Stereoselective Reduction of 1-O-Isopropyloxygenipin Enhances Its Neuroprotective Activity in Neuronal Cells from Apoptosis Induced by Sodium Nitroprusside

Genipin is a Chinese herbal medicine with both neuroprotective and neuritogenic activity. Because of its unstable nature, efforts have been to develop more stable genipin derivatives with improved biological activities. Among the new compounds reported in the literature, (1R)‐isopropyloxygenipin (IPRG001) is a more stable but less active compound compared with the parent, genipin. Here, two new IPRG001 derivatives generated by stereoselective reduction of the C6=C7 double bond were synthesized. The 1R and 1S isomers of (4aS,7S,7aS)‐methyl‐7‐(hydroxymethyl)‐1‐isopropoxy‐1,4a,5,6,7,7a‐hexahydrocyclopenta[c]pyran‐4‐carboxylate (CHR20 and CHR21) were shown to be very stable both in high‐glucose cell culture medium and in mice serum at 37 °C. Evaluation using an MTT assay and Hoechst staining showed that CHR20 and CHR21 promote the survival of rat adrenal pheochromocytoma (PC12) and retinal neuronal (RGC‐5) cells from injury induced by sodium nitroprusside (SNP). The neuroprotective effects of CHR20 and CHR21 were greater than both isomers of IPRG001, the parent compounds. These results indicate that reduction of 1‐O‐isopropyloxygenipin enhances its neuroprotective activity without affecting its stability. Remastering Chinese herbal medicine: Genipin is known to have neuroprotective activity but problematic stability under physiological conditions. Isomeric derivatives of isopropyloxygenipin, a synthetic genipin analogue, were synthesized by stereoselective reduction of the C6C7 double bond and found to exhibit improved neuroprotective activity and stability over the parent compounds.