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Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: synthesis, biological evaluation and molecular modelling studies.
Bioorg Med Chem. 2014 Aug 01; 22(15):3982-8.BM

Abstract

Novel amide derivatives of probenecid, a well-known uricosuric agent, were synthesized and evaluated as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1). The transmembrane isoforms (hCA IX and XII) were potently and selectively inhibited by some of them. The proposed chemical modification led to a complete loss of hCA II inhibition (K(i)s>10,000 nM) and enhanced the inhibitory activity against the tumour-associated hCA XII (compound 4 showed a K(i) value of 15.3 nM). The enzyme inhibitory data have also been validated by docking studies of the compounds within the active site of hCA XII.

Authors+Show Affiliations

Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: melissa.dascenzio@uniroma1.it.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.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, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), 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 Nutriceutical 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

25027802

Citation

D'Ascenzio, Melissa, et al. "Selective Inhibition of Human Carbonic Anhydrases By Novel Amide Derivatives of Probenecid: Synthesis, Biological Evaluation and Molecular Modelling Studies." Bioorganic & Medicinal Chemistry, vol. 22, no. 15, 2014, pp. 3982-8.
D'Ascenzio M, Carradori S, Secci D, et al. Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: synthesis, biological evaluation and molecular modelling studies. Bioorg Med Chem. 2014;22(15):3982-8.
D'Ascenzio, M., Carradori, S., Secci, D., Vullo, D., Ceruso, M., Akdemir, A., & Supuran, C. T. (2014). Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: synthesis, biological evaluation and molecular modelling studies. Bioorganic & Medicinal Chemistry, 22(15), 3982-8. https://doi.org/10.1016/j.bmc.2014.06.003
D'Ascenzio M, et al. Selective Inhibition of Human Carbonic Anhydrases By Novel Amide Derivatives of Probenecid: Synthesis, Biological Evaluation and Molecular Modelling Studies. Bioorg Med Chem. 2014 Aug 1;22(15):3982-8. PubMed PMID: 25027802.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: synthesis, biological evaluation and molecular modelling studies. AU - D'Ascenzio,Melissa, AU - Carradori,Simone, AU - Secci,Daniela, AU - Vullo,Daniela, AU - Ceruso,Mariangela, AU - Akdemir,Atilla, AU - Supuran,Claudiu T, Y1 - 2014/06/26/ PY - 2014/04/01/received PY - 2014/05/31/revised PY - 2014/06/02/accepted PY - 2014/7/17/entrez PY - 2014/7/17/pubmed PY - 2015/9/5/medline KW - Probenecid KW - Selective carbonic anhydrase IX inhibitors KW - Selective carbonic anhydrase XII inhibitors KW - Tertiary sulfonamides SP - 3982 EP - 8 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 22 IS - 15 N2 - Novel amide derivatives of probenecid, a well-known uricosuric agent, were synthesized and evaluated as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1). The transmembrane isoforms (hCA IX and XII) were potently and selectively inhibited by some of them. The proposed chemical modification led to a complete loss of hCA II inhibition (K(i)s>10,000 nM) and enhanced the inhibitory activity against the tumour-associated hCA XII (compound 4 showed a K(i) value of 15.3 nM). The enzyme inhibitory data have also been validated by docking studies of the compounds within the active site of hCA XII. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/25027802/Selective_inhibition_of_human_carbonic_anhydrases_by_novel_amide_derivatives_of_probenecid:_synthesis_biological_evaluation_and_molecular_modelling_studies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(14)00446-5 DB - PRIME DP - Unbound Medicine ER -