A Simple Yet Multifaceted Enzyme

Abstract

Carbonic anhydrases (CAs) are involved in many physiological and pathological .events in organisms all over the phylogenetic tree. Over the last three decades I was involved in unravelling the biochemical basic phenomena connected to these enzymes and in drug design of modulators of their activity (inhibitors and activators). The various approaches I developed were applied to many types of such enzymes and allowed the discovery of many classes of highly isoform-selective inhibitors. This afforded new applications of the inhibitors for the management of hypoxic tumors, neuropathic pain, cerebral ischemia, arthritis, degenerative disorders apart the classical ones connected with these drugs (diuretics, antiglaucoma, antiepileptic and antiobesity action). The study of CA activators showed that these enzymes may represent a crucial family of new targets for improving cognition as well as in therapeutic areas, such as phobias, obsessive-compulsive disorder, generalized anxiety, and post-traumatic stress disorders, for which few efficient therapies are available.

Novel Insights on Human Carbonic Anhydrase Inhibitors Based on Coumalic Acid: Design, Synthesis, Molecular Modeling Investigation, and Biological Studies

“…The reversible hydration of carbon dioxide is an important reaction involved in a plethora of fundamental processes taking place in organisms from across the phylogenetic tree [ 1 , 2 , 3 ]. However, this quite simple reaction slowly occurs in physiological conditions, requiring the aid of an enzyme that strongly accelerates it.…”

Pyridinium derivatives of 3-aminobenzenesulfonamide are nanomolar-potent inhibitors of tumor-expressed carbonic anhydrase isozymes CA IX and CA XII

“…Their structure is encoded by eight evolutionary unrelated gene families, namely, a-, b-, g-, d-, z-, η-, θ-, and i-CAs. [7,[32][33][34][35] Fourteen CA isozymes (hCAs), all belonging to the aclass, are currently known in humans, with different tissue and organ distribution, subcellular localization and catalytic properties. One can distinguish cytosolic isozymes (CA I, CA II, CA III, CA VII, and CA XIII), membrane-bound isoforms (CA IV, CA IX, CA XII, and CA XIV), mitochondrial isozymes (CA VA and CA VB) and even secreted isozymes (CA VI).…”

“…However, it was established that clinically used CA inhibitors (CAIs) 1-5, initially designed for efficient inhibition of CA II, are quite potent against the other CA isozymes [7,32,34,38,[41][42][43][44][45][46]48]. The low isozyme selectivity of these sulfonamides can be explained by the relatively high sequence homology of CA isoforms.…”

“…Another frequently used strategy to achieve isozyme selectivity is through membraneimpermeant inhibitors that inhibit only the membrane-bound isozymes, leaving the cytosolic isozymes unaffected. [7,32,34,38,[41][42][43][44][45][46]48] One strategy to obtain membrane-impermeant inhibitors was through conjugation of CAI warheads with very hydrophilic moieties, either polymers such as dextran, aminoethyldextran, polyethylene glycol [45,59,60] [68,73] (Chart 2). The salt-like nature of these pyridinium sulfonamides does not allow them to cross biological membranes, inhibiting the membrane-bound isozymes while leaving unaffected the cytosolic CA I and CA II, as proved by in vitro and in vivo studies [7,69,74].…”

Cytotoxic, antiglycation and carbonic anhydrase inhibition studies of chromium(III)-aroylhydrazine complexes

“…The acetazolamide, methazolamide, ethoxozolamide and dorazolamide are the standard CAIs, they have an important CA inhibitory properties [35][36][37][38]. Thiadiazole sulphonamides (such as benzolamide, acetazolamide and methazolamide) with multiple metals in which Zn(II), Fe(II), Hg(II), Cd(II), Co(II), V(IV), Cu(II), Cr(III), Ni(II) and lanthanides(III) have been examined by CA inhibition strengths against isozymes for their prospective pharmacological applications [39][40][41][42][43][44][45][46]. These complexes show very powerful action against CA I and CA II as linked to their sulphonamides [43].…”