Synthesis Of New Cyclopeptide Analogues Of The Miuraenamides

Based on their interesting biological activity, cyclic peptides and depsipeptides are excellent candidates for drug development [1]. Many of these structures are found as natural compounds produced by marine or terrestrial (micro)organisms. An especially interesting group is the cyclodepsipeptides of the jasplakinolide type. Jasplakinolide (Jaspamide) [2] and the structurally closely related geodiamolides [3] (Fig. 1) were isolated in the 1980s from sponges followed by the first total syntheses of these compounds [4]. The interest of the synthetic chemists [5] arose from the high cytotoxicity of these natural products. By far, most investigations concerning the biological activity and the mode of action were carried out with jasplakinolide (jaspamide), which shows high cytotoxicity towards a range of leukemia, breast and prostate cancer cell lines [6]. Jasplakinolide was found to initiate actin polymerization and stabilize already formed actin microfilaments, which causesABSTRACT Introduction: Miuraenamides belong to natural marine compounds with interesting biological properties. Materials and Methods: Miuraenamides initiate polymerization of monomeric actin and therefore show high cytotoxicity by influencing the cytoskeleton. New derivatives of the miuraenamides have been synthesized containing an N-methylated amide bond instead of the more easily hydrolysable ester in the natural products. Results: Incorporation of an aromatic side chain onto the C-terminal amino acid of the tripeptide fragment also led to highly active new miuraenamides. Conclusion: In this study, we showed that the ester bond of the natural product miuraenamide can be replaced by an N-methyl amide. The yields in the cyclization step were high and generally much better than with the corresponding esters. On the other hand, the biological activity of the new amide analogs was lower compared to the natural products, but the activity could significantly be increased by incorporation of a p-nitrophenyl group at the C-terminus of the peptide fragment.