Synthesis and biological evaluation of gephyronic acid derivatives: Initial steps towards the identification of the biological target of polyketide inhibitors of eukaryotic protein synthesis

摘要

Coupled to the development of a total synthesis of gephyronic acid, a series of diastereomeric analogues and their precursors have been prepared by employing complementary aldol strategies for the key coupling step of fragments 4 and 5. A biological evaluation revealed the importance of the epoxide for the cytotoxicity against L-929 (mouse fibroblast) and KB-3-1 (HeLa clone, human cervix carcinoma derived) cell lines. Moreover, variation of the configuration of the C3-C5 stereotriad and the C1 carboxylic acid were found to be important features. Improved activities compared with the natural product were observed when the carboxy terminus at C1 was replaced by a methyl ester or PMB-protected alcohol. Surprisingly, the derivatives (8R)-17d and (8S)-16a showed antibacterial activity against Pseudomonas aeruginosa. The cytotoxicity of polyketide gephyronic acid derivatives against some mammalian cell lines depends on the epoxide, the stereotriad, and the terminus R (R = CH_2OPMB, CO_2Me or CO_2H). The structure-activity relationships were deduced from a variety of diastereomeric analogues obtainable by stereocomplementary aldol reactions.