Insights towards sulfonamide drug specificity in α-carbonic anhydrases

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) are a group of metalloenzymes that play important roles in carbon metabolism, pH regulation, CO2 fixation in plants, ion transport etc., and are found in all eukaryotic and many microbial organisms. This family of enzymes catalyzes the interconversion of CO2 and HCO3−. There are at least 16 different CA isoforms in the alpha structural class (α-CAs) that have been isolated in higher vertebrates, with CA isoform II (CA II) being ubiquitously abundant in all human cell types. CA inhibition has been exploited clinically for decades for various classes of diuretics and anti-glaucoma treatment. The characterization of the overexpression of CA isoform IX (CA IX) in certain tumors has raised interest in CA IX as a diagnostic marker and drug target for aggressive cancers and therefore the development of CA IX specific inhibitors. An important goal in the field of CA is to identify, rationalize, and design potential compounds that will preferentially inhibit CA IX over all other isoforms of CA. The variations in the active sites between isoforms of CA are subtle and this causes non-specific CA inhibition which leads to various side effects. In the case of CA IX inhibition, CA II along with other isoforms of CA provide off-target binding sites which is undesirable for cancer treatment. The focus of this article is on CA IX inhibition and two different structural approaches to CA isoform specific drug designing: tail approach and fragment addition approach.

7-Aryl-triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrase IX and XII

“…Such a feature is highly desired in the current CAIs research as the main problem associated to the sulfonamide-type clinically used CAIs is represented by their indiscriminate inhibition of the hCAs leading thus to a plethora of side effects 10,[12][13][14][15][16][17] . Since many CA isoforms are involved in diverse physio/pathological conditions such as glaucoma (hCA I, II, IV and XII), edema (hCA II, IV, XIV as the most important), central nervous system (CNS)-related pathologies (hCAVII and XIV are particularly involved in the epilepsy) and tumors (hCA IX and hCA XII are strictly associated with hypoxic tumors), it is not surprising that CAIs are used in the clinic for some applications for almost 70 years [18][19][20][21][22][23][24] .…”

Structural elucidation of the hormonal inhibition mechanism of the bile acid cholate on human carbonic anhydrase II

“…The inhibition of HCA II has been utilized for the treatment of various diseases in the past, including glaucoma, epilepsy and altitude sickness (Supuran, 2008). Current clinically used inhibitors of HCA II include acetazolamide and brinzolamide, which incorporate a sulfonamide functional head group, have detrimental side effects including augmented diaeresis, fatigue, paresthesias and anorexia owing to the nonspecific inhibition of CA isoforms in other tissues than those targeted (Aggarwal et al, 2013). Additionally, an estimated 3% of the total population has an adverse drug reaction to sulfonamide-containing compounds, with higher rates of sulfa allergies seen in individuals with low metabolic process rates and in immunocompromised patients (Choquet-Kastylevsky et al, 2002).…”

Benzenesulfonamides with benzimidazole moieties as inhibitors of carbonic anhydrases I, II, VII, XII and XIII

“…Carbonic anhydrases (CAs) are widely investigated enzymes due to their involvement in various physiological and pathological processes [1][2][3][4] . There are a total of 15 CA isoforms found in humans.…”

“…The design of CA inhibitors as drugs has been impeded by the large number of isoforms, their diffusion among many tissues/organs and the lack of isozyme-selective inhibitors among existing sulfonamides 13 . As the differences between the active sites of the 12 catalytically active human CAs are very subtle, CAs have proved to be a challenging drug target for the development of isozyme-specific inhibitors 2,14 . Primary sulfonamides present an important class of compounds which have been studied as drugs and drug candidates against diseases such as glaucoma, inflammation, edema, epilepsy, dandruff, cancer and as antiviral compounds 15,16 .…”