Synthesis And Preliminary Anti-Hypoxic Activities Study Of Salidroside Analogues

Objective Plateau hypoxia can cause serious endothelial cells injury and apotosis, which is one of the risk factor for cardiovascular and cerebrovascular diseases. Therefore, it is significant to discover high-efficiency anti-hypoxic drugs. Among the existing drugs, salidroside has relatively high anti-hypoxia activity. Unfortunately, it is difficult to be synthesized, at the same time, bad stability and low bioavailability limits its application. Based on the pervious study, we designed and synthesised variety of salidroside derivatives, in order to discover the compound which has better efficacy.Content According to the structure of salidroside, we designed and synthesised a series of analogues, including different glycosidic linkage, side chain, and aromatic ring. And their pharmacological activity were determined to discuss the structure-activity relationship.Methods Chemical Synthesis Part:Trans-cinnamyl alcohol analogues was synthesized by benzaldehyde with different substituent groups via Knoevenagel condensation, esterification reaction,and reduction. Then, it was reacted with bromo acetyl glucose, glycosidation, deacetylation to get the target compounds. Trans-cinnamyl alcohol analogue was oxidized by activated MnO₂ to obtain aldehyde which was reacted with acetyl glucopyranosyl amine and Na BH?OAc?₃ to get compounds. Phenethyl alcohol with different substituent groups was directly condensation with bromo acetyl glucose to get the target compounds. Heteroaromatic aldehyde was reduced to alcohol, reacted with bromo acetyl glucose, glycosidation, deacetylation to get target compounds.Pharmacological Activity Screening Part: Their activities of inhibit hypoxia injury were determined by MTT via the model of anoxic endothelial cells.Results 50 compounds were synthesised, including 24 allyl glucopyranoside, 12 nitrogen derivatives, 4 heterocyclic ring substituent heteroside, 6 salidroside analogues with different substituent groups on benzene ring, compound LN-0, CH-1, D-1 and S-1, confirmed by ¹H-NMR and ESI-MS, 41 of which have not been reported yet. Results of activity screening of all the compounds by the model of anoxic endothelial cells showed that 18 compounds of them have higher activities of anti-hypoxic against salidroside.Conclusion Introducing allyl moiety in the linked chain of salidroside derivatives can significantly improve the anti-hypoxic activity. Aromatic ring replaced by halogen substituted in the ortho-position, and at the same time, methoxy substituted in the meta- and para-position all could enhance the anti-hypoxia activity. Finally, compared with the aromatic nucleus analogues, the aromatic heterocyclic ring in the core molecular structure showed better anti-hypoxic activity.