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Carbonic anhydrase inhibitors. Synthesis, and molecular structure of novel series N-substituted N'-(2-arylmethylthio-4-chloro-5- methylbenzenesulfonyl)guanidines and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII
Abstract
A series of novel N-substituted N'-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines 9 e41 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and cancer-associated isozymes CA IX and XII. Against the human CA I investigated compounds showed KI in the range of 87e6506 nM, toward hCA II ranging from 7.8 to 4500 nM, against hCA IX in the range of 4.7e416 nM and against hCA XII at range of 0.96e540 nM. Compounds 10, 12e14, 16, 18e20, 24e26, 31 and 32 exhibited a powerful inhibitory potency toward hCA IX (KI ¼ 4.7e21 nM) in comparison to the reference sulfonamides AAZ, MZA, EZA, DCP and IND (KI ¼ 24e50 nM). Compound 14 was the most potent inhibitor of hCA I (KI ¼ 87 nM), hCA IX (KI ¼ 4.7 nM) and hCA XII (KI ¼ 0.96 nM), while 26 was the most effective inhibitor of hCA II (KI ¼ 7.8 nM). The most promising compound 32 exerted the highest selectivity ratios toward hCA IX versus hCA I (hCA I/hCA IX ¼ 261) and hCA II (hCA II/hCA IX ¼ 26). The in vitro antitumor activity of compounds 10, 13, 14, 21, 22, 25, 32, 38 and 41 was evaluated at the US National Cancer Institute (NCI) against a panel of 60 human tumor cell lines. The most active antitumor agents 21 and 25, inhibiting 32e35 human tumor cell lines with GI50 in the range of 2.1e5.0 mM also showed relatively high inhibitory activity toward hCA IX and XII with KI from 18 to 40 nM.
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Authors (6)
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Beata Żołnowska
- Medical University of Gdańsk Department of Organic Chemistry
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Jarosław Sławiński
- Medical University of Gdańsk Department of Organic Chemistry
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Aneta Pogorzelska
- Medical University of Gdańsk Department of Organic Chemistry
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Daniela Vullo
- Universita degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica Dipartimento di Chimica
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Claudiu T. Supuran
- Universita degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica Dipartimento di Chimica, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche
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- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.ejmech.2013.10.081
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- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
no. 71,
pages 135 - 147,
ISSN: 0223-5234 - Language:
- English
- Publication year:
- 2014
- Bibliographic description:
- Żołnowska B., Sławiński J., Pogorzelska A., Chojnacki J., Vullo D., Supuran C.: Carbonic anhydrase inhibitors. Synthesis, and molecular structure of novel series N-substituted N'-(2-arylmethylthio-4-chloro-5- methylbenzenesulfonyl)guanidines and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII// EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. -Vol. 71, (2014), s.135-147
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.ejmech.2013.10.081
- Verified by:
- Gdańsk University of Technology
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