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Structural study of the location of the phenyl tail of benzene sulfonamides and the effect on human carbonic anhydrase inhibition.
Bioorg Med Chem. 2013 Nov 01; 21(21):6674-80.BM

Abstract

The crystal structure of 4-phenylacetamidomethyl-benzenesulfonamide (4ITP) bound to human carbonic anhydrase (hCA, EC 4.2.1.1) II is reported. 4ITP is a medium potency hCA I and II inhibitor (KIs of 54-75nM), a strong mitochondrial CA VA/VB inhibitor (KIs of 8.3-8.6nM) and a weak transmembrane CA inhibitor (KIs of 136-212nM against hCA IX and XII). This elongated compound binds in an extended conformation to hCA II, with its tail lying towards the hydrophobic half of the active site whereas the sulfonamide moiety coordinates the zinc ion. The present structure was compared to that of structurally related aromatic sulfonamides, such as 4-phenylacetamido-benzene-sulfonamide (3OYS), 4-(2-mercaptophenylacetamido)-benzene-sulfonamide (2HD6) and 4-(3-nitrophenyl)-ureido-benzenesulfonamide (3N2P). Homology models of the hCA I, VA, VB, IX and XII structures were build which afforded an understanding of the amino acids involved in the binding of these compounds to these isoforms. The main conclusion of the study is that the orientation of the tail moiety and the presence of flexible linkers as well polar groups in it, strongly influence the potency and the selectivity of the sulfonamides for the inhibition of cytosolic, mitochondrial or transmembrane CA isoforms.

Authors+Show Affiliations

Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy; Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazit, Istanbul, Turkey.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24012377

Citation

Güzel-Akdemir, Ozlen, et al. "Structural Study of the Location of the Phenyl Tail of Benzene Sulfonamides and the Effect On Human Carbonic Anhydrase Inhibition." Bioorganic & Medicinal Chemistry, vol. 21, no. 21, 2013, pp. 6674-80.
Güzel-Akdemir O, Biswas S, Lastra K, et al. Structural study of the location of the phenyl tail of benzene sulfonamides and the effect on human carbonic anhydrase inhibition. Bioorg Med Chem. 2013;21(21):6674-80.
Güzel-Akdemir, O., Biswas, S., Lastra, K., McKenna, R., & Supuran, C. T. (2013). Structural study of the location of the phenyl tail of benzene sulfonamides and the effect on human carbonic anhydrase inhibition. Bioorganic & Medicinal Chemistry, 21(21), 6674-80. https://doi.org/10.1016/j.bmc.2013.08.011
Güzel-Akdemir O, et al. Structural Study of the Location of the Phenyl Tail of Benzene Sulfonamides and the Effect On Human Carbonic Anhydrase Inhibition. Bioorg Med Chem. 2013 Nov 1;21(21):6674-80. PubMed PMID: 24012377.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural study of the location of the phenyl tail of benzene sulfonamides and the effect on human carbonic anhydrase inhibition. AU - Güzel-Akdemir,Ozlen, AU - Biswas,Shyamasri, AU - Lastra,Katherine, AU - McKenna,Robert, AU - Supuran,Claudiu T, Y1 - 2013/08/12/ PY - 2013/06/25/received PY - 2013/08/05/accepted PY - 2013/9/10/entrez PY - 2013/9/10/pubmed PY - 2014/5/27/medline KW - Carbonic anhydrase KW - Inhibitor KW - Phenylacetamido KW - Sulfonamide KW - Tail KW - X-ray crystallography SP - 6674 EP - 80 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 21 IS - 21 N2 - The crystal structure of 4-phenylacetamidomethyl-benzenesulfonamide (4ITP) bound to human carbonic anhydrase (hCA, EC 4.2.1.1) II is reported. 4ITP is a medium potency hCA I and II inhibitor (KIs of 54-75nM), a strong mitochondrial CA VA/VB inhibitor (KIs of 8.3-8.6nM) and a weak transmembrane CA inhibitor (KIs of 136-212nM against hCA IX and XII). This elongated compound binds in an extended conformation to hCA II, with its tail lying towards the hydrophobic half of the active site whereas the sulfonamide moiety coordinates the zinc ion. The present structure was compared to that of structurally related aromatic sulfonamides, such as 4-phenylacetamido-benzene-sulfonamide (3OYS), 4-(2-mercaptophenylacetamido)-benzene-sulfonamide (2HD6) and 4-(3-nitrophenyl)-ureido-benzenesulfonamide (3N2P). Homology models of the hCA I, VA, VB, IX and XII structures were build which afforded an understanding of the amino acids involved in the binding of these compounds to these isoforms. The main conclusion of the study is that the orientation of the tail moiety and the presence of flexible linkers as well polar groups in it, strongly influence the potency and the selectivity of the sulfonamides for the inhibition of cytosolic, mitochondrial or transmembrane CA isoforms. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/24012377/Structural_study_of_the_location_of_the_phenyl_tail_of_benzene_sulfonamides_and_the_effect_on_human_carbonic_anhydrase_inhibition_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(13)00693-7 DB - PRIME DP - Unbound Medicine ER -