Abstract:At least 14 different carbonic anhydrase (CA, EC 4.2

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The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti- carbonic anhydrase, diuretic, hypoglycemic and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial antitumor activity in vitro and in vivo. Although they have a common chemical motif of aromatic/heterocyclic or amino acid sulfonamide, there are a variety of mechanisms of their antitumor action, such as carbonic anhydrase inhibition, cell cycle perturbation in the G1 phase, disruption of microtubule assembly, functional suppression of the transcriptional activator NF-Y, and angiogenesis (matrix metalloproteinase, MMP) inhibition among others. Some of these compounds selected via elaborate preclinical screenings or obtained through computer-based drug design, are currently being evaluated in clinical trials. The review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed as effective tumor cell growth inhibitors, or for the treatment of different types of cancer. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Thus, at least two clinically used HIV protease inhibitors possess sulfonamide moieties in their molecules, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with less toxicity or activity against drug-resistant viruses. Several non nucleoside HIV reverse transcriptase or HIV integrase inhibitors containing sulfonamido groups were also reported. Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. Most compounds with antiviral activity possessing this mechanism of action incorporate in their molecules primary sulfonamide groups. Some small molecule chemokine antagonists acting as HIV entry inhibitors also possess sulfonamide functionalities in their scaffold.

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Carbonic anhydrase IX (CAIX) is a hypoxia-inducible enzyme that is overexpressed by cancer cells from many tumor types, and is a component of the pH regulatory system invoked by these cells to combat the deleterious effects of a high rate of glycolytic metabolism. CAIX functions to help produce and maintain an intracellular pH (pHi) favorable for tumor cell growth and survival, while at the same time participating in the generation of an increasingly acidic extracellular space, facilitating tumor cell invasiveness. Pharmacologic interference of CAIX catalytic activity using monoclonal antibodies or CAIX-specific small molecule inhibitors, consequently disrupting pH regulation by cancer cells, has been shown recently to impair primary tumor growth and metastasis. Many of these agents are in preclinical or clinical development and constitute a novel, targeted strategy for cancer therapy.