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Novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(1,3,5-triazin-2-ylamino)guanidine derivatives: Inhibition of human carbonic anhydrase cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII, anticancer activity, and molecular modeling studies
Abstract
A series of novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(6-substituted-4-chloro-1,3,5-triazin-2-ylamino)guanidine derivatives 9–20 have been synthesized by substitution of chlorine atom at the 1,3,5-triazine ring in compounds 5–8 with 3- or 4-aminobenzenesulfonamide and 4-(aminomethyl)benzenesulfonamide hydrochloride. All the synthesized compounds were evaluated for their inhibitory activity toward hCA I, II, IX and XII as well as anticancer activity against HeLa, HCT-116 and MCF-7 human tumor cell lines. The investigated compounds showed weak inhibitory potency against the human CA I, while activity toward hCA II was differentiated and depended on structure of inhibitor (KI: 5.4–933.1 nM). Compounds containing the 4-sulfamoylphenyl moiety (9–12) exhibited the strongest inhibitory activity against hCA IX with KI values from 37.1 to 42.9 nM, as well as against hCA XII in range of 31–91.9 nM. The most promising compound 12 (KI = 41 nM) showed the highest selectivity toward hCA IX versus hCA I (hCA I/hCA IX = 18) and hCA II (hCA II/hCA IX = 4). Compound 12 displayed prominent cytotoxic effect selectively toward HeLa cancer cells (IC50 = 17 μM) and did not exhibit toxicity to the non-cancerous HaCaT cells. In silico analysis suggested that despite the lack of a single binding pose, the selective affinity is conferred by specific interactions with an arginine moiety, as well as better-defined binding modes within the active site.
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Authors (10)
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Beata Żołnowska
- Gdański Uniwersytet Medyczny Katedra Chemii Organicznej
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Jarosław Sławiński
- Gdański Uniwersytet Medyczny Katedra Chemii Organicznej
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Krzysztof Szafrański dr
- Gdański Uniwersytet Medyczny Katedra Chemii Organicznej
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Andrea Angeli
- Universita degli Studi di Firenze Dipartimento di Chimica
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Claudiu T. Supuran
- Universita degli Studi di Firenze Dipartimento di Chimica
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Anna Kawiak
- Uniwersytet Gdański Katedra Biotechnologii
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Joanna Zielińska
- Gdański Uniwersytet Medyczny Katedra Chemii Farmaceutycznej
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Tomasz Bączek
- Gdański Uniwersytet Medyczny Katedra Chemii Farmaceutycznej
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Full text
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- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.ejmech.2017.11.005
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- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
no. 143,
pages 1931 - 1941,
ISSN: 0223-5234 - Language:
- English
- Publication year:
- 2018
- Bibliographic description:
- Żołnowska B., Sławiński J., Szafrański K., Angeli A., Supuran C., Kawiak A., Wieczór M., Zielińska J., Bączek T., Bartoszewska S.: Novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(1,3,5-triazin-2-ylamino)guanidine derivatives: Inhibition of human carbonic anhydrase cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII, anticancer activity, and molecular modeling studies// EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. -Vol. 143, (2018), s.1931-1941
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.ejmech.2017.11.005
- Verified by:
- Gdańsk University of Technology
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