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Novel sulfonamide incorporating piperazine, aminoalcohol and 1,3,5-triazine structural motifs with carbonic anhydrase I, II and IX inhibitory action.
Bioorg Chem. 2018 04; 77:25-37.BC

Abstract

A new series of s-triazine derivatives incorporating sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and piperazine or aminoalcohol structural motifs is reported. Molecular docking was exploited to select compounds from virtual combinatorial library for synthesis and subsequent biological evaluation. The compounds were prepared by using step by step nucleophilic substitution of chlorine atoms from cyanuric chloride (2,4,6-trichloro-1,3,5-triazine). The compounds were tested as inhibitors of physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms. Specifically, against the cytosolic hCA I, II and tumor-associated hCA IX. These compounds show appreciable inhibition. hCA I was inhibited with KIs in the range of 8.5-2679.1 nM, hCA II with KIs in the range of 4.8-380.5 nM and hCA IX with KIs in the range of 0.4-307.7 nM. As other similar derivatives, some of the compounds showed good or excellent selectivity ratios for inhibiting hCA IX over hCA II, of 3.5-18.5. 4-[({4-Chloro-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)methyl] benzene sulfonamide demonstrated subnanomolar affinity for hCA IX (0.4 nM) and selectivity (18.50) over the cytosolic isoforms. This series of compounds may be of interest for the development of new, unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX.

Authors+Show Affiliations

University of Veterinary and Pharmaceutical Sciences, Faculty of Pharmacy, Department of Chemical Drugs, Palackého 1-3, CZ-612 42 Brno, Czech Republic; Masaryk University, Faculty of Science, Department of Chemistry, Centre for Syntheses at Sustainable Conditions and Their Management, University Campus, Kamenice 753/5, CZ-625 00 Brno, Czech Republic. Electronic address: havrankova.e@mail.muni.cz.University of Veterinary and Pharmaceutical Sciences, Faculty of Pharmacy, Department of Chemical Drugs, Palackého 1-3, CZ-612 42 Brno, Czech Republic.University of Florence, Polo Scientifico, Neurofarba Department, Via Ugo Shiff 6, 500 19 Sesto Fiorentino (Florence), Italy.Comenius University in Bratislava, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Odbojárov 10, 832 32 Bratislava, Slovakia.Masaryk University, Faculty of Science, Department of Chemistry, Centre for Syntheses at Sustainable Conditions and Their Management, University Campus, Kamenice 753/5, CZ-625 00 Brno, Czech Republic.University of Florence, Polo Scientifico, Neurofarba Department, Via Ugo Shiff 6, 500 19 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29324250

Citation

Havránková, Eva, et al. "Novel Sulfonamide Incorporating Piperazine, Aminoalcohol and 1,3,5-triazine Structural Motifs With Carbonic Anhydrase I, II and IX Inhibitory Action." Bioorganic Chemistry, vol. 77, 2018, pp. 25-37.
Havránková E, Csöllei J, Vullo D, et al. Novel sulfonamide incorporating piperazine, aminoalcohol and 1,3,5-triazine structural motifs with carbonic anhydrase I, II and IX inhibitory action. Bioorg Chem. 2018;77:25-37.
Havránková, E., Csöllei, J., Vullo, D., Garaj, V., Pazdera, P., & Supuran, C. T. (2018). Novel sulfonamide incorporating piperazine, aminoalcohol and 1,3,5-triazine structural motifs with carbonic anhydrase I, II and IX inhibitory action. Bioorganic Chemistry, 77, 25-37. https://doi.org/10.1016/j.bioorg.2017.12.034
Havránková E, et al. Novel Sulfonamide Incorporating Piperazine, Aminoalcohol and 1,3,5-triazine Structural Motifs With Carbonic Anhydrase I, II and IX Inhibitory Action. Bioorg Chem. 2018;77:25-37. PubMed PMID: 29324250.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel sulfonamide incorporating piperazine, aminoalcohol and 1,3,5-triazine structural motifs with carbonic anhydrase I, II and IX inhibitory action. AU - Havránková,Eva, AU - Csöllei,Jozef, AU - Vullo,Daniela, AU - Garaj,Vladimír, AU - Pazdera,Pavel, AU - Supuran,Claudiu T, Y1 - 2018/01/03/ PY - 2017/10/05/received PY - 2017/11/16/revised PY - 2017/12/30/accepted PY - 2018/1/13/pubmed PY - 2019/1/1/medline PY - 2018/1/12/entrez KW - 1,3,5-Triazine KW - Benzene sulfonamides KW - Carbonic anhydrase KW - Enzyme inhibition KW - Isoform selectivity SP - 25 EP - 37 JF - Bioorganic chemistry JO - Bioorg. Chem. VL - 77 N2 - A new series of s-triazine derivatives incorporating sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and piperazine or aminoalcohol structural motifs is reported. Molecular docking was exploited to select compounds from virtual combinatorial library for synthesis and subsequent biological evaluation. The compounds were prepared by using step by step nucleophilic substitution of chlorine atoms from cyanuric chloride (2,4,6-trichloro-1,3,5-triazine). The compounds were tested as inhibitors of physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms. Specifically, against the cytosolic hCA I, II and tumor-associated hCA IX. These compounds show appreciable inhibition. hCA I was inhibited with KIs in the range of 8.5-2679.1 nM, hCA II with KIs in the range of 4.8-380.5 nM and hCA IX with KIs in the range of 0.4-307.7 nM. As other similar derivatives, some of the compounds showed good or excellent selectivity ratios for inhibiting hCA IX over hCA II, of 3.5-18.5. 4-[({4-Chloro-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)methyl] benzene sulfonamide demonstrated subnanomolar affinity for hCA IX (0.4 nM) and selectivity (18.50) over the cytosolic isoforms. This series of compounds may be of interest for the development of new, unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/29324250/Novel_sulfonamide_incorporating_piperazine_aminoalcohol_and_135_triazine_structural_motifs_with_carbonic_anhydrase_I_II_and_IX_inhibitory_action_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(17)30764-2 DB - PRIME DP - Unbound Medicine ER -