Synthesis Of New Type Analgesic Drug-Hyperin And Its Derivatives

Hyperin(quercetin-3-O- P -galactopyranoside,Hyp),a flavonol glycoside,was extracted from Chinese medicine herb Abelmesechus manihot I. medic.Hyperin showed significant local analgesic effects in animal tests,and its pellicle was satisfactory with treating stomatocace in the clinic. Some studies suggested that its analgesic effects were caused by inhibiting inward flow of calcium ion and it was a calcium channel inhibitor. The analgesic potency of Hyp was less than morphine,more than aspirin and non-dependence. So it was a new type local analgesic.Some studies showed that Hyperin had protective effects against myocardial ischemia,cerebral ischemia-reperfusion injury and cerebral infarction. It has been considered that its protective effects may be related to the reduction of the free intracellular calcium concentration,inhibit excess NO producing and scavenge free radical.Some studies suggested that its local analgesic effects were not from quercetin,but associated with galactopyranose at 3 position by comparing analgesic effects of hyperin with quercetin's. Meantime,the relationship of structure-activity of antioxidation and scavenging free radical showed that the presence of free hydroxyl group at C-5 and C-7 in A ring,C-3' and C-4' in B ring,the double bond between C-2 and C-3,the carbonyl at C-4 in C ring were essential to keep their activities.In order to find new compounds which has high potency,low toxicity,we designed two type target molecules by modifying the galactopyranose at 3position of hyperin:1. The D-galactose of hyperin was substituted with D-glucose,D-arabinose and D-xylose.Comparing with D-glucose,D-arabionse (a five carbon furanose) and D-xylose (a five carbon pyranose) are difference in carbon number and conformation. We hoped to investigate their influence on inhibiting inwar flow of calcium ion. Meatime,substituting for D-glucose,we would get natural product-Isoquercetin,which had wide and greatly biological effects.2. Using -CH2OCH3 and -CH2COOH to substitute for D-galactose.In order to investigate its influence on local analgesic,we used -CH2OCH3 to block hydroxy group at C-3,and in order to investigate influence by carboxylic acid complexing calcium ion,we used -CH2COOH to substitute for galactose of Hyprin.According to above ideas,we designed a concise route to synthesis series of target compounds respectively:1. The synthesis of quercetin-3-O-glycosideRutoside reacted with an excess of benzoyl chloride in 10% KCOs sol. to produce 5,7,3',4'-tetra-O-rutoside,then hydrolyzed in hydrochloride acid/ethanol under reflux to yield 5,7,3',4'-tetra-O-benzoylquercetin. According to Koenigs-Knorr reaction,5,7,3',4'-tetra-O-benzoylquercetin was allowed to react with a -acetoglycosyl bromide in the presence of silver oxide/quinoline,then hydrolyzed to give target compound.2. The synthesis of quercetin-3-O-ethers 5,7,3',4'-tetra-O-benzoylquercetin reacted with correspondent halidecompounds in the presence of K2CO3/acetone or KCCVDMF,then hydrolyzed to give target molecules.Otherwise,we designed the route of total synthesis of hyperin:phloroacetophenone were condensed with the correspondent aryl aldehyde to give the chalcone,but via Algar-Flynn-Oyamada(AFO) reaction,we acquired aurone,not anticipated flavonol. The AFO reaction mechanism was discussed.Seven compounds were designed and synthesized,among them,four compounds are natural products. The natural product-isoquercetin,quercetin-3-a -arabinofuranoside,quercetin-3-O- -xylopyranoside and quercetin-3-O-ethers were first synthesis. The structure of the target compounds were confirmed by IR/H-NMRandMS.The method of hydrolysis of 5,7,3',4'-tetra-O-benzoylrutoside was modified,and the yields of 5,7,3',4'-tetra-O-benzoylquercetin and hyperin were improvedThe study of physiological activity of title compounds is in progress.