Synthesis and evaluation of 26-amino acid methyl ester substituted sarsasapogenin derivatives as neuroprotective agents for Alzheimer’s disease

Abstract Sarsasapogenin, extracted from Anemarrhena asphodeloides Bunge., has been reported to protect neurons from H 2 O 2 -induced damage. In the current study, four series of 26-amino acid methyl ester substituted sarsasapogenin derivatives ( 5a – 5e , 5f – 5j , 6a – 6e and 7a – 7e ) were synthesized and tested for neuroprotective activity by evaluating their neuroprotective ratio against SH-SHY5Y cell lines. Studies showed that most of the target compounds displayed better neuroprotective effects than that of sarsasapogenin. Structure-activity relationship analysis suggested that 3-methoxy derivatives ( 5f – 5j ) were more potent than other series and the phenylalanine methyl ester moiety at C-26 was important for exhibiting apparent neuroprotective activity. It was worth noting that compound 5h exhibited optimal neuroprotective activity (102.2%) compared with sarsasapogenin (27.3%) and trolox (40.5%), and this encouraged us to investigate the cellular mechanism of 5h further. Our investigation revealed that 5h could attenuate H 2 O 2 -induced cell damage by inhibiting the expression of cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspase-3 as well as rescuing the downregulation of brain-derived neurotrophic factor (BDNF) and its tyrosine receptor kinase B (TrkB). Taken together, these results suggest that the representative compound 5h is a profound lead compound for further investigation and the sarsasapogenin skeleton could be a promising structural template for the development of new anti-Alzheimer drug candidates.