Synthesis Of Scutellarin Analogues And Study Of Their Anti-heart Ischemia Activities In Rats

Objective Cardiovascular and cerebrovascular diseases are a class of common diseases putting serious threats on human health and life, the the principal diseases leading to the death of the old. Breviscapine is flavonoid extracted from Erigeron (Erigeron breviscapus (Vant.) Hand.-Mazz), its preparations have exact therapeutic effect on clinical therapy of heart and brain ischemia. Besides pharmacokinetic characters of low oral bioavailability, short half life, breviscapine itself is a mixture of many compounds. All of these increase incident of adverse reaction, and limit its international clinical application. Scutellarin, with structure of5,6,4’-trihydroxyflavone-7-O-glucuronide, is the main active component of breviscapine(>90%). For the complex synthesis route, it is difficult for commercialization production of this compound. With scutellarin as the leading compound, a series of representative scutellarin analogue was synthesized in this paper, to provide SAR information and find indication compounds, which could be available through a simple systhesis route.Content With scutellarin as the reference compound, a series of flavone Derivatives with different number hydroxyl groups were designed and synthesized. Then the anti-hypoxia activity of these compound were tested and a preliminary structure-activity relationship of scutellarin was discussed.Methods With resorcin and apaston as the starting materials, a series of flavone Derivatives were synthesized by acylation, improved Baker-VenKataraman rearrange, cyclization, esterification, etherification and sulfonation reaction.①With resorcin as the starting materials, a series of7-dydroxy4’-displ flavones was systhsized.②With apaston as the starting materials, a series of5,7-didydroxy4’-displ flavones was systhsized.③flavone ester derivatives were synthesized by reaction between acyl chloride and flavones parent nucleus synthesized.④Scutellarein ether derivatives were synthesized by between different kinds of alkylogen with flavones parent nucleus synthesized.⑤flavone sufonate sodium was synthesized by sulfonation reaction with concentrated sulfuric acid as the solution and sulfonating agent. Most compounds’ pharmacolog activities on model of hypoxic injured rat heart cells were tested with MTT method.Results53scutellarin analogues were synthesized,in which there are10flavone intermediates,14flavone ester,28favone ethers and one sodium flavone sufonate.31compounds of them have not been reported. All the structures were confirmed by1H NMR and ESI-MS. The result of activity test showed that the protective effects of compound D1(7-hydroxy-4’-methylflavone), E1(7-hydroxy-4’-methoxyflavone), E5(7-ethoxy-4’-methoxyflavone),J2(5-hydroxy-7-benzoyloxy-4’-bromoflavone)on hypoxic injured rat cardiac myocytes was stronger than the control scutellarin.Conclusion Part of the compounds synthesized have protective effect on hypoxia rat heart cell, and are available through relative simple synthesis route. The preliminary SAS results are showed as follows. The5-OH is not the prerequisite group for its anti-hypoxia activity, while the6-OH plays the important role in its anti-hypoxia activity. The exposure of7-OH can improve cardioprotective effect significantly. There is better anti-hypoxia activity when4’position is substituted by electron donating group. The results provided theory and practice ground for further research on finding of indication scutellarin analogue, which has ideal activity and is available through simple synthesis route for less hydroxyl substitution.