Studies On Synthesis And Antitumor Activities Of Prenyl Flavonoids

Prenyl flavonoids,with diverse structures and interesting pharmacological activities compared with ordinary flavonoids,have attracted much attention.Morusin,isolated from the root bark of Morus alba L.as one of the Traditional Chinese medicines,is one kind of prenyl flavonoids.Due to its intriguing molecular structure and broad spectrum cytotoxicities against human cancer cells,it has many potential medicinal values.This dissertation describes the design,synthesis,structural determination and activity evaluation of a series of prenyl flavonoids at the C-8 position,the total amount of the synthetic compounds is up to 53,including 41 new compounds with no literature reported.Among them,31 morusin analogues have been structurally confirmed and biologically evaluated.The detailed content of this dissertation is divided into the following four parts:Part 1: Mini-review of research on flavonoidsSome basic properties of flavonoids are summarized,including their basic structures and classification,physical and chemical properties,biological activities,and their various categories of the main synthetic methods of flavones.Part 2: Mini-review of research on the antitumor activities of flavonoidsSimple introduction of the antitumor activities of a variety of typical prenyl flavonoids reported in recent years has been listed,including the relative research methods and the important results,which clarifies the necessity of the research on the anticancer activities of prenyl flavonoids.Part 3: The research on the synthesis of prenyl flavonoidsAccording to the structure of morusin,one of famous natural prenyl flavonoids,we designed a series of morusin analogues,and then chose the suitable synthetic strategies,which used 3,5-dimethoxy phenol as the starting material.Upon Friedel Crafts acylation,reduction,Friedel Crafts acylation,carbanion reaction,alkylation and dehydration cyclization reaction,the designed compounds were successfully synthesized.The synthetic compounds were characterized by nuclear magnetic resonance hydrogen spectrum(1H NMR),nuclear magnetic resonance carbon spectroscopy(13C NMR),massspectrometry(MS-ESI)and high resolution mass spectrometry(HRMS-ESI),which comfirmed their molecular structures.Part 4: The research on the biological activities of the synthetic flavonoids.Applying the known CCK8 method for the biological activities of each target compound,the inhibition data against human breast cancer cell MDA-MB-231 proliferation could be obtained;finally through SPSS software,fitting inhibition rate curve is calculated for the corresponding IC50 value.As a result,compared with quercetin,the tested results indicated:(1)morusin displayed more potent activity than quercetin(IC50: 22.5 μmol/L vs 69.3 μmol/L);(2)the activity could be increased(IC50 : 8.99 μmol/L)if the cycloolefin ether in morusin was disconnected,namely,Prenyl was installed at the C-8 position,and all the phenolic hydroxyl groups were methoxylated;the potent activity could be retained when the substituent at C-3 position was replaced by the different bulky hydrophobic groups(H,Me,Et,Pr,Bn,allyl,CH2 OH and EtOCH2),respectively;introduction of the hydrophobic groups to the C-5 position might be favorable to the inhibitory activity;the para methoxy group at B cycle in the flavonoid seemed to have an important effect on the activity;finally,IC50 value of the most potent compound 38(7aah-1)was up to 6.46 μmol/L.