Chapter 4 - Macrocyclic N-Methylated Cyclic Peptides and Depsipeptides

Abstract

Marine microorganisms and fungi are sources of cyclopeptides and cyclodepsipeptides that have numerous biological activities including antifungal, immunosuppressive, and anticancer. Some have been through clinical trials including didemnin B discussed in this review. These interesting properties of cyclopeptides and cyclodepsipeptides have resulted in a huge increase in research activity in the last few years. In this review, discussion of four families and some miscellaneous cyclopeptides and cyclodepsipeptides is presented. Aureobasidins (Abs) are the first group discussed. The isolation protocol of the Abs from the yeast-like fungus, Aureobasidium pullulans, structural characterization, and synthetic efforts, particularly for the most active antifungal derivative, AbA, is outlined. In addition to this, the biological activities of Abs including their mode of action are considered explaining the importance of the unnatural amino acids including β-OHMeVal, largely responsible for their antifungal activity. The second part of the review discusses the cyclosporin cyclopeptide family. The review on this family covers the isolation of the compounds, the classification, the structural assignments, the biological activities, and also the synthetic attempts concerned with cyclosporins. Cyclosporins from Tolypocladium inflatum are a family of cycloundecapeptide with hindered N-methylated residues similar to the Abs with an unusual amino acid, MeBmt, found as a characteristic feature of the cyclosporin structure. This family has a narrow antifungal activity and an excellent immunosuppressive property accounting for its use in the clinic. Its immunosuppressant properties are unique with narrow therapeutic actions that make this group most interesting. Dolastatins are a family of compounds isolated from the sea hare Dollabella auricularia consisting of various natural products including unusual peptides, depsipeptides, cyclopeptides, and also cyclodepsipeptides. In this review, the discussion is limited to the cyclopeptides and the cyclodepsipeptides of the dolastatin family, which possess cytotoxic, antineoplastic, and anticancer properties. Efforts toward the preparation of the cyclic dolastatins, as well as structural characteristics of the cyclic dolastatins, are highlighted that are important for biological activity. The last group discussed is the cyclohexadepsipeptidic didemnins. This section also discusses the isolation, classification, characterization, biological activity, and synthesis of the didemnins. Didemnins are a family of cyclodepsipeptides with a side-chain structural feature that has raised a lot of interest particularly in the case of didemnin B having been the first marine secondary metabolite entering clinical trials as an anticancer agent. Syntheses of didemnins are discussed. The presence of side chain in the didemnins makes the synthetic attempts an interesting discussion point not to mention the impressive biological activities of the didemnins. The discussion on Abs, cyclosporins, dolastatins, and the didemnins shows the importance of the cyclopeptides and the cyclodepsipeptide as sources of biologically active secondary metabolites. Access to these compounds and their analogs may help in the design of more powerful or potent natural products as candidates for drug development.