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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.
Eur J Med Chem. 2018 Jan 01; 143:1931-1941.EJ

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.

Authors+Show Affiliations

Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland. Electronic address: zolnowska@gumed.edu.pl.Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland. Electronic address: jaroslaw@gumed.edu.pl.Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.Dipartimento di Chimica, Universita degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy; Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, 50019 Sesto Fiorentino, Florence, Italy.Dipartimento di Chimica, Universita degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy; Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, 50019 Sesto Fiorentino, Florence, Italy.Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, ul. Abrahama 58, 80-307 Gdańsk, Poland; Laboratory of Human Physiology, Medical University of Gdańsk, ul. Tuwima 15, 80-210 Gdańsk, Poland.Department of Physical Chemistry, Gdańsk University of Technology, ul. Narutowicza 11/12, 80-233 Gdańsk, Poland.Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.Department of Inorganic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29146134

Citation

Żołnowska, Beata, et al. "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, pp. 1931-1941.
Żołnowska B, Sławiński J, Szafrański K, et al. 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. Eur J Med Chem. 2018;143:1931-1941.
Żołnowska, B., Sławiński, J., Szafrański, K., Angeli, A., Supuran, C. T., Kawiak, A., Wieczór, M., Zielińska, J., Bączek, T., & Bartoszewska, S. (2018). 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, 143, 1931-1941. https://doi.org/10.1016/j.ejmech.2017.11.005
Żołnowska B, et al. 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. Eur J Med Chem. 2018 Jan 1;143:1931-1941. PubMed PMID: 29146134.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Żołnowska,Beata, AU - Sławiński,Jarosław, AU - Szafrański,Krzysztof, AU - Angeli,Andrea, AU - Supuran,Claudiu T, AU - Kawiak,Anna, AU - Wieczór,Miłosz, AU - Zielińska,Joanna, AU - Bączek,Tomasz, AU - Bartoszewska,Sylwia, Y1 - 2017/11/04/ PY - 2017/09/28/received PY - 2017/10/26/revised PY - 2017/11/02/accepted PY - 2017/11/18/pubmed PY - 2018/1/6/medline PY - 2017/11/18/entrez KW - Anticancer KW - Benzenesulfonamide KW - Carbonic anhydrase inhibitors KW - Molecular dynamics KW - Synthesis SP - 1931 EP - 1941 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 143 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/29146134/Novel_2__2_arylmethylthio_4_chloro_5_methylbenzenesulfonyl__1__135_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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(17)30889-9 DB - PRIME DP - Unbound Medicine ER -