Covering: up to 2008 Ecteinascidins are marine natural products consisting of two or three linked tetrahydroisoquinoline subunits and an active carbinolamine functional group. Their potent antiproliferative activity against a variety of tumor cells makes them attractive candidates for development as anticancer agents. The lead compound, Yondelis ^® (trabectedin, ET-743) is the first marine anticancer agent approved in the European Union for patients with soft tissue sarcoma (STS). Positive results of a large randomized Phase III clinical trial in ovarian cancer have recently been presented. The low amounts present in its natural source, the tunicate Ecteinascidia turbinata, made it necessary to develop efficient synthetic procedures. The original total synthesis is reviewed as well as a new semisynthetic process from the readily available cyanosafracin B, which has solved the supply problem.

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogues of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB-231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data, the SAR study concluded that more than 75% of the open-chain Lam-D analogues tested showed cytotoxicity in a low micromolar GI50 range.