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New amide derivatives of Probenecid as selective inhibitors of carbonic anhydrase IX and XII: biological evaluation and molecular modelling studies.
Bioorg Med Chem. 2015 Jul 01; 23(13):2975-81.BM

Abstract

Novel amide derivatives of Probenecid were synthesized and discovered to act as potent and selective inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII. The proposed chemical transformation of the carboxylic acid into an amide group led to a complete loss of hCA I and II inhibition (Kis >10,000nM) and enhanced the inhibitory activity against hCA IX and XII, with respect to the parent compound (incorporating a COOH function). These promising biological results have been corroborated by molecular modelling studies within the active sites of the four studied human carbonic anhydrases, which enabled us to rationalize both the isoform selectivity and high activity against the tumor-associated isoforms hCA IX/XII.

Authors+Show Affiliations

Department of Pharmacy, 'G. D'Annunzio' University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy. Electronic address: simone.carradori@unich.it.Department of Pharmacy, 'G. D'Annunzio' University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, Vatan Caddesi, 34093 Fatih, Istanbul, Turkey.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 Dept., Section of Pharmaceutical and Nutraceutical Sciences, Via U. 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

26007302

Citation

Carradori, Simone, et al. "New Amide Derivatives of Probenecid as Selective Inhibitors of Carbonic Anhydrase IX and XII: Biological Evaluation and Molecular Modelling Studies." Bioorganic & Medicinal Chemistry, vol. 23, no. 13, 2015, pp. 2975-81.
Carradori S, Mollica A, Ceruso M, et al. New amide derivatives of Probenecid as selective inhibitors of carbonic anhydrase IX and XII: biological evaluation and molecular modelling studies. Bioorg Med Chem. 2015;23(13):2975-81.
Carradori, S., Mollica, A., Ceruso, M., D'Ascenzio, M., De Monte, C., Chimenti, P., Sabia, R., Akdemir, A., & Supuran, C. T. (2015). New amide derivatives of Probenecid as selective inhibitors of carbonic anhydrase IX and XII: biological evaluation and molecular modelling studies. Bioorganic & Medicinal Chemistry, 23(13), 2975-81. https://doi.org/10.1016/j.bmc.2015.05.013
Carradori S, et al. New Amide Derivatives of Probenecid as Selective Inhibitors of Carbonic Anhydrase IX and XII: Biological Evaluation and Molecular Modelling Studies. Bioorg Med Chem. 2015 Jul 1;23(13):2975-81. PubMed PMID: 26007302.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - New amide derivatives of Probenecid as selective inhibitors of carbonic anhydrase IX and XII: biological evaluation and molecular modelling studies. AU - Carradori,Simone, AU - Mollica,Adriano, AU - Ceruso,Mariangela, AU - D'Ascenzio,Melissa, AU - De Monte,Celeste, AU - Chimenti,Paola, AU - Sabia,Rocchina, AU - Akdemir,Atilla, AU - Supuran,Claudiu T, Y1 - 2015/05/14/ PY - 2015/02/25/received PY - 2015/05/05/revised PY - 2015/05/06/accepted PY - 2015/5/27/entrez PY - 2015/5/27/pubmed PY - 2016/3/8/medline KW - Molecular modelling KW - Probenecid KW - Selective carbonic anhydrase IX inhibitors KW - Selective carbonic anhydrase XII inhibitors KW - Tertiary sulfonamides SP - 2975 EP - 81 JF - Bioorganic & medicinal chemistry JO - Bioorg. Med. Chem. VL - 23 IS - 13 N2 - Novel amide derivatives of Probenecid were synthesized and discovered to act as potent and selective inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII. The proposed chemical transformation of the carboxylic acid into an amide group led to a complete loss of hCA I and II inhibition (Kis >10,000nM) and enhanced the inhibitory activity against hCA IX and XII, with respect to the parent compound (incorporating a COOH function). These promising biological results have been corroborated by molecular modelling studies within the active sites of the four studied human carbonic anhydrases, which enabled us to rationalize both the isoform selectivity and high activity against the tumor-associated isoforms hCA IX/XII. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/26007302/New_amide_derivatives_of_Probenecid_as_selective_inhibitors_of_carbonic_anhydrase_IX_and_XII:_biological_evaluation_and_molecular_modelling_studies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(15)00413-7 DB - PRIME DP - Unbound Medicine ER -