Cyclodepsipeptide natural products apratoxins A and C and their analogs

Abstract

In this study, the total syntheses of apratoxins A and C and their analogs were carried out. Apratoxins A and C and their oxazoline analogs exhibited potent cytotoxicities against cancer cells as well as similar 3D structures in solution as analyzed by a distance geometry method. The oxazoline analogs were slightly less, but highly, potent as they exhibited similar conformations as their parent compounds. As the MoCys moiety possibly induced severe toxicity owing to the ability of a Michael acceptor and instability of the thiazoline ring under acidic and basic conditions, MoCys and MeAlaMeIle were substituted by other simple amino acids. In addition, the combinatorial synthesis of these mimetics was carried out by the split and mix method with solidphase peptide synthesis and solutionphase macrolactamization in parallel. Apratoxin M7 in which MoCys was replaced by piperidine4carboxylic acid was found to exhibit a conformation similar to that of apratoxin A, and indicated moderate activity. Based on apratoxin M7, the further optimization of the Tyr(Me) MeAlaMeIle tripeptide led to the discovery of apratoxin M16 (Bph/Tyr(Me)), which is as potent as apratoxin A. The growth inhibitory activity of apratoxin A and apratoxin M16 against 10 cancer cell lines was comparable, suggesting that the target of apratoxin M16 should be the same as that of apratoxin A.