2020 Volume 140 Issue 2 Pages 129-137
(−)-2S,3S,4S,5S-Talaumidin (1) exhibits potent neurotrophic activities such as neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in nerve growth factor (NGF)-differentiated PC12 cells. To examine the stereochemistry-activity relationship of 1, systematic syntheses of seven stereoisomers of 1 were accomplished via Evans aldol reaction, diastereoselective hydroboration, and Mitsunobu reaction. All stereoisomers showed moderate-to-potent neurite-outgrowth promotion in NGF-differentiated PC12 cells. In particular, (−)-2S,3R,4S,5R-1e having all-cis-substituted configuration exhibited the most significant neurite-outgrowth promotion. Subsequently, we developed a short-step synthetic route for talaumidin derivatives so as to explore new neurotrophic compounds that could be obtained on a large scale. First, we synthesized derivative 2a, which is a racemic compound of (−)-1e, and compared its neurotrophic activity with (−)-1e. It was found that the neurotrophic activity of racemic 2a was similar to that of (−)-1e. Using the same synthetic route, several talaumidin derivatives were synthesized to optimize the oxy-functionality on aromatic rings. Thereby, bis(methylenedioxybenzene) derivative 2b was found to exhibit the highest neurotrophic activity. In addition, examination of the structure-activity relationship of 2b indicated that the 2,5-diphenyl structure was crucial moiety, and the two methyl groups on the tetrahydrofuran (THF) ring could enhance the neurotrophic activity. Furthermore, 2a and 2b were found to induce mouse optic nerve regeneration in vivo.
