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.
Eur J Med Chem. 2014 Jan; 71:135-47.EJ

Abstract

A series of novel N-substituted N'-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines 9-41 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 87-6506 nM, toward hCA II ranging from 7.8 to 4500 nM, against hCA IX in the range of 4.7-416 nM and against hCA XII at range of 0.96-540 nM. Compounds 10, 12-14, 16, 18-20, 24-26, 31 and 32 exhibited a powerful inhibitory potency toward hCA IX (K(I) = 4.7-21 nM) in comparison to the reference sulfonamides AAZ, MZA, EZA, DCP and IND (K(I) = 24-50 nM). Compound 14 was the most potent inhibitor of hCA I (K(I) = 87 nM), hCA IX (K(I) = 4.7 nM) and hCA XII (K(I) = 0.96 nM), while 26 was the most effective inhibitor of hCA II (K(I) = 7.8 nM). The most promising compound 32 exerted the highest selectivity ratios toward hCA IX versus hCA I (hCA I/hCA IX = 261) and hCA II (hCA II/hCA IX = 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 32-35 human tumor cell lines with GI₅₀ in the range of 2.1-5.0 μM also showed relatively high inhibitory activity toward hCA IX and XII with KI from 18 to 40 nM.

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Authors+Show Affiliations

Żołnowska B

Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.

Sławiński J

Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland. Electronic address: jaroslaw@gumed.edu.pl.

Pogorzelska A

Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.

Chojnacki J

Department of Inorganic Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Poland.

Vullo D

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.

Supuran CT

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.

MeSH

Antigens, NeoplasmAntineoplastic AgentsCarbonic Anhydrase ICarbonic Anhydrase IICarbonic Anhydrase IXCarbonic Anhydrase InhibitorsCarbonic AnhydrasesCell Line, TumorCytosolGuanidinesHumansIsoenzymesModels, MolecularNeoplasmsStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24291567

Citation

Żołnowska, Beata, et al. "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, pp. 135-47.

Żołnowska B, Sławiński J, Pogorzelska A, et al. 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. Eur J Med Chem. 2014;71:135-47.

Żołnowska, B., Sławiński, J., Pogorzelska, A., Chojnacki, J., Vullo, D., & Supuran, C. T. (2014). 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, 71, 135-47. https://doi.org/10.1016/j.ejmech.2013.10.081

Żołnowska B, et al. 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. Eur J Med Chem. 2014;71:135-47. PubMed PMID: 24291567.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - 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. AU - Żołnowska,Beata, AU - Sławiński,Jarosław, AU - Pogorzelska,Aneta, AU - Chojnacki,Jarosław, AU - Vullo,Daniela, AU - Supuran,Claudiu T, Y1 - 2013/11/10/ PY - 2013/07/12/received PY - 2013/10/21/revised PY - 2013/10/31/accepted PY - 2013/12/3/entrez PY - 2013/12/3/pubmed PY - 2014/9/19/medline KW - Anticancer activity KW - Carbonic anhydrase isozymes I, II, IX and XII inhibitors KW - Sulfonamide KW - Sulfonylguanidine KW - Synthesis SP - 135 EP - 47 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 71 N2 - A series of novel N-substituted N'-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines 9-41 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 87-6506 nM, toward hCA II ranging from 7.8 to 4500 nM, against hCA IX in the range of 4.7-416 nM and against hCA XII at range of 0.96-540 nM. Compounds 10, 12-14, 16, 18-20, 24-26, 31 and 32 exhibited a powerful inhibitory potency toward hCA IX (K(I) = 4.7-21 nM) in comparison to the reference sulfonamides AAZ, MZA, EZA, DCP and IND (K(I) = 24-50 nM). Compound 14 was the most potent inhibitor of hCA I (K(I) = 87 nM), hCA IX (K(I) = 4.7 nM) and hCA XII (K(I) = 0.96 nM), while 26 was the most effective inhibitor of hCA II (K(I) = 7.8 nM). The most promising compound 32 exerted the highest selectivity ratios toward hCA IX versus hCA I (hCA I/hCA IX = 261) and hCA II (hCA II/hCA IX = 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 32-35 human tumor cell lines with GI₅₀ in the range of 2.1-5.0 μM also showed relatively high inhibitory activity toward hCA IX and XII with KI from 18 to 40 nM. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/24291567/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(13)00738-1 DB - PRIME DP - Unbound Medicine ER -

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