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 - Publication - Bridge of Knowledge

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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)

  • Photo of Beata Żołnowska

    Beata Żołnowska

    • Gdański Uniwersytet Medyczny Katedra Chemii Organicznej
  • Photo of Jarosław Sławiński

    Jarosław Sławiński

    • Gdański Uniwersytet Medyczny Katedra Chemii Organicznej
  • Photo of dr Krzysztof Szafrański

    Krzysztof Szafrański dr

    • Gdański Uniwersytet Medyczny Katedra Chemii Organicznej
  • Photo of Andrea Angeli

    Andrea Angeli

    • Universita degli Studi di Firenze Dipartimento di Chimica
  • Photo of Claudiu T. Supuran

    Claudiu T. Supuran

    • Universita degli Studi di Firenze Dipartimento di Chimica
  • Photo of Anna Kawiak

    Anna Kawiak

    • Uniwersytet Gdański Katedra Biotechnologii
  • Photo of dr inż. Miłosz Wieczór

    Miłosz Wieczór dr inż.

  • Photo of Joanna Zielińska

    Joanna Zielińska

    • Gdański Uniwersytet Medyczny Katedra Chemii Farmaceutycznej
  • Photo of Tomasz Bączek

    Tomasz Bączek

    • Gdański Uniwersytet Medyczny Katedra Chemii Farmaceutycznej
  • Photo of Sylwia Bartoszewska

    Sylwia Bartoszewska

    • Gdański Uniwersytet Medyczny Katedra Chemii Nieorganicznej

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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:
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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