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 alpha-ketoester, sulfonate esterification then elimination, and finally reaction with Grignard reagent. The total yield was 20.8%similar to 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 alpha-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-3 beta,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-kappa B) 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-alpha (TNF-alpha) and Interleukin-1 beta (IL-1 beta), indicating that 8c is a potential anti-neuroinflammatory compound.