Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors

Jason C Morris; Johanna Chiche; Caroline Grellier; Marie Lopez; Laurent F Bornaghi; Alfonso Maresca; Claudiu T Supuran; Jacques Pouysségur; Sally-Ann Poulsen

doi:10.1021/jm200892s

Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors

J Med Chem. 2011 Oct 13;54(19):6905-18. doi: 10.1021/jm200892s. Epub 2011 Sep 2.

Authors

Jason C Morris¹, Johanna Chiche, Caroline Grellier, Marie Lopez, Laurent F Bornaghi, Alfonso Maresca, Claudiu T Supuran, Jacques Pouysségur, Sally-Ann Poulsen

Affiliation

¹ Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia.

PMID: 21851094
DOI: 10.1021/jm200892s

Abstract

Carbonic anhydrase (CA) enzymes, specifically membrane-bound isozymes CA IX and CA XII, underpin a pH-regulating system that enables hypoxic tumor cell survival and proliferation. CA IX and XII are implicated as potential targets for the development of new hypoxic cancer therapies. To date, only a few small molecules have been characterized in CA-relevant cell and animal model systems. In this paper, we describe the development of a new class of carbohydrate-based small molecule CA inhibitors, many of which inhibit CA IX and XII within a narrow range of low nanomolar K(i) values (5.3-11.2 nM). We evaluate for the first time carbohydrate-based CA inhibitors in cell-based models that emulate the protective role of CA IX in an acidic tumor microenvironment. Our findings identified two inhibitors (compounds 5 and 17) that block CA IX-induced survival and have potential for development as in vivo cancer cell selective inhibitors.

Publication types

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

MeSH terms

Antigens, Neoplasm / metabolism*
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors / chemical synthesis*
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology
Carbonic Anhydrases / metabolism*
Cell Hypoxia
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Click Chemistry
Drug Screening Assays, Antitumor
Glucosides / chemical synthesis*
Glucosides / chemistry
Glucosides / pharmacology
Humans
Hydrogen-Ion Concentration
Isoenzymes / antagonists & inhibitors
Sulfonamides / chemical synthesis*
Sulfonamides / chemistry
Sulfonamides / pharmacology

Substances

4-(4-((2',3',4',6'-tetra-O-acetylglucopyranosyl)thiomethyl)-5-iodo-1-H-1,2,3-triazol-1-yl)benzenesulfonamide
4-(4-((glucopyranosyl)thiomethyl)-5-iodo-1-H-1,2,3-triazol-1-yl)benzenesulfonamide
Antigens, Neoplasm
Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Glucosides
Isoenzymes
Sulfonamides
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII