Antitumor compounds from tunicates

Abstract

Of the six marine-derived compounds that have reached clinical trials as antitumor agents three-didemnin B, Aplidine, and ecteinascidin 743-are derived from tunicates. Di-demnin B (DB), a cyclic depsipeptide from the compound tunicate Trididemnum solidum, was the first marine-derived compound to enter Phases I and II clinical trials. The Phase II studies, sponsored by the U. S. National Cancer Institute, indicated complete or partial remissions with non-Hodgkins lymphoma, but cardiotoxicity caused didemnin B to be dropped from further study. The closely related dehydrodidemnin B (DDB, Aplidine) was isolated in 1988 from a second colonial tunicate, Aplidium albicans, and spectroscopic studies assigned a structural formula in which a pyruvyl group in DDB replaced the lactyl group in DB and syntheses of DDB have been achieved. Aplidine is more active than DB and lacks DB's cardiotoxicity. It was introduced by PharmaMar into Phase I clinical trials in January 1999. The second family of tunicate-derived antitumor agents are the ecteinascidins (ETs), from the mangrove tunicate Ecteinascidia turbinata. The antitumor extracts of E. turbinata were first described in 1969, but the small amount of ETs in E. turbinata prevented their isolation for over a decade. The structures of ETs have been assigned mainly by spectroscopy. Phase II clinical trials with ET 743 are underway. Future supplies of ET's should be available from aquaculture or synthesis.