4.6 Article

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?

Journal

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 36, Issue 1, Pages 2118-2127

Publisher

TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2021.1982933

Keywords

Vanillin; carbonic anhydrase; enzyme inhibitors; molecular docking; enones

Funding

  1. Italian Ministry for Research (MIUR) (PRIN) [2017XYBP2R]
  2. UNLP (Argentina)
  3. CONICET (Argentina)
  4. NVIDIA Corporation

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New C-glycosides and alpha,beta-unsaturated ketones containing the vanillin moiety have been studied as inhibitors of carbonic anhydrase isoforms. Some derivatives show selectivity for tumor-associated CA isoforms, indicating potential for therapeutic applications in hypoxic tumors and other pathologies.
New C-glycosides and alpha,beta-unsaturated ketones incorporating the 4-hydroxy-3-methoxyphenyl (vanillin) moiety as inhibitors of carbonic anhydrase (CA, EC 4.2.1.1) 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.

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