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Sulfocoumarin-, Coumarin-, 4-Sulfamoylphenyl-Bearing Indazole-3-carboxamide Hybrids: Synthesis and Selective Inhibition of Tumor-Associated Carbonic Anhydrase Isozymes IX and XII.
ChemMedChem. 2017 10 09; 12(19):1578-1584.C

Abstract

A series of sulfocoumarin-, coumarin-, and 4-sulfamoylphenyl-bearing indazole-3-carboxamide hybrids were synthesized and investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). Compounds 6 a-g (amide derivatives) and 7 a-h (triazoles) act as "prodrugs", and their hydrolysis products are the de facto CA inhibitors. These compounds displayed sub-micromolar to high-nanomolar inhibitory activity against hCA isoforms IX and XII, which were recently validated as antitumor drug targets. Moreover, no inhibition of the off-target hCA I and II isoforms was observed. Compounds 8 a-f (another set of triazoles) exhibited nanomolar inhibition against hCA isoforms I, II, IX and XII, among which compounds 8 c, 8 d, and 8 f were found to inhibit the tumor-associated hypoxia-induced hCA isoform IX with Ki values of 1.8, 2.3, and 2.0 nm respectively. Further exploration of these compounds could be useful for the development of novel antitumor agents with selective mechanisms of CA inhibitory action.

Authors+Show Affiliations

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad, 500037, India.Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad, 500037, India.NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Florence, Italy.NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Florence, Italy.Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad, 500037, India.

Pub Type(s)

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

Language

eng

PubMed ID

28940980

Citation

Angapelly, Srinivas, et al. "Sulfocoumarin-, Coumarin-, 4-Sulfamoylphenyl-Bearing Indazole-3-carboxamide Hybrids: Synthesis and Selective Inhibition of Tumor-Associated Carbonic Anhydrase Isozymes IX and XII." ChemMedChem, vol. 12, no. 19, 2017, pp. 1578-1584.
Angapelly S, Sri Ramya PV, Angeli A, et al. Sulfocoumarin-, Coumarin-, 4-Sulfamoylphenyl-Bearing Indazole-3-carboxamide Hybrids: Synthesis and Selective Inhibition of Tumor-Associated Carbonic Anhydrase Isozymes IX and XII. ChemMedChem. 2017;12(19):1578-1584.
Angapelly, S., Sri Ramya, P. V., Angeli, A., Supuran, C. T., & Arifuddin, M. (2017). Sulfocoumarin-, Coumarin-, 4-Sulfamoylphenyl-Bearing Indazole-3-carboxamide Hybrids: Synthesis and Selective Inhibition of Tumor-Associated Carbonic Anhydrase Isozymes IX and XII. ChemMedChem, 12(19), 1578-1584. https://doi.org/10.1002/cmdc.201700446
Angapelly S, et al. Sulfocoumarin-, Coumarin-, 4-Sulfamoylphenyl-Bearing Indazole-3-carboxamide Hybrids: Synthesis and Selective Inhibition of Tumor-Associated Carbonic Anhydrase Isozymes IX and XII. ChemMedChem. 2017 10 9;12(19):1578-1584. PubMed PMID: 28940980.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sulfocoumarin-, Coumarin-, 4-Sulfamoylphenyl-Bearing Indazole-3-carboxamide Hybrids: Synthesis and Selective Inhibition of Tumor-Associated Carbonic Anhydrase Isozymes IX and XII. AU - Angapelly,Srinivas, AU - Sri Ramya,P V, AU - Angeli,Andrea, AU - Supuran,Claudiu T, AU - Arifuddin,Mohammed, Y1 - 2017/09/22/ PY - 2017/07/28/received PY - 2017/08/20/revised PY - 2017/9/25/pubmed PY - 2017/10/31/medline PY - 2017/9/24/entrez KW - antitumor agents KW - carbonic anhydrase KW - coumarins KW - indazole-3-carboxamide hybrids KW - selective inhibition SP - 1578 EP - 1584 JF - ChemMedChem JO - ChemMedChem VL - 12 IS - 19 N2 - A series of sulfocoumarin-, coumarin-, and 4-sulfamoylphenyl-bearing indazole-3-carboxamide hybrids were synthesized and investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). Compounds 6 a-g (amide derivatives) and 7 a-h (triazoles) act as "prodrugs", and their hydrolysis products are the de facto CA inhibitors. These compounds displayed sub-micromolar to high-nanomolar inhibitory activity against hCA isoforms IX and XII, which were recently validated as antitumor drug targets. Moreover, no inhibition of the off-target hCA I and II isoforms was observed. Compounds 8 a-f (another set of triazoles) exhibited nanomolar inhibition against hCA isoforms I, II, IX and XII, among which compounds 8 c, 8 d, and 8 f were found to inhibit the tumor-associated hypoxia-induced hCA isoform IX with Ki values of 1.8, 2.3, and 2.0 nm respectively. Further exploration of these compounds could be useful for the development of novel antitumor agents with selective mechanisms of CA inhibitory action. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/28940980/Sulfocoumarin__Coumarin__4_Sulfamoylphenyl_Bearing_Indazole_3_carboxamide_Hybrids:_Synthesis_and_Selective_Inhibition_of_Tumor_Associated_Carbonic_Anhydrase_Isozymes_IX_and_XII_ L2 - https://doi.org/10.1002/cmdc.201700446 DB - PRIME DP - Unbound Medicine ER -