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Targeting Tumor Associated Carbonic Anhydrases IX and XII: Highly Isozyme Selective Coumarin and Psoralen Inhibitors.

ABSTRACT: A small library of psoralen carboxylic acids and their corresponding benzenesulfonamide derivatives were designed and synthesized to evaluate their activity and selectivity toward tumor associated human carbonic anhydrase (hCA) isoforms IX and XII. Both psoralen acids and sulfonamides exhibited potent inhibition of IX and XII isozymes in the nanomolar concentration range. However, psoralen acids resulted as the most selective in comparison with the corresponding benzenesulfonamide derivatives. Our data indicate that the psoralen scaffold is a promising starting point for the design of highly selective tumor associated hCA inhibitors.

SUBMITTER: Melis C

PROVIDER: S-EPMC6047168 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Targeting Tumor Associated Carbonic Anhydrases IX and XII: Highly Isozyme Selective Coumarin and Psoralen Inhibitors.

Melis Claudia C Distinto Simona S Bianco Giulia G Meleddu Rita R Cottiglia Filippo F Fois Benedetta B Taverna Domenico D Angius Rossella R Alcaro Stefano S Ortuso Francesco F Gaspari Marco M Angeli Andrea A Del Prete Sonia S Capasso Clemente C Supuran Claudiu T CT Maccioni Elias E

ACS medicinal chemistry letters 20180606 7

A small library of psoralen carboxylic acids and their corresponding benzenesulfonamide derivatives were designed and synthesized to evaluate their activity and selectivity toward tumor associated human carbonic anhydrase (hCA) isoforms IX and XII. Both psoralen acids and sulfonamides exhibited potent inhibition of IX and XII isozymes in the nanomolar concentration range. However, psoralen acids resulted as the most selective in comparison with the corresponding benzenesulfonamide derivatives. O ...[more]

PMID: 30034608

Similar Datasets

Selective inhibition of carbonic anhydrase IX and XII by coumarin and psoralen derivatives.

Project description:A small library of coumarin and their psoralen analogues EMAC10157a-b-d-g and EMAC10160a-b-d-g has been designed and synthesised to investigate the effect of structural modifications on their inhibition ability and selectivity profile towards carbonic anhydrase isoforms I, II, IX, and XII. None of the new compounds exhibited activity towards hCA I and II isozymes. Conversely, both coumarin and psoralen derivatives were active against tumour associated isoforms IX and XII in the low micromolar or nanomolar range of concentration. These data further corroborate our previous findings on analogous derivatives, confirming that both coumarins and psoralens are interesting scaffolds for the design of isozyme selective hCA inhibitors.

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Potent and Selective Carboxylic Acid Inhibitors of Tumor-Associated Carbonic Anhydrases IX and XII.

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Discovery of new 6-ureido/amidocoumarins as highly potent and selective inhibitors for the tumour-relevant carbonic anhydrases IX and XII.

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Ureidobenzenesulfonamides as Selective Carbonic Anhydrase I, IX, and XII Inhibitors.

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Continued Structural Exploration of Sulfocoumarin as Selective Inhibitor of Tumor-Associated Human Carbonic Anhydrases IX and XII.

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Heterocoumarins Are Selective Carbonic Anhydrase IX and XII Inhibitors with Cytotoxic Effects against Cancer Cells Lines.

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Project description:Different 2,4-thiazolidinedione-tethered coumarins 5a-b, 10a-n and 11a-d were synthesised and evaluated for their inhibitory action against the cancer-associated hCAs IX and XII, as well as the physiologically dominant hCAs I and II to explore their selectivity. Un-substituted phenyl-bearing coumarins 10a, 10 h, and 2-thienyl/furyl-bearing coumarins 11a-c exhibited the best hCA IX (KIs between 0.48 and 0.93 µM) and hCA XII (KIs between 0.44 and 1.1 µM) inhibitory actions. Interestingly, none of the coumarins had any inhibitory effect on the off-target hCA I and II isoforms. The sub-micromolar compounds from the biochemical assay, coumarins 10a, 10 h and 11a-c, were assessed in an in vitro antiproliferative assay, and then the most potent antiproliferative agent 11a was tested to explore its impact on the cell cycle phases and apoptosis in MCF-7 breast cancer cells to provide more insights into the anticancer activity of these compounds.

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