California Sea Grant College Program

This thesis presents an effort to contribute to the discovery and development of struc­turally and mechanistically novel anticancer drugs. In order to reach this goal it focusses on the biologically active secondary metabolites of marine invertebrates of the class As­cidiacea (phylum Chordata, subphylum Urochordata (Tunicata), class Ascidacea).

Three distinct areas of research were combined. The first part concerns the discovery of two novel, naturally occurring didemnin depsipeptides, tamandarins A and B. The tamandarins were isolated from an unidentified Brazilian ascidian of the family Didemnidae. Their structures were determined by FABMS and extensive 20 NMR spec­ troscopy, the absolute configurations by alkaline hydrolysis and by Marfey analysis of the acid hydrolyzates. The cytotoxic activity of tamandarin A against various human cancer cell lines was evaluated and this metabolite was found to inhibit protein biosynthesis. A qualitative discussion on the conformation of tamandarin A in solution, obtained from J-values, variable temperature experiments and NOE/ROE data, is included.

The next section reports preliminary studies aimed at gaining a better under­standing of the mechanism of cytotoxic action of diazonamide A, a recently isolated ascidian metabolite that shows potent and selective anticancer activity.

The last part describes the synthesis of dianestatin 1, the first conjugate be­tween a tumor-homing peptide and didemnin B. This work, performed in collaboration with researchers at the Burnham Institute in La Jolla, is aimed at the development of an alternative form of cancer treatment by targeted delivery of potent, non-selective cytotoxins using tumor-homing peptides.