N-Substituted and ring opened saccharin derivatives selectively inhibit transmembrane, tumor-associated carbonic anhydrases IX and XII

Jekaterīna Ivanova; Fabrizio Carta; Daniela Vullo; Janis Leitans; Andris Kazaks; Kaspars Tars; Raivis Žalubovskis; Claudiu T Supuran

doi:10.1016/j.bmc.2017.04.007

N-Substituted and ring opened saccharin derivatives selectively inhibit transmembrane, tumor-associated carbonic anhydrases IX and XII

Bioorg Med Chem. 2017 Jul 1;25(13):3583-3589. doi: 10.1016/j.bmc.2017.04.007. Epub 2017 Apr 7.

Authors

Jekaterīna Ivanova¹, Fabrizio Carta², Daniela Vullo³, Janis Leitans⁴, Andris Kazaks⁴, Kaspars Tars⁵, Raivis Žalubovskis⁶, Claudiu T Supuran⁷

Affiliations

¹ Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia; Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Paula Valdena Str. 3/7, Riga LV-1048, Latvia.
² Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di ScienzeFarmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
³ Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
⁴ Latvian Biomedical Research and Study Center, Rātsupītes 1, LV-1067 Riga, Latvia.
⁵ Latvian Biomedical Research and Study Center, Rātsupītes 1, LV-1067 Riga, Latvia; Faculty of Biology, Department of Molecular Biology, University of Latvia, Jelgavas 1, LV-1004 Riga, Latvia.
⁶ Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia; Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Paula Valdena Str. 3/7, Riga LV-1048, Latvia. Electronic address: raivis@osi.lv.
⁷ Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di ScienzeFarmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 28416101
DOI: 10.1016/j.bmc.2017.04.007

Abstract

A series of N-substituted saccharins incorporating aryl, alkyl and alkynyl moieties, as well as some ring opened derivatives were prepared and investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The widespread cytosolic isoforms CA I and II were not inhibited by these sulfonamides whereas transmembrane, tumor-associated ones were effectively inhibited, with K_Is in the range of 22.1-481nM for CA IX and of 3.9-245nM for hCA XII. Although the inhibition mechanism of these tertiary/secondary sulfonamides is unknown for the moment, the good efficacy and especially selectivity for the inhibition of the tumor-associated over the cytosolic, widespread isoforms, make these derivatives of considerable interest as enzyme inhibitors with various pharmacologic applications.

Keywords: Carbonic anhydrase; Inhibitor; Isoform selectivity; Saccharin; Secondary/tertiary sulfonamide.

Publication types

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

MeSH terms

Antigens, Neoplasm / metabolism
Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Dose-Response Relationship, Drug
Humans
Molecular Structure
Saccharin / chemical synthesis
Saccharin / chemistry
Saccharin / pharmacology*
Structure-Activity Relationship

Substances

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