Synthesis And Biological Evaluation Of Sarsasapogenin Derivatives

Alzheimer’s disease(AD)is a chronic central neurodegenerative disease and the most common type of dementia in the elderly.Although the etiology of AD is not completely known,a number of studies have shown that it is mainly related to the β-amyloid(Aβ)deposition,low levels of acetylcholine,tau hyperphosphorylation,and oxidative stress.Abnormal deposition of Aβ in the brain is a central factor in the occurrence and development of AD.Development of Aβ aggregation inhibitors is one of the main concerns of AD drug development workers.Natural products have always been an important source of active lead compounds and even drugs.Research on structural modifications with the pharmacodynamic backbone of natural products and their templates to obtain lead compounds or candidate drugs with novel structures,enhanced pharmacological activities,and improved drug-like properties are one of the important approaches for the development of new drugs.Accordingly,the search for drugs for the treatment of AD from natural products has become a hot topic for domestic and foreign scholars.Chinese herbal Anemarrhenae is the dry root of Anemarrhena asphodeloides Bge.with various pharmacological activities such as improving senile dementia,learning and memory impairment,anti-tumor,anti-depression and anti-inflammatory.Sarsasapogenin(SG)is the main active ingredient of traditional Chinese medicine Anemarrhenae,which can improve neurodegenerative diseases.Its research in the treatment of AD has received more and more attention.In recent years,research on the derivatization of SG has also attracted the interest of researchers.In this article,SG was used as the parent compound,and the molecular docking technology in computer-aided drug design was used as a guide to carry out the studies of diversity-oriented synthesis of SG.To search for more efficient anti-Alzheimer agents,different pharmacodynamic fragments were introduced to the structure of SG.Its C3 and F rings were modified and 86 derivatives were designed and synthesized.Among them,57 derivatives were new compounds that were not reported in the literature.The structures of the obtained derivatives were confirmed by 1H NMR,13C NMR,MS.The pharmacological results showed that the sarsasapogenin-triazolyl hybrids had better Aβ aggregation inhibitory activity,among them,the more potent compounds 47 and 52 did not show obvious toxicity to SH-SY5Y cells at the concentration of 50 μM.In addition,compounds 47 and 52 exhibited moderate neuroprotective effects against H2O2-induced neurotoxicity in SH-SY5Y cells.Further in vivo experiments showed that compounds 47 and 52 could significantly improve the learning and memory ability of Aβ-induced dementia mice.The results of histological section staining showed that compounds 47 and 52 could reduce the cytotoxicity of Aβ to neurons in hippocampus.Western blot analysis suggested that compounds 47 and 52 could exhibit in vivo neuroprotective effects possible by lowering the levels of Bax and cleaved-PARP and increasing the expression of Bcl-xl,pro-caspase3 and PARP to protect neurons from apoptosis.In addition,the cytotoxic activities of some sarsasapogenin derivatives were evaluated.Among them,compounds 33(A series)and 63(D series)had potent cytotoxic activities.The preliminary cellular mechanism studies of compounds 33 and 63 were conducted.Compound 33 could cause G2/M phase arrest of MCF-7 cells and induce apoptosis of MCF-7 cells.Compound 63 could inhibit the colony formation and induce apoptosis of MCF-7 cells through the mitochondrial pathway.