Studies On The Synthesis Of Soybean Isoflavone Deravitives And The Evaluation Of Their Anticancer Activities

ANSmCT1n this tbesis, we bave revbo the ment advances in tbe studies on the composition,syntbesis and pharmacolOgy of soybeau isofi8vones. A novel modificatiOu of Roeschprocedure for the preparahons of Polybydric dmpbenzoins bas invented. Genistein,daidzein, and tkeir homologUes were synthesbe aud tbase Sgutbetic isodsvoues werehybrided with some amino acids edoseIectiveIy and areientty Based upon tbe evaluationof tbeir anticaucer activihes, tke Synthetic genist6in skowed an equiraIent grOwt inhibitiouof tomor cen and a weaker toticity compared witk the natUral pnduc' and therefOre is apromising candidat6 fOr the pmcntion of bumau cancer-l) After reviewed the recent advances in the stUdies on the composition, synthesis andpharmacology of soybean isoflavones, we chose the aPproach to the synthesis of isonavones viathe ring closures of a suitab1e Cl unit on to deoXybenzoins. We also designed to modify thesynthetic isonavones with amino acid derivatives to improve their bioavailability and to decreasetheir toxicity.2) After six procedures for the synthesis of deoxybenzoins reported recently were studiedcareful1y' we finally invented a new method to prepare polyhydric deoxybenzoins. This newmethod is an efficient modification of traditional Hoesch procedure, and POsse55ed the advantagesof higher yields, shorter reaction times and reedily workup. It is esPecial1y suitable for thepreparation of polyhydroxyisofiavones such as geni stein, daidze in and the ir homologues. Th irtee ndeoxybenzoins have been syntheshed according tO this invention, among which the yield of2,4,6,4'- t6trahydro xydeoXybenZOin, an inaccessib[e importan intermediate of genistein, was th reetimes higher than traditional Hoesch procedure.3) Genistein, daidzein and their therteen homolOgus were prepared via the ring closure of DMFC, unit on tO an aPpropriate deoxybenzoins. Further investigation of the macroscale preparaionand especial the Purification ofgenistein is Still in progress.4) lH'NMR study on fOurteen isoflavones with various parasubstitUentS on B ring is reported. Theeffects of substitUentS on the chemical shifts of A, B and C ring protons are discussed.Unambiguous assigrUnend ofunsubStitUted B ring lH resonance spectra were mfor with the aid ofsuPerconductiv NMR Spectroanalysis. There is lfor relationship betWere the chemical shifts ofB ring protonS and the subtw parambo. The chemicai shifts of 2'(6'y lH and 3'(5'y lHshOw a linear cormlation with Hanunatt conStan o p and subedtUent parameter S. mpctivelY'The resonance shifts of 3'(5'y IH trise from the eIectron and magntic anisotroPy effectS, whilethe resonance shifts of 2'(6'Y lH respond to the electron effects of the substituents Primarily.5) In order to get acN with the reachve featUreS of ~lation and esteffication ofisonavonoids, we Pmpared ten methy ether or acetic eSter of the above synthedc isonavones,arnong which sis were new comPounds.6) An efficien and regioselechve aPPrOaCh tO hybridhe isoflavones wun amino acids wasdeveloPed. twhae novel N-[ Q 'isonavonesrrpoetOl aminO acid methl eSter derivatives,which Possess the simiIar mctheI bo as the not 6',-ndonylisonmp were Pr'epeand their StTUctUre were confirmed by 'HN'MR. uCNMR. MS and EA. It is exPected that theterminal carboxyl grOuP of these isoflavone analogues will help fOr increasing the aqueoussolubilfy of isOflavones, and therefOre hoprove their bioavailabilities and decrease their tokicities.f-ca(R)de ler,In'Th R00coo1theR-ou 0 O',W tUR-N[ Q -(isollavo~eto] ooamino acid methyl eSters nha 6ruO malonylisofiaVneThe evalusion of the Phannacology of these novel isOflavone analogueS is in progress.v) some of the synthetc isonavones and deoxybenzoins were teSted for anthemor activity and theresultS showed mat all the isonavones with phioroglucinOl Pattern in A ring exceP 5,7doproxy-4'-bromoisoflavone were bioactive. Based upon the MMT methOd, the Synthetic ghostein showedan equival...