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Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as potent carbonic anhydrase inhibitors: synthesis, biological evaluation, and enzyme--ligand X-ray studies.
J Med Chem. 2010 Mar 25; 53(6):2401-8.JM

Abstract

Following previous studies we herein report the exploration of the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects and enzyme selectivity of a small class of 1-(cyclo)alkylisoquinolines containing a sulfonamide function considered a key feature for inhibiting CA. The results of enzymatic assays against human (h) CA isoforms, hCA I and hCA II (cytosolic, ubiquitous enzymes), hCA IX (transmembrane, tumor-associated), and hCA XIV (transmembrane), suggested that the presence of C-1 small substituents on isoquinoline scaffold controls both inhibitory potency and selectivity. Some derivatives showed potent hCA IX and hCA XIV inhibitory effects at nanomolar concentrations as well as low affinity for the ubiquitous hCA II. Moreover, we report the X-ray crystal structure of one of these derivatives in complex with dominant human isoform II, thus confirming the sulfonamide--zinc interactions. Finally, the results of docking experiments suggested the hypothetic interactions in the catalytic binding site for the most active and selective hCA IX and hCA XIV inhibitor.

Authors+Show Affiliations

Dipartimento Farmaco-Chimico, Universita di Messina, Viale Annunziata, I-98168 Messina, Italy. rgitto@pharma.unime.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

20170095

Citation

Gitto, Rosaria, et al. "Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as Potent Carbonic Anhydrase Inhibitors: Synthesis, Biological Evaluation, and Enzyme--ligand X-ray Studies." Journal of Medicinal Chemistry, vol. 53, no. 6, 2010, pp. 2401-8.
Gitto R, Agnello S, Ferro S, et al. Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as potent carbonic anhydrase inhibitors: synthesis, biological evaluation, and enzyme--ligand X-ray studies. J Med Chem. 2010;53(6):2401-8.
Gitto, R., Agnello, S., Ferro, S., De Luca, L., Vullo, D., Brynda, J., Mader, P., Supuran, C. T., & Chimirri, A. (2010). Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as potent carbonic anhydrase inhibitors: synthesis, biological evaluation, and enzyme--ligand X-ray studies. Journal of Medicinal Chemistry, 53(6), 2401-8. https://doi.org/10.1021/jm9014026
Gitto R, et al. Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as Potent Carbonic Anhydrase Inhibitors: Synthesis, Biological Evaluation, and Enzyme--ligand X-ray Studies. J Med Chem. 2010 Mar 25;53(6):2401-8. PubMed PMID: 20170095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as potent carbonic anhydrase inhibitors: synthesis, biological evaluation, and enzyme--ligand X-ray studies. AU - Gitto,Rosaria, AU - Agnello,Stefano, AU - Ferro,Stefania, AU - De Luca,Laura, AU - Vullo,Daniela, AU - Brynda,Jiri, AU - Mader,Pavel, AU - Supuran,Claudiu T, AU - Chimirri,Alba, PY - 2010/2/23/entrez PY - 2010/2/23/pubmed PY - 2010/5/5/medline SP - 2401 EP - 8 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 53 IS - 6 N2 - Following previous studies we herein report the exploration of the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects and enzyme selectivity of a small class of 1-(cyclo)alkylisoquinolines containing a sulfonamide function considered a key feature for inhibiting CA. The results of enzymatic assays against human (h) CA isoforms, hCA I and hCA II (cytosolic, ubiquitous enzymes), hCA IX (transmembrane, tumor-associated), and hCA XIV (transmembrane), suggested that the presence of C-1 small substituents on isoquinoline scaffold controls both inhibitory potency and selectivity. Some derivatives showed potent hCA IX and hCA XIV inhibitory effects at nanomolar concentrations as well as low affinity for the ubiquitous hCA II. Moreover, we report the X-ray crystal structure of one of these derivatives in complex with dominant human isoform II, thus confirming the sulfonamide--zinc interactions. Finally, the results of docking experiments suggested the hypothetic interactions in the catalytic binding site for the most active and selective hCA IX and hCA XIV inhibitor. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/20170095/Identification_of_34_Dihydroisoquinoline_2_1H__sulfonamides_as_potent_carbonic_anhydrase_inhibitors:_synthesis_biological_evaluation_and_enzyme__ligand_X_ray_studies_ L2 - https://dx.doi.org/10.1021/jm9014026 DB - PRIME DP - Unbound Medicine ER -