Dual Carbonic Anhydrase - Cyclooxygenase-2 Inhibitors

Abstract

Cyclooxygenase is a key enzyme responsible for metabolisation of arachidonic acid into prostaglandins and thromboxane. This enzyme is the target of non steroidal anti-inflammatory drugs (NSAIDs), used against inflammation and pain. The inducible COX-2 was associated with inflammatory conditions, whereas the constitutive form (COX-1) was responsible for the beneficial effects of the PGs. This observation led to the development of COX-2 inhibitors or "coxibs" of which rofecoxib (Vioxx) characterized by a methylsulfone moiety and the sulfonamides celecoxib (Celebrex) and valdecoxib (Bextra). Initially described as COX-2 "selective" inhibitors, recent reports revealed a nanomolar inhibition activity of the sulfonamide COX-2 inhibitors for several carbonic anhydrase (CA) isoforms, confirmed by X-ray crystal structures for the adducts of celecoxib and valdecoxib with isozyme CA II. This dual activity may help to explain differences in clinical observation between sulfonamide and methylsulfone COX-2 inhibitors. Moreover, the inhibition of CA isozymes, critical for the development and invasion of cancer cells, such as CA II, IX and XII, may constitute an important mechanism of antitumor action of such sulfonamide compounds.

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

“…Part of the core structure of the oxicam class includes a S-N bond into a ring structure, dioxothiazine ring structurally resembling the sulfonamide bond. COX-2 inhibitors valdecoxib, celecoxib, and metamizole also inhibit CAII [41]. No studies have been done that evaluate the potential role for carbonic anhydrase II inhibition in the pathogenesis of SJS.…”

Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: From biology to clinical use

“…Different classes of sulfonamides and related compounds can efficiently inhibit CA IX in vitro and some of them showed anticancer effect also in vivo in xenografted subcutaneous or metastatic animal models [77,84]. Interestingly, CA IX activity can be inhibited also by celecoxib and valdecoxib, sulfonamide inhibitors of cyclooxygense 2 (COX-2), which is a key enzyme of arachidonic acid metabolism involved in colorectal carcinoma [147,148]. This may suggest that the mode of action of these COX-2 inhibitors could involve targeting of CAs.…”

Inhibition of Ion Channels and Heart Beat in Drosophila by Selective COX-2 Inhibitor SC-791

“…Indeed, Macias and coauthors have shown that celecoxib can prolong action potential duration in mouse cardiac myocytes while shortening it in guinea pig cardiac myocytes [13]. An additional layer of complexity to this picture is added by possible interaction of coxibs with other molecular targets that could alter cell functioning but are not related to ion channels, such as the coxibs' main receptor, COX-2, or carbonic anhydrases [1], [7]. Thus, although apparently no single ‘ideal’ model organism for studying ion channel-related effects of coxibs exists, the well-studied Drosophila , which conveniently lacks cyclooxygenases, provides a good experimental setting for basic research in this direction.…”

“…For instance, the drug inhibits carbonic anhydrases with nanomolar affinity [1], while at low micromolar concentrations it alters functioning of voltage-activated Na + , K + and Ca 2+ channels [2], [3], [4], [5], induces cytotoxicity towards cardiomyocytes [6], triggers apoptosis and blocks cell cycle progression [1], [7].…”