Design, Synthesis And Activity Characterization Of Ligustrazine Flavonoid Derivatives

The thesis topic was based on the preliminary work,which mainly study on the several groups of classic drugs such as Chuanxiong-Angelica,Chuanxiong-Tianma,etc..The main ingredients of each drug were choosen as start materials.Taking the active ingredient TMP as the basic nucleus,combination principles were used to design synthesize.We have designed and synthesized phenylpropanoids,alkaloids,terpenoids and other chemical components of Traditional Chinese Medicine.The compounds' actives had been tested by cell model in vitro.Flavonoid compounds were widespread in the plant kingdom,which was a class of secondary metabolites,and had a wealth of pharmacological effects.So basic on the early work,the TMP-flavonoids were designed,synthesized and tested the activities.The thesis was divided into five chapters:Chapter ? the literature review;Chapter ? The design and synthesis of TMP-flavonoids;Chapter ? Screening TMP-flavonoids activities;Chapter IV The structure-activity relationship of TMP-flavonoids;Chapter V The results and discussion.(This study was financially supported by the National Natural Science Foundation of China(No.81173519)Chapter ? Literature reviewFlavonoids are secondary metabolites of plants,which widely distributed in the plant kingdom,and its pharmacological activities were varied,including anti-tumor activity,cardiovascular activity,antioxidant activity of free radicals,anti-aging,anti-inflammatory and analgesic activity.The activities of anti-tumor,cardiovascular protection,anti-oxidant of flavonoids and their mechanism of action were summed up from a series of relevant research literatures.Through summing up the literatures;we want to get ideas to guide the work of synthesis and screening activities later.Basic on the preliminary work,the review of TMP was not to discuss again.Chapter ? The design and synthesis of TMP-flavonoidsBased on the previous research articles of flavonoids,we chose luteolin,apigenin,baicalein,chrysin,daidzein,fisetin,genistein,naringenin,quercetin as the materials which we study frrther.The structures can be divided into four types,such as flavonoids,flavonols,isoflavones and flavanones.These structures were combinated with the TMP through chemical methods.Synthesis line:The first step is the dehydration reaction of TMP,then monobrominated with NBS to prepared TMP-Br intermediates;second step was nucleophilic substitution of TMP-Br and flavonoids,synthesized TMP-flavonoid derivatives.The 16 new compounds were identified by 1H-NMR,13C-NMR,MS spectra.The C-O bond of C ring of naringenin derivatives was disconnected to form a chalcone stracture.Chapter ? Screening activities of TMP-flavonoids by cell modelFrom the literature review,TMP and flavonoids showed good effect on the prevention of anti-tumor and cardiovascular disease.According to the the bioactivities of TMP and flavonoids,we designed and tested the activities of TMP-flavonoids derivativesand raw materials from cell level in vitro.The several cell models were established such as:human umbilical vein endothelial cells(HUVEC-12)and its hydrogen peroxide damage model,five lines of tumor cell model(HT-29,Bel-7402,HepG-2,Hela,MCF-7)and hepatic stellate cells model(HSC).The pharmacological activity of TMP-flavonoids derivatives were tested respectively.The activies of compounds CH-7,CH-10 were better than the raw materials.IC50 values:(CH-7:34.17?10.85?20.84?30.26?16.47?16.94 ?mol·L-1;CH-10:9.86?29.11?14.34?15.35?10.59?24.99 ?mol·L-1).Luteolin exhibited good activies among the flavonoids tested,IC50 values:(19.34?14.05?11.37?21.62?17.12?15.69 ?mol·L-1)Chapter ? :Structure-activity relationship of TMP-FlavonoidsThrough a series of bioactive of TMP-flavonoids derivatives and raw materials,summed up the relationship between the actives and structures of compounds,for further guidance on the ideas of design and synthesis.The bioactivities of flavonoids have relationship with their special functional groups such as 3',4'-OH,5-OH,7-OH and 2,3-double bound.And the order of active of flavonoids nucleus was flavonoids,flavonols>isoflavones>flavonones.Because the activity data of TMP-flavonoids derivatives were not complete,it is not possible to analyze the structure-activity relationship of TMP-flavonoids derivatives.Chapter ? Results and discussionThe subject was basic on the preliminary experiments,using combination priciples theory,synthesized 16 of TMP-flavonoid compounds,which structure had been identified.By using cell model in vitro,several structures showed better activities of 16 compounds(CH-7,CH-10),but most of the compounds were not ideal.The bioactivities of flavonoids have relationship with their special functional groups such as 3',4'-OH,5-OH,7-OH and 2,3-double bound.And the order of active of flavonoids nucleus was flavonoids,flavonols>isoflavones>flavonones.Therefore,how can we effectively get the new good structures with efficiency effect from the active ingredients in Chinese medicine?It was depending on further study.