Thalidomide analogues: Derivatives of an orphan drug with diverse biological activity

Introduced as a sedative during the late 1950s, the realisation of the potent human embryotoxicity of thalidomide led to its withdrawal from the market in early 1961. Although the drug was discontinued, its teratogenic properties attracted unceasing interest as evidenced by numerous reports over the years. As investigations into its teratogenicity continued, thalidomide was serendipitously found, in separate investigations, to be effective therapy for the symptoms of leprosy (erythema nodosum leprosum). Later, the compound was found to be active against the aphthous ulcers of Behcet's syndrome and effective as a substitute for immunosuppressive therapy for graft-versus-host disease. The relevance of thalidomide in immunosuppressive therapy has also included ailments such as cachexia, HIV wasting and Crohn's disease. Although reports dating from the mid 1990s have disclosed the antiangiogenic activity of thalidomide, its inhibition of TNF-α, together with its immunomodulatory properties and therapeutic effectiveness in multiple myeloma, have been fast gaining attention. Consequently, a number of synthetic and biological investigations have targeted analogues with higher potencies in several of the above-mentioned therapeutic areas, as well as having lower undesirable side effects. As a result, a number of interesting compounds of varied structure have been synthesised and tested for their ability to inhibit angiogenesis or act as immunosuppressant, immunomodulatory, anti-inflammatory or anticancer agents.