Therapeutic applications of sulfamates

Abstract

Sulfamic acid, a rather simple molecule used widely by medicinal chemists for the design of a host of derivatives with pharmacological applications, may give rise to at least four types of derivatives, the O-substituted-, N-substituted- or di-/tri-substituted sulfamates, which also show specific biological activities. Sulfamate inhibitors of aminoacyl-tRNA synthetases were reported to constitute a new class of antibiotics, useful in the fight of drug-resistant infections. Antiviral agents incorporating sulfamate moieties have also been obtained: the nucleoside/nucleotide HIV reverse transcriptase inhibitors, and the HIV protease inhibitors. In the increasing armamentarium of anticancer drugs, the sulfamates occupy a special position, with at least two important targets evidenced so far: the steroid sulfatase (STS) and the carbonic anhydrases (CAs). Some STS inhibitors, such as 667COUMATE, might be useful for the treatment of hormone-dependent tumours (breast and prostate cancers). Among the many isozymes of CAs, at least two, CA IX and XII, are highly overexpressed in tumours. Inhibition of tumour-associated CAs was hypothesised to lead to novel therapeutic approaches for the treatment of cancer. Many sulfamates act as very potent CA inhibitors. The X-ray crystal structure of the best studied isozyme, CA II, with three sulfamates (sulfamic acid, topiramate and EMATE) has recently been reported. A large number of anticonvulsant sulfamates have been described, with topiramate being widely used clinically as an anti-epileptic drug. The use of this drug and related sulfamates for the treatment of obesity was recently proposed. The rationale of this use is based on the inhibition of the mitochondrial isozyme CA V, involved in lipogenesis. Some sulfamates were also shown to possess potent inhibitory activity against acyl coenzyme A:cholesterol acyltransferase. One such agent, avasimibe, is in advanced clinical trials for the treatment of hyperlipidaemia and atherosclerosis. Thus, the sulfamate moiety offers very attractive possibilities for the drug design of various pharmacological agents.

• antibiotic
• anticancer drug
• anticonvulsant
• anti-obesity drug
• antiviral agent
• carbonic anhydrase inhibitor
• COUMATE
• steroid
• sulfatase inhibitor
• sulfamate
• topiramate