Study On Synthesis And Activity Of Chrysin Derivatives

Chrysin is a kand of natural polyphenolic brass compound extracted from the Oroxylum indicum of the Asteraceae family and is widely found in honey and propolis.Through continuous research on chrysin,its anti-cancer,anti-inflammatory,anti-viral,anti-allergic,antibacterial,anxiolytic,and aromatase inhibiting activities were revealed step by step.New mechanisms of action and active binding sites were discovered and reported.Because of the various pharmacological effects and low toxicity of chrysin,it has attracted wide attention.However,the structure of chrysin determines that its water-solubility and fat-solubility are not good.Oral administration will in turn cause serious"first-pass effects",which will rapidly form glucuronidation is rapidly formed on the 5-and 7-hydroxyl groups to be metabolized in the body.The structural modifications of the 5-and 7-hydroxyl groups of chrysin have resulted in significant improvements in anti-cancer and anti-bacterial activities.The structural modification of chrysin 6 and 8 to replace the secretion of NO,IL-6 and PGE2 in RAW264.7 cells,and the anti-inflammatory activity was significantly improved.However,the yield of the reaction step is not high.In this line of thought,the present study used the more readily performed Mannich reaction to select a piperidine ring,a piperazine ring,and a heterocyclic ring such as morpholine,thiomorpholine and the like as the substituents to synthesize chrysin.Mannich Alkaline derivatives,trying to find new ways of derivatization.In this dissertation,18 kinds of Mannich base derivatives were synthesized by the reaction of chrysin with 37%formaldehyde solution and nitrogen-containing heterocycles.The progress of the experiment was tracked by thin layer chromatography and the compounds were purified by silica gel column chromatography and recrystallization.The structures were determined by melting point measurements,IR,~1H-NMR and high resolution mass spectrometry.Nine of them are new compounds that have not been reported in the literature.By MTT assay,cytotoxicity experiments were performed on some chrysin derivatives in the range of 10-80?M.Among them,derivatives containing piperidine ring had obvious toxicity to RAW264.7 cells,and had certain concentration dependence.Derivatives 3,11,12b,13a,13b,and 14 containing morpholine,thiomorpholine,and piperazine ring were not toxic to RAW264.7 cells and had the effect of promoting the proliferation of RAW264.7 cells.These proliferation-promoting compounds were selected for the next step of anti-inflammatory and antioxidant activity experiments.Inhibition of NO and IL-6 production by RAW264.7 cells at a concentration of10?M in blank,model,positive control,chrysin,and chrysin derivatives using RAW264.7 cell model.The results showed that the substitutional hybrids containing N,O,S and these lone-paired electrons had good activity,and the best activity of 6,8-bis(morpholine methylene)-chrysin(11)was compared with the positive control.The drug was equivalent,and the inhibitory capacity for NO and IL-6 secretion was2.5 and 2.4 times that of chrysin.At the cellular level,a derivative with a protective effect against oxidative damage induced by hydrogen peroxide in RAW264.7 cells were initially screened by MTT assay.The results showed that the derivatives containing morpholine,thiomorpholine,and piperazine ring all significantly increased the cell viability of oxidativelyinjuredcells,amongwhichthecompound6,8-bis(thiomorpholinomethyl)-cresin(12b).The most active at 5?M.At the same time,using chemical methods to study its scavenging activities of free radicals DPPH·,ABTS·,and did not get the same results with the cells,which may be related to different levels of antioxidant mechanisms at the cellular level and the chemical level.