Substituted benzene sulfonamides incorporating 1,3,5-triazinyl moieties potently inhibit human carbonic anhydrases II, IX and XII

Amrita K Saluja; Meena Tiwari; Daniela Vullo; Claudiu T Supuran

doi:10.1016/j.bmcl.2014.01.048

Substituted benzene sulfonamides incorporating 1,3,5-triazinyl moieties potently inhibit human carbonic anhydrases II, IX and XII

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1310-4. doi: 10.1016/j.bmcl.2014.01.048. Epub 2014 Jan 27.

Authors

Amrita K Saluja¹, Meena Tiwari², Daniela Vullo³, Claudiu T Supuran⁴

Affiliations

¹ Shri G.S. Institute of Technology and Science, Department of Pharmacy, 23, Park Road, Indore 452003, Madhya Pradesh, India.
² Shri G.S. Institute of Technology and Science, Department of Pharmacy, 23, Park Road, Indore 452003, Madhya Pradesh, India. Electronic address: mtiwari@sgsits.ac.in.
³ Università degli Studi di Firenze, Dipartimento di Chimica, Lab. Chimica Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy; Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, I-50019 Sesto Fiorentino (Florence), Italy.
⁴ Università degli Studi di Firenze, Dipartimento di Chimica, Lab. Chimica Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy; Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, I-50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 24507918
DOI: 10.1016/j.bmcl.2014.01.048

Abstract

A series of benzene sulfonamides incorporating 1,3,5-triazinyl moieties were synthesized using cyanuric chloride as starting material. Inhibition studies against human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I, II (cytosolic) and IX, XII (transmembrane, tumor-associated) isoforms were performed with the new compounds. hCA I was modestly inhibited (KIs in the range of 87 nM-4.35 μM), hCA II was moderately inhibited by most of the new compounds (KIs in the range of 12.5-130 nM), whereas the tumor associated isoforms were potently inhibited, with KIs in the range of 1.2-34.1 nM against hCA IX and of 2.1-33.9 against hCA XII, respectively. Docking studies of some of the new compounds showed an effective binding mode within the enzyme active site, as demonstrated earlier by X-ray crystallography for structurally-related sulfonamides incorporating 1,3,5-triazinyl functionalities.

Keywords: 1,3,5-Triazine; Benzene sulfonamides; Carbonic anhydrase; Enzyme inhibition; Isoform selectivity; Molecular docking.

Publication types

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

MeSH terms

Antigens, Neoplasm / chemistry*
Antigens, Neoplasm / metabolism
Benzene / chemistry
Binding Sites
Carbonic Anhydrase II / antagonists & inhibitors*
Carbonic Anhydrase II / metabolism
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors / chemistry*
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrase Inhibitors / pharmacology
Carbonic Anhydrases / chemistry*
Carbonic Anhydrases / metabolism
Catalytic Domain
Enzyme Activation / drug effects
Humans
Molecular Docking Simulation
Protein Binding / drug effects
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / metabolism
Sulfonamides / pharmacology
Triazines / chemistry*

Substances

Antigens, Neoplasm
Carbonic Anhydrase Inhibitors
Sulfonamides
Triazines
Carbonic Anhydrase II
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII
Benzene