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Vanillin enones as selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII. The out of the active site pocket for the design of selective inhibitors?

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journal contribution
posted on 13.01.2022, 17:02 by Leonardo E. Riafrecha, Macarena S. Le Pors, Martín J. Lavecchia, Silvia Bua, Claudiu T. Supuran, Pedro A. Colinas

New C-glycosides and α,β-unsaturated ketones incorporating the 4-hydroxy-3-methoxyphenyl (vanillin) moiety as inhibitors of carbonic anhydrase (CA, EC isoforms have been investigated. The inhibition profile of these compounds is presented against four human CA (hCA) isozymes, comprising hCAs I and II (cytosolic, ubiquitous enzymes) and hCAs IX and XII (tumour associated isozymes). Docking analysis of the inhibitors within the active sites of these enzymes has been performed and is discussed, showing that the observed selectivity could be explained in terms of an alternative pocket out of the CA active site where some of these compounds may bind. Several derivatives were identified as selective inhibitors of the tumour-associated hCA IX and XII. Their discovery might be a step in the strategy for finding an effective non-sulfonamide CA inhibitor useful in therapy/diagnosis of hypoxic tumours or other pathologies in which CA isoforms are involved.


This work was financed in part by an Italian Ministry for Research (MIUR) grant to CTS (PRIN: rot. 2017XYBP2R), grants from UNLP and CONICET to PAC (Argentina). MSL is a fellow of CONICET. LER, MJL, and PAC are members of the Scientific Research Career of CONICET. We gratefully acknowledge the support of NVIDIA Corporation with the donation of the Titan X Pascal GPU used for this research.