Synthesis And PreliminaryAnti-hypoxic Activities Study Of Salidroside O-Glycosides Analogues And Aromatic Heterocyclic Propylene Derivatives

Objective Hypoxia refers to insufficient oxygen supply for tissue or oxygen barrier,thus resulting in organizational function,metabolism and abnormal change of morphology.Plateau hypoxia can lead to temporary or permanent change in vivo systems,which maybe cause a variety of hypoxia-induced diseases,and even cardio-cerebral vascular diseases.Therefore,it is necessary to research and develop anti-altitude hypoxia drugs of high pharmacological activity and low toxicity.Salidroside is the main active ingredient of Tibetan medicine rhodiola,which show good anti-hypoxic injury protection and the capability of scavenging free radical.Owing to the difficulty in synthetic route,low extraction efficiency and poor bioavailability,its application in clinical is limited.Based on the pervious study,salidroside and its aglycone tyrosol were choosed as model compounds,a series of different substituents salidroside O-glycosides analogues and aromatic heterocyclic propylene derivatives were synthesized,in order to obtain lead compounds with better pharmacological activities.Content Based on the structure of salidroside and tyrosol,we designed and synthesized a series of salidroside O-glycosides analogues and aromatic heterocyclic propylene derivatives by varing the the substituents of aromatic ring,the type of side-chain and aromatic ring,the anti-hypoxia pharmacological activity were measured and the preliminary structure-activity relationships were discussed.Methods Chemical Synthesis Part:(1)The substituted phenethyl alcohol derivatives were prepared from substituted benzaldehydes by Wittig reaction,hydrolysis reaction and NaBH4 reduction reaction,which can then be easily reacted with bromo acetylation glucose by Koenigs-Knorr reaction and subsequent deacetylation to give the salidroside O-glycosides analogues.(2)The substituted phenethyl alcohol direct reacts with bromo acetylation glucose and removed the acetyl protection to give the target compounds.(3)The substituted aromatic heterocyclic formaldehydes as the starting materials,through the Knoevenagel condensation reaction,esterification reaction and LiAlH4 reduction reaction to give aromatic heterocyclic acrylic acid,ester,alcohol derivatives respectively.Pharmacological Activity Screening Part: Establish the hypoxia model by endothelial cells(EA.hy926)and myocardial cells(H9c2)respectively,the anti-hypoxia and the cellular metabolic activity were determined by MTT method.Results 34 compounds were synthesized,including 20 salidroside O-glycosides analogues and 14 aromatic heterocyclic propylene derivatives,of which 18 were new compounds.All the structures were characterized by ~1H NMR and HRMS.The results of anti-hypoxia pharmacological screening indicated that 15 compounds exhibited better anti-hypoxic activity than salidroside or tyrosol.Conclusion Introducing the electron donating groups to the phenyl ring of salidroside O-glycosides analogues,which can improve the anti-hypoxic activity.It is potential to enhance the anti-hypoxia activity of compounds if the ortho-,meta-,or para-position of the phenyl ring introduce halogen atoms.Aromatic heterocyclic O-glycosides analogues show better activity than phenyl O-glycosides analogues.The aromatic heterocyclic propylene derivatives with the aromatic heterocyclic ring and the allylic link has a potential application value.