Structure–Activity Relationship Study on Odoamide: Insights into the Bioactivities of Aurilide-Family Hybrid Peptide–Polyketides

Odoamide is a cytotoxic peptide–polyketide hybrid molecule isolated from the Okinawan marine cyanobacterium Okeania sp. For an efficient structure–activity relationship study of the peptide part of odoamide, a facile synthetic protocol was established using a solid-phase peptide synthesis. Among a series of peptides, the d-MeAla6 isomer exhibited a more potent cytotoxicity than natural odoamide. It was also demonstrated that the 26-membered macrocyclic natural odoamide and the 24-membered isomer with comparable cytotoxicities were slowly interconvertible, and both isomers contributed to the potent cytotoxicity of odoamide. Examination of the physicochemical properties revealed that the in vitro cytotoxicity was affected by the serum protein binding of odoamide derivatives, while the differences in the macrocyclic structures had no significant effect on the membrane permeability.