| Objective Cardiovascular and cerebrovascular diseases are a class of common diseases which threat to human health and lives seriously. Both its incidence and mortality are high and are growing rapidly year by year. It is the main cause of death second only cancer and the principal diseases leading to the death of the old. Breviscapine is such a Chinese materia medica preparation which has exact therapeutic effect to heart and brain ischemia in clinical. Breviscapine is flavonoid extracted from Erigeron (Erigeron breviscapus (Vant.) Hand.-Mazz), and it is effective in treating cerebral thrombosis, cerebral ischemia, cerebral vascular sequela, prevention of platelet aggregation and other aspects. However, Breviscapine’s solubility is poor in various solvents, oral bioavailability is low and half-life is short. All these are limiting its clinical application. Most study of breviscapine up to now focused on formulation improvement areas, such as its PEG technology to increase the aqueous solubility and so on. However, these methods were not a fundamental solution to the problem of its absorption and metabolism. Scutellarin, whose chemical structure is5,6,4’-trihydroxyflavone-7-O-glucuronide, is the main active compound of breviscapine. Using scutellarin as a lead compound, this study worked on structural modification of scutellarin and synthesized a series of representative scutellarin derivatives, expecting to improve its solubility and pharmacokinetic properties, enhance its pharmacological activity, and find indication compounds with values of development.Content With the carboxyl on the glycuronic acid of scutellarin, glycosyl, phenolic hydroxyls on the scutellarein and the C-3’,5’on the B ring as modification positions, a series of scutellarin derivatives were designed and synthesized. The anti-hypoxia-ischemia pharmacological activity of each compound was tested and a preliminary structure-activity relationship of scutellarin was discussed.Methods With scutellarin as lead compound, different kinds of scutellarin derivatives were synthesized by hydrolysis, esterification, glycosidation, etherification and sulfonylation.①Scutellarin esters were synthesized by reacting with alkylogens after being transformed to sodium.Their solubility in deionized water and LogP value was detected.②With scutellarein which was from the acid hydrolysis of scutellarin as one of the reactants, glycosyl changed scutellarein glycoside derivatives were synthesized by the phase transfer catalysis method.③Scutellarein ether derivatives were synthesized by reacting with kinds of alkylogen directly or indirectly.④Scutellarein ester derivatives were synthesized by reacting with acid anhydride or acyl chloride.⑤Scutellarein sufonate sodium was synthesized by sulfonation reaction with concentrated sulfuric acid as the solution and sulfonating agent.Most compounds’ protective effect on hypoxic injured rat heart cells and SHSY5Y cells was tested by MTT method.Results26scutellarin derivatives were synthesized. In which there are two ester derivatives, one glycoside,14scutellarein ethers,3scutellarein esters, one sodium scutellarein sufonate and5intermediates.18compounds of them have not been reported. All the structures were confirmed by1H NMR and ESI-MS. The result of activity test shows that the protective effect of compound A1(benzyl-5,6,4’-trihydroxyflavone-7-O-glucuronide ester), B1(5,6,7,4’-tetrahydroxyflavone), C3(5,6,4’-trihydroxy-7-benzyloxyflavone), E1(5,6,7,4’-tetrahydroxyflavone-3’-sulfonic acid5’-sulfonic acid sodium)on hypoxic injured rat cardiac myocytes and SHSY5Y cells was stronger than scutellarin.Conclusion Both making scutellarin to be esters by esterification and be scutellarein by hydrolysis didn’t reduce its activity. The glycosyl and the7-OH are not the prerequisite group for its anti-hypoxia activity while the4’-OH plays the most important role in its anti-hypoxia activity.We may gain scutellarin derivatives with better activity or pharmacokinetics characters by changing on the unnecessary points. |
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