity for the inhibition of the tumour associated (CA IX/XII) over the cytosolic (CA I/II) isoforms. Although the CA inhibition mechanism with these new compounds is unknown for the moment, we hypothesize that it may be similar to that of the sulfocoumarins, i.e. hydrolysis to the corresponding sulfonic acids which thereafter anchor to the zinc-coordinated water molecule within the enzyme active site.

Keywords
Carbonic anhydrase, sulfocoumarin, homo-sulfocoumarins, inhibitor
DOI
10.1080/14756366.2017.1316720
Hyperlink
http://www.tandfonline.com/doi/full/10.1080/14756366.2017.1316720

Pustenko, A., Stepanovs, D., Žalubovskis, R., Vullo, D., Kazaks, A., Leitans, J., Tārs, K., Supuran, C. 3H-1,2-Benzoxathiepine 2,2-Dioxides: a New Class of Isoform-Selective Carbonic Anhydrase Inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, Vol.32, Iss.1, pp.767-775. ISSN 1475-6366. e-ISSN 1475-6374. Available from: doi:10.1080/14756366.2017.1316720

Publication language
English (en)