Inhibition of tumor-associated human carbonic anhydrase isozymes IX and XII by a new class of substituted-phenylacetamido aromatic sulfonamides

Atilla Akdemir; Ozlen Güzel-Akdemir; Andrea Scozzafava; Clemente Capasso; Claudiu T Supuran

doi:10.1016/j.bmc.2013.06.029

Inhibition of tumor-associated human carbonic anhydrase isozymes IX and XII by a new class of substituted-phenylacetamido aromatic sulfonamides

Bioorg Med Chem. 2013 Sep 1;21(17):5228-32. doi: 10.1016/j.bmc.2013.06.029. Epub 2013 Jun 20.

Authors

Atilla Akdemir¹, Ozlen Güzel-Akdemir, Andrea Scozzafava, Clemente Capasso, Claudiu T Supuran

Affiliation

¹ Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, Vatan Caddesi, 34093 Fatih, Istanbul, Turkey.

PMID: 23842519
DOI: 10.1016/j.bmc.2013.06.029

Abstract

Here, we investigate 28 structurally new sulfonamides and their subsequent testing for enzyme inhibition of cytosolic and tumor-associated carbonic anhydrases (CAs, EC 4.2.1.1). The compounds showed very potent inhibition of four physiologically relevant human (h) CA isoforms, namely hCA I, II, IX and XII. Interestingly, the KI values were in the nanomolar range for the tumor-associated hCA IX and hCA XII. Docking studies have revealed details regarding the very favorable interactions between the scaffolds of this new class of inhibitors and the active sites of the investigated CA isoforms. As there are reported cases of tumors overexpressing both CA II and IX, such potent inhibitors for the two isoforms as those detected in this work, may have applications for targeting more than one CA present in tumors.

Keywords: Carbonic anhydrases; Cytosolic isoforms I and II; Docking; Sulfonamides; Tumor-associated isoforms IX and XII.

Publication types

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

MeSH terms

Antigens, Neoplasm / chemistry*
Antigens, Neoplasm / metabolism
Binding Sites
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry*
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrases / chemistry*
Carbonic Anhydrases / metabolism
Catalytic Domain
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Molecular Docking Simulation
Protein Binding
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / metabolism

Substances

Antigens, Neoplasm
Carbonic Anhydrase Inhibitors
Isoenzymes
Sulfonamides
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII