Polymer-Assisted Solution-Phase Synthesis and Neurite-Outgrowth-Promoting Activity of 15-Deoxy-DELTA~(12,14)-PGJ_2 Derivatives

摘要

An efficient solution-phase synthesis of rac-15-deoxy-DELTA~(12,14)-PGJ_2 (15dPGJ_2) derivatives that contain variable alpha and omega chains based on a polymer-assisted strategy and their neurite-outgrowth-promoting activity are described.The strategy for the synthesis of PGJ_2 derivatives involves the use of a vinyl iodide bearing cyclopentenone as a key intermediate,which undergoes Suzuki-Miyaura coupling and subsequent Lewis acid catalyzed aldol condensation for incorporation of the to and a chains,respectively.For easy access to the PGJ_2 derivatives,a polymer-supported catalyst and scavengers were adapted for use in these four diverse steps,in which workup and purification can be performed by simple filtration of the solid-supported reagents.By using this methodology,we succeeded in the synthesis of 16 PGJ_2 derivatives with four alkyl boranes and four aldehydes.The neurite-outgrowth-promoting activity of the 16 synthetic compounds in PC12 cells revealed that the side-chains play a major role in modulating their biological activity.The carboxylic acid on the alpha chain improved the biological activity,although it was not absolutely required.Furthermore,a PGJ_2 derivative with a phenyl moiety on the to chain was found to exhibit an activity comparable to that of natural 15dPGJ_2.