Designing of novel carbonic anhydrase inhibitors and activators.

Carbonic anhydrases (CAs, EC 4.2.1.1) are wide spread enzymes, present in mammals in at least 14 different isoforms: some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII), while others are membrane-bound (CA IV, CA IX, CA XII and CA XIV); CA V is mitochondrial, and CA VI is secreted in the saliva. Three acatalytic forms are also known (CARP VIII, CARP X and CARP XI). Several important physiological and physio-pathological functions are played by many CA isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides. The catalytic and inhibition mechanisms of these enzymes are understood in great detail, and this greatly helped in the design of potent inhibitors, some of which possess important clinical applications. The use of such CA inhibitors (CAIs) as antiglaucoma drugs will be discussed in detail, together with the recent developments that led to isozyme-specific and organ-selective inhibitors. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: many potent CAIs were shown to inhibit the growth of several tumor cell lines in vitro and in vivo, constituting thus interesting leads for developing novel antitumor therapies. Future prospects for drug design applications for inhibitors of these ubiquitous enzymes will be dealt with. Although activation of CAs has been a controversial issue for some time, recent kinetic, spectroscopic and X-ray crystallographic experiments offered an explanation for this phenomenon, based on the catalytic mechanism. It has been demonstrated recently, that molecules that act as carbonic anhydrase activators (CAAs) bind at the entrance of the enzyme active site participating in facilitated proton transfer processes between the active site and the reaction medium. In addition to CA II--activator adducts, X-ray crystallographic studies have also been reported for ternary complexes of this isozyme with activators and anion (azide) inhibitors. Structure-activity correlations for diverse classes of activators will be discussed for the isozymes for which the phenomenon has been studied, i.e., CA I, II, III and IV. The possible physiologic relevance of CA activation will also be addressed, together with the recent pharmacological applications of blood CA isozymes activators, as potential memory enhancing drugs.