oa Editorial [Hot Topic: Carbonic Anhydrases: Again, and Again, and Again (Executive Editor: Claudiu T. Supuran)]

I use this title to introduce this issue of Curr Pharm Des. dedicated to the carbonic anhydrase (CA) conference held in September 2009 in Florence, Italy, as I found it in the not very happy comments of a reviewer of one of my manuscripts sent recently for publication, who was complaining that we publish too much in this field. Thus, I found this situation quite illustrative for this entire research field, in which important advancements have been achieved ultimately with a very high frequency. In fact, the prevalent view of many “important” scientists from both academia and industry was that CAs are “boring enzymes”, at least until recently. For several good reasons: (i) they catalyze a very simple reaction, CO2 hydration to bicarbonate and protons, which anyhow can occur without a catalyst [1]; (ii) their inhibition was not very successful in the past from the pharmaceutical viewpoint, especially considering the diuretic or antiepileptic activity of some old drugs, such as acetazolamide, ethoxzolamide, etc. [1]; (iii) these enzymes are widespread in many tissues/cells, and their inhibition by compounds originally designed for other applications, may only lead to side effects and complications with FDA or other regulatory agencies, when a new such drug has to be launched clinically. There are in fact examples of pharmaceutical companies which published very unrealistic inhibition data of their compounds (e.g., both topiramate and zonisamide were claimed to be weak or very weak CA inhibitors (CAIs) by their discoverers, whereas they are low nanomolar ones against many relevant isoforms [1]). However this distorted view started to change steadfastly in the last years. And again for multiple reasons. For example, when we proposed sulfonamide CAIs as anticancer agents more than 10 years ago, there was a great reluctance to accept this idea and the first paper presenting such data [2] had great difficulties to be published. Nowadays several CA isozymes are widely accepted as antitumor drug targets [1,3-5], the mechanims of action of such compounds started to be understood both at the molecular level and as pharmacology, and there are drug companies developing them both as imaging tools for hypoxic tumors or as anticancer drugs [3-5]. This aspect is presented in several reviews of this issue [3-5], both from the biochemical, medicinal chemistry and pharmacological points of view. It has been in fact possible to understand in detail these aspects due to the report of the X-ray crystal structure of isoform CA IX, the main anticancer target in this family of enzymes, which is reviewed in the second paper of the issue from De Simone's group [4]. The latest developments regarding the biochemistry, molecular biology, genetic regulation and pharmacology of CA IX are then detailed in the next paper, by Pastorekova's group [5], which are in fact the discoverers of this highly interesting enzyme. Their contributions in understanding many aspects related to CA IX were seminal in all the years that passed since their initial report of this first tumor-associated isoform. The next paper, from Parkkila's group [6], deals with a rather neglected topic in the CA research, and more precisely the acatalytic isoform CA VIII. In this excellent review a thorough analysis of the genetics, phylogeny, possible physiologic and pathological roles and distribution of CA VIII are provided, allowing thus a much better understanding of this and possibly of the related acatalytic isoforms, CA X and XI [6]. Many novel chemotypes of CAIs have been discovered ultimately (coumarins, polyamines, etc), as shown in the introductory paper [3], but sulfonamides still remain the main class of such derivatives. One of the highly versatile and innovative techniques which has been used to generate large libraries of such compounds is the “click chemistry”, which is reviewed for the first time here by Poulsen's group [7]. The next paper, by Said's group [8], deals just with such a group of sulfonamides which seem to be useful in the treatment of brain cancers, again by inhibiting CA IX, the isoform overexpressed in many hypoxic tumors. The next two papers deal with CAs isolated, characterized and studied from the inhibition point of view from pathogenic bacteria, such as Mycobacterium tuberculosis [9] and Brucella suis [10]. Indeed, many pathogenic bacteria contain one or more CAs, generally belonging to the β-CA class. Only recently, several groups showed that these enzymes may be drug targets for developing antibacterials with a novel mechanism of action [9,10], although this fact is difficult to accept for many scientists (who generally make quite bad reviews to such papers in which this innovative approach is being proposed). However, this was exactly the same situation with the anticancer effects of CAIs (as I stressed above), and probably sooner or later this idea will start to be widely accepted, but we still have to fight a lot to impose it. And these two reviews [9,10] on the inhibition of important human pathogens (but Brucella spp. also provokes zoonotic disease in many species) are thus welcome in this emerging new field. It should be stressed that these are the first reviews on mycobacterial or Brucella CAs.The next paper, by Guzel et al. [11] deals with the drug design campains of a very particular scaffold, i.e., 3-phenyl-1H-indole-5- sulfonamides, which have led ultimately to a range of highly potent inhibitors directed both against mammalian, α-CA isoforms, but also some β-CAs from pathogenic bacteria (Mycobacterium tuberculosis) or fungi (Candida albicans, Cryptococcus neoformans, etc). This field has also not been reviewed up until now, and as this is the most interesting new scaffold which has emerged, this review presents an updated view of drug design of sulfonamide CAIs based on the ring approach [11]. β-CAs are also present in fungi and yeasts, and Saccharomyces cerevisiae is no exception. Thus, the last paper in this issue deals just with the enzyme cloned, characterized and studied in this important species by Kockar et al. [12]. In conclusion, CAs are widely spread enzymes, found all over the phylogenetic tree, in prokaryotes and eukaryotes, being present in humans under the form of multiple isozymes with various activity, susceptibility to inhibition and diverse physiological roles. Their inhibitors are clinically used as antiglaucoma agents with topical activity, anticonvulsants, antipain, antiobesity and probably soon, as antitumor agents/diagnostic tools for cancer therapy [13]. Furthermore, although it is still difficult to make this idea widely acceptable, there is a real potential to develop anti-infectives (antimalarials, antifungal and antibacterial agents) belonging to the CAIs, targeting enzymes from various pathogens. Last but not least, the recent years saw the discovery of many new chemotypes showing significant CA inhibitory activity and a novel mechanism of action, in addition to the classical sulfonamides and their bioisosteres. All these facts prove how dynamic this research field is, where novel drug targets and novel chemotypes are emerging constantly worldwide, and why there is a CA conference each three years.