Structure Design Synthesis And Characterization Of 6-Acetyl-Chrysin Mannich Base Derivatives

Natural Flavonoids are widely present in many fruits, vegetables and herbs, with a variety of biologically active of anti-inflammatory, anti-oxidant, anti-bacterial, protecting liver, anti-cancer, and so on. Flavonoids are not directly kill cells, with different mechanisms of normal and tumor cells redox state, through regulating intracellular reactive of oxygen species selectively induce apoptosis cancer cells without affecting normal cell function. Chrysin is the main active ingredient of propolis, with attracting increasingly widespread attention in the medical and health care. But Chrysin has the poor water-soluble property, a massive amount of glucuronidation metabolism and low bioavailability, with limiting Chrysin's clinical application. In order to get a new anti-cancer drug candidate with selective efficiency and low toxicit, the structure of Chrysin will be modified by Mannich reaction.In this paper,3-Hydroxy acetophenone hydrate (yield 85.8% and purity 98.0%) was synthesized from phloroglucinol dihydrate and acetonitrilen through the reaction of Hoesch acetylation with phosphorus oxychloride as the catalyst, getting 3-Hydroxyl benzene ethyleneimine, and then the reaction mixture was boiled for hydrolysis; 6-Acetyl-Chrysin (yield 65.0% and purity 95.0%) was synthesized from 3-Hydroxy acetophenone hydrate and Benzoyl acetic ester in acetonitrile through heating and depressurisation; 7 kinds of 6-Acetyl-Chrysin Mannich bases derivatives was synthesized from 6-Acetyl-Chrysin, organic secondary amine and formaldehyde in organic solvent through Mannich reaction. 6-Acetyl-8-Piperidine alcohol methylene-Chrysin (yield 92.0% and purity 98.5%),6-Acetyl-8-Hydroxyethyl piperazine methylene-Chrysin,6-Acetyl-8-Preserved ammonia alcohol (+) methylene-Chrysin,6-Acetyl-8-Morpholine methylene-Chrysin,6-Acetyl-8-Sulfur morpholine methylene-Chrysin,6-Acetyl-8-Methylpiperazine methylene-Chrysin and 6-Acetyl-8-Piperidine methylene-Chrysin were confirmed by spectral characterization and these new compounds were not reported in literatures.The 6-Acetyl-Chrysin Mannich base derivatives partition coefficient was measured. Among them, logP 1.63 of 6-Acetyl-8-Piperidinol methylene-Chrysin was most excellent.MTT method was used for screening of the ability of inhibiting human gastric cancer cells BGC-823 in vitro among the 6-Acetyl-Chrysin Mannich bases derivatives designed and synthesized by our team in this paper. The results indicated that within the scope of 1.25- 20?M, the 6-Acetyl-Chrysin Mannich bases derivatives was ability-concentration dependent. 6-Acetyl-8-Piperidine alcohol methylene-Chrysin was further screened on 5 kinds of tumor cells. Results showed that the antiproliferative activity of 6-Acetyl-8-Piperidine alcohol methylene-Chrysin (IC506.1 ?M,2.5?g/ml) was 4 times higher than chrysin (IC50 25 microns).To sum up, among the 7 kinds of 6-Acetyl-Chrysin Mannich bases derivatives,6-Acetyl-8-Piperidine alcohol methylene-Chrysin was the best, and was expected to become a new anticancer drug candidate.