Sea squirts

Ecteinascidin 743 is a trace secondary metabolite isolated from the marine tunicate, Ecteinascidia turbinata. Ecteinacidin 743 a most potent antitumor agent, is currently in Phase II clinical trials in Europe and in the USA. A cell-free extract of Ecteinascidia turbinata was used to investigate the biogenetic origin of the ecteinascidins. Incubation experiments with radiolabeled diketopiperazines indicated that the diketopiperazine of tyrosine is the first committed intermediate in the biosynthesis of ecteinascidins. Phenylalanine diketopiperazine was not transformed into the ecteinascidins indicating that this cyclic dipeptide is not an intermediate in the biosynthesis of ecteinascidins. The diketopiperazine of DOPA was used as a cold carrier demonstrating that the diketopiperazine of tyrosine is oxidized to DOPA diketopiperazine and then further transformed to the ecteinascidins.

A family of tetrahydroisoquinoline alkaloids, the ecteinascidins, are a group of biologically active secondary metabolites produced by the marine tunicate Ecteinascidia turbinata. Ecteinascidins have shown in vivo anti-tumor activity against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and LX-1 human lung and MX-1 human mammary carcinoma xenografts in laboratory mice. Because ecteinascidins are produced in low yields, 1x10^-4%, supply for clinical development is a significant problem. The ultimate goal of this study is to develop an enzyme-based synthesis of the ecteinascidins. In this regard, the biosynthesis of these alkaloids has been investigated. Optimal conditions for in vitro ecteinascidin biosynthesis were found. The origin of the C22-C1 two-carbon unit was identified as pyruvate and the tyrosine and DOPA diketopiperazines were identified as key intermediates. Methods were developed for an in-the-sea aquaculture of the colonal marine ascidian Ecteinascidia turbinata.