Total Sythesis Of1β-hydroxyalantolactone And Structural Modification Of α-santonin And Anti-inflammatoy And Antitumor Activities Evolution Of Derivatives

Sesquiterpene lactones (SQLs) are an important class of secondary metabolites innature.In traditional medicine, SQLs are always the active constituents. Modernpharmacological studies have revealed their diverse biological activities, includinganti-inflammatory, antitumor, anti-proliferative, antimicrobial and antiprotozoal effects,among others. In recent years, their potent anti-inflammatory and antitumor propertieshave received considerable attention by medicinal chemists. The thesis consists of twoparts, mainly on the total synthesis of1β-hydroxyalantolactone and structural modificationof α-santonin and biological activities of derivations.The first part centers on the synthesis of1β-hydroxyalantolactone, which belongs toeudesmane type sesquiterpene lactones. In2010, our research group got it from theJapanese Inula and following by the preliminary screening,1β-hydroxyalantolactonesignificantly inhibited the incidence and severity of CIA.In order to further study its physiological activity, the topics mainly exploredsynthetic route of1β-hydroxyalantolactone. We finalized its preliminary synthetic route.Initially, we intend to build six-membered ring by Aldol reaction, Michael addition andRobinson annulation.However, we find some intermediates are in very low yield withexploring. And the chiral of angular methylcan not be controlled. To solve the problem, weutilize asymmetric decarboxylation allylation reaction to control the chiral of angularmethyl. Meanwhile, we want to build the six membered ring by olefin metathesis afterintroducing a terminal olefin. On the other hand, we plan to construct theα-methylene-γ-butyrolactone by Taylor’s "one-pot" approach. And this method also cansolve the configuration problem of the two chiral carbons in the lactone ring.The second part describes the structural modification of α-santonin and inhibitoryeffects of NO production and anti-hepatoma activities of derivations. A guaiane frameworkwas scaffolded by photochemical rearrangement reactions using α-santonin as a starting material. Then, using a series of reactions, we synthesized the key intermediates3and8,then, we synthesized65derivatives by esterification condensation.The inhibitory activities of compound3and its derivatives on nitric oxide (NO)release were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7macrophages.Their cytotoxicities were also estimated using an MTT assay. Compounds1g、2k、2h、2iand3g exhibited significant inhibitory effects on NO production, with IC50values of14.8、17.4、22.3、18.3and7.0μM, respectively. The structure–activity relationships of thesecompounds were discussed.For compound8and its derivatives, study the activities ofanti-hepatoma and cytotoxicity on hepatoma cell line QGY-7703, HepG-2, SMMC-7721and normal liver QSG-7701. These derivatives all had stronger anti-hepatoma activity andhad weaker cytotoxicity then5-Fu. Among them, compound5h had the stongestanti-hepatoma activity on QGY-7703, HepG-2, SMMC-7721cells with IC50values of7.51,3.06,4.08μM, respectively. Furthmore, compound5h displayed no cytotoxicity onQSG-7701. At last, we discussed the structure–activity relationships of these derivatives ofcompound8.