Synthesis And Antiproliferative Activity Of Polymethoxy Flavones And Their Aminoalkyl Derivatives

Flavonoids are a type of natural products that are widely present in nature,especially plants.They are pharmacologically active ingredients in certain plants and play an important role in various biological processes.In order to further develop and utilize the medicinal value of flavonoids,this paper uses rutin as a raw material for chemical conversion and structural modification to semi-synthesize a series of polymethoxy flavonoids and amine alkyl flavonoids derivatives and studied their biological activity.1.Rutin,which is rich and cheap in nature,as a raw material,methylation with dimethyl sulfate,and then hydrolyze the deglycosyl group under the acidic conditions of ethanol/concentrated sulfuric acid to obtain 3-hydroxy-5,7,3’,4’-tetramethoxyflavone（2-1）;then using compound 2-1 as a substrate,nucleophilic substitution with 1,4-dibromobutane to give3-bromobutoxy-5,7,3’,4’-tetramethoxyflavone（2-2）;then,in acetonitrile solvent,under KI catalytic conditions,2-2 and various secondary amines undergo Hofmann alkylation reaction to obtain a series of unreported amine alkyl containing nitrogen flavonoid derivatives 2-3a～2-3h.2.Rutin as the starting material,methylated by dimethyl sulfate,catalyzed hydrolysis of sulfuric acid by sulfuric acid to obtain substrate 2-1,which undergoes nucleophilic substitution with isopentenyl bromide obtain 3-O-prenyl polymethoxy flavonoid（3-1）;take 2-1 as the substrate,through the 6th and 8th positions of NBS bromoflavonoids,and then Ullmann nucleophilic substitution with Cu Br catalyst,introduce methoxy groups into the flavonoid structure,obtained the natural product3-3（Natsudaidain）,then prenylated to give compound 3-5;nucleophilically substituted with ethyl chloroacetate,demethylated,and acidified much methoxy carboxy Acid flavonoids（3-7）;3-O-methylated,demethylated at the 5-position obtained polymethoxy flavonoids 3-4,3-6.3.Using the CCK-8 method,aminoalkyl nitrogen-containing flavonoid derivatives were tested for anti-proliferative activity on three cancer cells（Hela,SKOV-3,HCC1954）,cisplatin was used as a positive control.Some of the synthesized compounds have anti-cancer activity,which of compound 2-3d has the best anti-cancer activity.While all synthesized polymethoxy flavonoids act on Hela cells,compound 3-4 and 3-6 have the best antiproliferative activity.4.Nuclear magnetic resonance hydrogen spectroscopy（¹H NMR）,carbon spectroscopy(¹³C NMR),mass spectrometry（MS）and other spectroscopy methods were used to confirm the structure of all synthetic compounds.