Tags

Type your tag names separated by a space and hit enter

Novel sulfonamides incorporating 1,3,5-triazine and amino acid structural motifs as inhibitors of the physiological carbonic anhydrase isozymes I, II and IV and tumor-associated isozyme IX.
Bioorg Chem. 2018 12; 81:241-252.BC

Abstract

A new series of thirty s-triazinyl-substituted aminoalkylbenzenesulfonamides, incorporating a symmetric pair of amino acid moieties, is reported, together with inhibition studies of physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms. Specifically, against the cytosolic hCA I, II, transmembrane hCA IV and the tumor-associated, membrane-bound hCA IX. The compounds were prepared by nucleophilic substitution of chlorine atoms from cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) using environmentally friendly water-based synthetic conditions. The products yields ranged in the interval of 43-97%. Purity of the products was verified by the HPLC-DAD-ESI-Q-TOF MS method. Identity of the products was confirmed by the same method plus NMR and IR. The products showed weak inhibition of the cytosolic, off-target isozyme hCA II, but some of them were low nanomolar (i.e. strong) inhibitors of the tumor-associated hCA IX. The series offered representatives selective towards isozymes hCA I, IV and IX. 2,2'-((6-((4-sulfamoylphenethyl)amino)-1,3,5-triazine-2,4-diyl)bis(imino))disuccinic acid demonstrated highest selectivity to the tumor-associated isoform hCA IX over off-target isozymes, with impressive KI ratio (hCA II/hCA IX) 213.9 and inhibition constant equal to acetazolamide (KI = 25.8 nM). Although the selectivities of some other products, e.g. those conjugating Leu and Glu, were a bit lower (188.7 and 84.3, respectively) their inhibition constants were similar to acetazolamide too (24.0 and 27.1, respectively). The selected most impressive results from the inhibition study were interpreted via molecular modeling experiment (docking in Glide) revealing different inter-molecular enzyme-substrate interaction of 2,2'-((6-((4-sulfamoylphenethyl)amino)-1,3,5-triazine-2,4-diyl)bis(imino))disuccinic acid within specific hCA IX and hCA II microregions. Therefore, several selected compounds from this study can be considered as highly effective and selective inhibitors of hCA IX, worthy to further (preclinical) investigation.

Authors+Show Affiliations

Comenius University in Bratislava, Faculty of Pharmacy, Department of Pharmaceutical Analysis and Nuclear Pharmacy, Odbojárov 10, SK-83232 Bratislava, Slovak Republic; Comenius University in Bratislava, Faculty of Pharmacy, Toxicological and Antidoping Centre, Odbojárov 10, SK-83232 Bratislava, Slovak Republic. Electronic address: mikus@fpharm.uniba.sk.Comenius University in Bratislava, Faculty of Pharmacy, Department of Pharmaceutical Analysis and Nuclear Pharmacy, Odbojárov 10, SK-83232 Bratislava, Slovak Republic. Electronic address: krajciova.dominika@fpharm.uniba.sk.Comenius University in Bratislava, Faculty of Pharmacy, Department of Pharmaceutical Analysis and Nuclear Pharmacy, Odbojárov 10, SK-83232 Bratislava, Slovak Republic. Electronic address: mikulova43@uniba.sk.Comenius University in Bratislava, Faculty of Pharmacy, Department of Nuclear Magnetic Resonance, Odbojárov 10, SK-83232 Bratislava, Slovak Republic. Electronic address: horvath@fpharm.uniba.sk.Comenius University in Bratislava, Faculty of Pharmacy, Department of Pharmaceutical Analysis and Nuclear Pharmacy, Odbojárov 10, SK-83232 Bratislava, Slovak Republic; Comenius University in Bratislava, Faculty of Pharmacy, Toxicological and Antidoping Centre, Odbojárov 10, SK-83232 Bratislava, Slovak Republic. Electronic address: pecher1@uniba.sk.Comenius University in Bratislava, Faculty of Pharmacy, Toxicological and Antidoping Centre, Odbojárov 10, SK-83232 Bratislava, Slovak Republic; Comenius University in Bratislava, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Odbojárov 10, SK-83232 Bratislava, Slovak Republic. Electronic address: garaj1@uniba.sk.Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, University of Florence, Italy. Electronic address: silvia.bua@unifi.it.Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, University of Florence, Italy. Electronic address: andrea.angeli@unifi.it.Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, University of Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

Pub Type(s)

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

Language

eng

PubMed ID

30153589

Citation

Mikuš, Peter, et al. "Novel Sulfonamides Incorporating 1,3,5-triazine and Amino Acid Structural Motifs as Inhibitors of the Physiological Carbonic Anhydrase Isozymes I, II and IV and Tumor-associated Isozyme IX." Bioorganic Chemistry, vol. 81, 2018, pp. 241-252.
Mikuš P, Krajčiová D, Mikulová M, et al. Novel sulfonamides incorporating 1,3,5-triazine and amino acid structural motifs as inhibitors of the physiological carbonic anhydrase isozymes I, II and IV and tumor-associated isozyme IX. Bioorg Chem. 2018;81:241-252.
Mikuš, P., Krajčiová, D., Mikulová, M., Horváth, B., Pecher, D., Garaj, V., Bua, S., Angeli, A., & Supuran, C. T. (2018). Novel sulfonamides incorporating 1,3,5-triazine and amino acid structural motifs as inhibitors of the physiological carbonic anhydrase isozymes I, II and IV and tumor-associated isozyme IX. Bioorganic Chemistry, 81, 241-252. https://doi.org/10.1016/j.bioorg.2018.08.005
Mikuš P, et al. Novel Sulfonamides Incorporating 1,3,5-triazine and Amino Acid Structural Motifs as Inhibitors of the Physiological Carbonic Anhydrase Isozymes I, II and IV and Tumor-associated Isozyme IX. Bioorg Chem. 2018;81:241-252. PubMed PMID: 30153589.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel sulfonamides incorporating 1,3,5-triazine and amino acid structural motifs as inhibitors of the physiological carbonic anhydrase isozymes I, II and IV and tumor-associated isozyme IX. AU - Mikuš,Peter, AU - Krajčiová,Dominika, AU - Mikulová,Mária, AU - Horváth,Branislav, AU - Pecher,Daniel, AU - Garaj,Vladimír, AU - Bua,Silvia, AU - Angeli,Andrea, AU - Supuran,Claudiu T, Y1 - 2018/08/16/ PY - 2018/07/03/received PY - 2018/07/27/revised PY - 2018/08/06/accepted PY - 2018/8/29/pubmed PY - 2019/4/19/medline PY - 2018/8/29/entrez KW - 1,3,5-Triazine KW - Amino acids KW - Benzene sulfonamides KW - Carbonic anhydrase KW - Enzyme inhibition KW - Isoform selectivity SP - 241 EP - 252 JF - Bioorganic chemistry JO - Bioorg. Chem. VL - 81 N2 - A new series of thirty s-triazinyl-substituted aminoalkylbenzenesulfonamides, incorporating a symmetric pair of amino acid moieties, is reported, together with inhibition studies of physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms. Specifically, against the cytosolic hCA I, II, transmembrane hCA IV and the tumor-associated, membrane-bound hCA IX. The compounds were prepared by nucleophilic substitution of chlorine atoms from cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) using environmentally friendly water-based synthetic conditions. The products yields ranged in the interval of 43-97%. Purity of the products was verified by the HPLC-DAD-ESI-Q-TOF MS method. Identity of the products was confirmed by the same method plus NMR and IR. The products showed weak inhibition of the cytosolic, off-target isozyme hCA II, but some of them were low nanomolar (i.e. strong) inhibitors of the tumor-associated hCA IX. The series offered representatives selective towards isozymes hCA I, IV and IX. 2,2'-((6-((4-sulfamoylphenethyl)amino)-1,3,5-triazine-2,4-diyl)bis(imino))disuccinic acid demonstrated highest selectivity to the tumor-associated isoform hCA IX over off-target isozymes, with impressive KI ratio (hCA II/hCA IX) 213.9 and inhibition constant equal to acetazolamide (KI = 25.8 nM). Although the selectivities of some other products, e.g. those conjugating Leu and Glu, were a bit lower (188.7 and 84.3, respectively) their inhibition constants were similar to acetazolamide too (24.0 and 27.1, respectively). The selected most impressive results from the inhibition study were interpreted via molecular modeling experiment (docking in Glide) revealing different inter-molecular enzyme-substrate interaction of 2,2'-((6-((4-sulfamoylphenethyl)amino)-1,3,5-triazine-2,4-diyl)bis(imino))disuccinic acid within specific hCA IX and hCA II microregions. Therefore, several selected compounds from this study can be considered as highly effective and selective inhibitors of hCA IX, worthy to further (preclinical) investigation. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/30153589/Novel_sulfonamides_incorporating_135_triazine_and_amino_acid_structural_motifs_as_inhibitors_of_the_physiological_carbonic_anhydrase_isozymes_I_II_and_IV_and_tumor_associated_isozyme_IX_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(18)30641-2 DB - PRIME DP - Unbound Medicine ER -