Discovery Of Antithrombotic Components & Study Of Pyrazoles With Antitumor Activity

Natural products include the extracts of animals and plants,the compositions and metabolites of insects,marine ogranisms and microorganisms,as well as many endogenous components in humans and animals.The structures of natural products are diverse,which contain protein,polysaccharides,flavones,phenols,alkaloids,terpenes,steroids and so on.Natural products have various bioactivities.Recently,searching for active compounds from natural products and then conducting structural modifications have been a hot spot of medicinal chemistry,in order to obtain lead compounds or drugs.This dissertation consists of two parts.The first part deals with the discovery of antithrombiotic compounds from medicinal plants,while the other part discusses the design and synthesis of pyrazoles with antitumor activity,together with the structure-activity relationship?SAR?.In the first part,we investigated the chemical constituents of three medicinal plants,Palhinhaea cernua?L.?Franco et Vasc.,Cydonia oblonga mill.and Amomum villosum Lour.by utilizations of many column chromatography(silica gel,MCI gel CHP-20P,Chromatorex C₁₈,TSK gel Toyopearl HW-40F,Sephadex LH-20 and preparative HPLC).As a result,74 compounds?1-74?were identified,including 10 novel compounds.Their structures were elucidated based on extensive spectroscopy and X-ray.Five new serratene-type triterpenoids?1-5?,along with thirteen known compounds were isolated from P.cernua.The possible biogenetic pathway of the new compounds was postulated based on the reported papers.Three new dibenzofurans?40-42?,one lignans?43?and twenty-one known compounds were isolated from the leaves of C.oblonga.All these compounds contain triterpenoids,lignans,flavones and dibenzofurans.Thirty-one compounds were identified from the fruits of A.villosum,including terpenes,alkaloids,phenols and steroids,among of which one is novel compound?44?.We studied the anti-platelet aggregation activities of the most compouds.The results showed that the known compound 36 and the new compound 42exhibited potent anti-platelet aggregation activities.When the final concentration was10?M,the rates of anti-platelet aggregation?compound 36,42?in rats induced by ADP were both more than 40%.In the second part,we designed and synthesized 69 compounds,belonging to three types of structures,including 1,5-diarylpyrazoles?W1-W35?,1,2-diaryl pyrazolones?W36-W41?and 1,4-diaryl pyrazolones?W42-W69?.Besides,an efficient new method for construction of 1,4-diaryl pyrazolones was found.We tested the antiproliferative activities of these compounds against A549,SMMC-7721,HL-60 cell lines using CCK-8 method and summaried the structure-activity relationship.W24 and W29 exhibited potent growth inhibitory activities against SMMC-7721 cell line with IC₅₀ values of 0.7,0.03?M,respectively.Furthermore,in vivo pharmacology evaluations of compounds W24,W29 in mice tumor xenograft models were also tested.The work may lay a foundation for the discovery of antitumor agents.