Cephalostatins and ritterazines.

This review article is a tribute to the numerous chemists whose relentless effort for the last quarter of a century resulted in the isolation, identification, and finally the chemical synthesis of a family of bis-steroidal pyrazine alkaloids of marine origin. In the task of defeating cancer, the search for bioactive substances among the naturally occurring compounds is, without any doubt, a preferential approach. The remarkable contribution of Petitt, Fusetani, and their coworkers allowed to discover this family of marine alkaloids that emerge as potential therapeutic anticancer agents, although there is still a long way to go. The challenging and dangerous task of collecting living organisms from deep-waters was followed by a laborious isolation, elucidation of the complicated structures and biological tests. The outcome of this paramount effort was the identification of 45 compounds that stand, to date, as some of the most potent anticancer agents. The intriguing structures of the isolated alkaloids drew the attention of synthetic chemists, valiant enough to undertake the challenging task of synthesizing some of the most active members of the family. Fuchs, Heathcock, Winterfeldt, Suarez, Shair, and their associates pioneered in the establishment of feasible synthetic routes for the preparation of some of the naturally occurring compounds and a large number of synthetic analogs, allowing to establish SAR criteria that have guided the design of new synthetic analogs. Numerous analogs have been prepared to investigate the mechanism of action of bis-steroidal pyrazines, e.g. cephalostatin analogs bearing a strained spiroketal moiety. However, the mechanism of action and the biological target of these compounds remain far from being understood. Therefore, the rational design of simpler, yet highly active analogs seems at the current stage elusive. It is still 1 to clear why these compounds need to be dimeric to show high biological activity. Furthermore, it is not known whether the central pyrazine ring is simply a linker or has some additional function. This could be tested by examining the biological activity of steroidal dimers with other linkers, e.g. with a benzene ring. Such analogs have been actually prepared but without functional groups necessary for biological activity. The clinical trials of cephalostatins have got stuck due to a shortage of material. There is an urgent need to provide highly active, yet not too complex analogs, which could be available in substantial amounts for advanced pharmacological studies.