Synthesis and Anti-neuroinflammatory Activities of 25-Hydroxycholesterol and Its Analogues
25-Hydroxycholesterol(25HC)has many important biological activities and is also a key intermediate for the synthesis of calcifediol,calcitriol,etc.It is of great significance to develop a new synthetic route which is easy to available raw materials,simple process,and easy to scale up.In this report,three 25-hydroxycholesterol and its analogues were synthesized from hyodeoxycholic acid via esterification of hydroxyl groups,decarboxylation iodization of carboxyl groups,ketonic hydrolysis after nucleophilic substitution with α-ketoester,sulfonate esterification then elimination,and finally reaction with Grignard reagent.The total yield was 20.8％～23.0％.The new route is simple to operate and easy to scale up,and is expected to be further developed into an industrial synthetic route.Similar analogues of 25-hydroxycholesterol can be easily prepared by changing α-ketoesters and Grignard reagents.Among the 15 compounds synthesized,there are 9 new compounds.Their biological activities were evaluated.The results showed that 26,27-diethylcholest-5-ene-3β,25-diol(8c)has good anti-neuritis activity and can inhibit NO release from LPS(lipopolysaccharides)-induced BV-2(mouse microglia)cells by inhibiting Nuclear Factor kappa-B(NF-κB)and Mitogen-activated protein kinase/c-Jun N-terminal Kinase(MAPK/JNK)signaling pathways,and down-regulating mRNA-levels of inflammatory cytokines such as Interleukin-6(IL-6),Tumor Necrosis Factor-α(TNF-α)and Interleukin-1 β(IL-1β),indicating that 8c is a potential anti-neuroinflammatory compound.
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