Enrichment, Structural Modification And Potential Anti-AD Activity Of A Pentacyclic Triterpenoid Compound (RLMS) From Rosa Laevigat

Rosa laevigata Michx.is a plant of Rosaceae It mainly has antibacterial,anti-inflammatory,insecticidal and other activities.In this thesis,a pentacyclic triterpenoid compound（RLMS,2α,3β,19α,23-tetrahydroxy-12ene-28-oic acid）from Rosa laevigata Michx.was modified to obtain 2 intermediates and 16 compounds.The acetylcholinesterase,butyrylcholinesterase,neurone protection,molecular docking and dynamics simulation of the modified compounds were studied.Some compounds have good activity and reveal their potential anti-Alzheimer’s disease（AD）effect.The main research results are as follows:（1）Previous molecular docking simulation results showed that RLMS derivatives with aromatic groups could significantly improve acetylcholinesterase inhibitory activity.Therefore,the hydroxyl groups at C-2,C-3,C-19 and C-23 of RLMS were esterified with different benzoyl chlorides,and eight compounds were obtained after further purification.The A-ring of RLMS was modified to obtain two intermediates（compound 9,10）.Eight compounds were obtained by esterification and purification of the hydroxyl groups at C-19 and C-23 of compound 10 with different acyl chlorides.The structures of the compounds were determined by ¹H NMR,¹³C NMR and HRMS as follows:2α,3β-dihydrocinnamoyl-19α,23-dihydroxy-12-ene-28-oic acid（1）,3β-hydrocinnamoyl-2α,19α,23-trihydroxy-12-ene-28-oic acid（2）,2α,19α-di-o-（p-chlorobenzoyl）-3β,23-dihydroxy-12-ene-28-oic acid（3）,2α,3β-di-o-（p-chlorobenzoyl）-19α,23-dihydroxy-12-ene-28-oic acid（4）,2α,3β,23-tri-o-（p-chlorobenzoyl）-19α-hydroxy-12-ene-28-oic acid（5）,2α-o-[p-（trifluoromethyl）benzoyl]-3β,19α,23-trihydroxy-12-ene-28-oic acid（6）,2α,3β-di-o-[p-（trifluoromethyl）benzoyl]-19α,23-dihydroxy-12-ene-28-oic acid（7）,19α-o-（p-methoxybenzoyl）-2α,3β,23-trihydroxy-12-ene-28-oic acid（8）,4-formyl-A（2）-homo-2α,19α-dihydroxy-12-en-28-oic acid（9）,2-formyl-A（1）-norursa-19α,23-dihydroxy-2,12-dien-28-oic acid（10）,2-formyl-A（1）-norursa-23–o-（p-fluorobenzoyl）-19α-hydroxy-2,12-dien-28-oic acid（11）,2-formyl-A（1）-norursa-19α,23-o-di-（p-chlorobenzoyl）-2,12-dien-28-oic acid（12）,2-formyl-A（1）-norursa-23-o-[p-（trifluoromethyl）benzoyl]-19α-hydroxy-2,12-dien-28-oic acid（13）,2-formyl-A（1）-norursa-19α,23-di-o-（p-methoxybenzoyl）-2,12-dien-28-oic acid（14）,2-formyl-A（1）-norursa-19α-o-（p-methoxybenzoyl）-23-hydroxy-2,12-dien-28-oic acid（15）,2-formyl-A（1）-norursa-23-o-（1-butyryl）-19α-hydroxy-2,12-dien-28-oic acid（16）,2-formyl-A（1）-norursa-23-o-（1-hexanoyl）-19α-hydroxy-2,12-dien-28-oic acid（17）,2-formyl-A（1）-norursa-23-hydrocinnamoyl-19α-hydroxy-2,12-dien-28-oic acid（18）.（2）Cholinesterase inhibition experiments and nerve cell protection activities of all compounds were carried out.The results showed that most derivatives showed significant inhibition of AChE activity,and were superior to RLMS.The functional group of compound 1 was phenylpropanyl with the strongest inhibitory activity,and the IC₅₀ for AChE was 4.48μg/mL（the selective index value was 5.4）.Compound 1 has a good protective effect on H₂O₂-induced SH-SY5Y neuronal injury（76.64%）.（3）Further molecular docking and dynamic simulation analysis confirmed that compound 1 was bound to the surrounding anionic sites and partially biased towards the catalytic activity sites of AChE.Combined with pharmacological activity analysis and docking studies,compound 1 was the most potential lead drug for AD in all compounds.