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6-Triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrases IX and XII.
Bioorg Med Chem Lett. 2014 Mar 01; 24(5):1256-60.BM

Abstract

A series of 6-substituted sulfocoumarins incorporating substituted-1,2,3-triazol-4-yl-/5-yl moieties were synthesized by employing click chemistry. The new sulfocoumarins incorporated cycloalkyl, tert-butyl and substituted aryl moieties at the triazole ring, and were investigated for the inhibition of four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, the cytosolic hCA I and II; and the transmembrane, tumor-associated hCA IX and XII. The triazole-substituted sulfocoumarins did not inhibit the ubiquitous, off-target cytosolic isoforms hCA I and II (KIs >10 μM) but showed effective inhibition against the two transmembrane CAs, with KIs ranging from 7.2 to 10.5 nM against hCA IX, and between 5.5 and 17.7 nM against hCA XII. As hCA IX and XII are validated anti-tumor targets, such prodrug, isoform-selective inhibitors as the sulfocoumarins reported here, may be useful for identifying suitable drug candidates for clinical trials.

Authors+Show Affiliations

Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia.Università 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 Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia. Electronic address: raivis@osi.lv.Università 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 Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 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

24518190

Citation

Grandane, Aiga, et al. "6-Triazolyl-substituted Sulfocoumarins Are Potent, Selective Inhibitors of the Tumor-associated Carbonic Anhydrases IX and XII." Bioorganic & Medicinal Chemistry Letters, vol. 24, no. 5, 2014, pp. 1256-60.
Grandane A, Tanc M, Zalubovskis R, et al. 6-Triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrases IX and XII. Bioorg Med Chem Lett. 2014;24(5):1256-60.
Grandane, A., Tanc, M., Zalubovskis, R., & Supuran, C. T. (2014). 6-Triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrases IX and XII. Bioorganic & Medicinal Chemistry Letters, 24(5), 1256-60. https://doi.org/10.1016/j.bmcl.2014.01.076
Grandane A, et al. 6-Triazolyl-substituted Sulfocoumarins Are Potent, Selective Inhibitors of the Tumor-associated Carbonic Anhydrases IX and XII. Bioorg Med Chem Lett. 2014 Mar 1;24(5):1256-60. PubMed PMID: 24518190.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 6-Triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrases IX and XII. AU - Grandane,Aiga, AU - Tanc,Muhammet, AU - Zalubovskis,Raivis, AU - Supuran,Claudiu T, Y1 - 2014/02/02/ PY - 2013/12/30/received PY - 2014/01/22/revised PY - 2014/01/23/accepted PY - 2014/2/13/entrez PY - 2014/2/13/pubmed PY - 2014/10/29/medline KW - 1,4-Substituted 1,2,3-triazole KW - 1,5-Substituted 1,2,3-triazole KW - Carbonic anhydrase KW - Click chemistry KW - Isoform-selective inhibitor KW - Sulfocoumarin KW - Tumor-associated carbonic anhydrase SP - 1256 EP - 60 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 24 IS - 5 N2 - A series of 6-substituted sulfocoumarins incorporating substituted-1,2,3-triazol-4-yl-/5-yl moieties were synthesized by employing click chemistry. The new sulfocoumarins incorporated cycloalkyl, tert-butyl and substituted aryl moieties at the triazole ring, and were investigated for the inhibition of four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, the cytosolic hCA I and II; and the transmembrane, tumor-associated hCA IX and XII. The triazole-substituted sulfocoumarins did not inhibit the ubiquitous, off-target cytosolic isoforms hCA I and II (KIs >10 μM) but showed effective inhibition against the two transmembrane CAs, with KIs ranging from 7.2 to 10.5 nM against hCA IX, and between 5.5 and 17.7 nM against hCA XII. As hCA IX and XII are validated anti-tumor targets, such prodrug, isoform-selective inhibitors as the sulfocoumarins reported here, may be useful for identifying suitable drug candidates for clinical trials. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/24518190/6_Triazolyl_substituted_sulfocoumarins_are_potent_selective_inhibitors_of_the_tumor_associated_carbonic_anhydrases_IX_and_XII_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(14)00106-1 DB - PRIME DP - Unbound Medicine ER -