Kulokekahilide-2, a 26-membered cyclodepsipeptide, was isolated from Hawaiian marine mollusk and possessed potent cytotoxicity in mammalian tumor cells. In the present study, we synthesized kulokekahilide-2 and its derivatives and examined the structure-activity relationships of these peptides in human cancer cells (A549, K562, and MCF7 cells). This study demonstrated that the cyclization of depsipeptide and the chirality of the 21 position in Ala in kulokekahilide-2 were important for its cytotoxic property and that addition of halogen at the para position of phenyl group in the 24-d-MePhe in kulokekahilide-2 as well as some derivatives remarkably increased their cytotoxicity in human cancer cells. These results suggest that the modifications of 24-d-MePhe in kulokekahilide-2, preserving its cyclization and the chirality at the 21-position, are promising strategy for exploring new derivative of kulokekahilide-2 as anti-tumor drug.
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