Synthesis Of Resveratrol Derivatives And Study On Antioxidant Capacities

As a natural polyphenolic compound,resveratrol(3,4’,5-trihydroxystilbene)possesses a large abroad biological and pharmacological activities.The bioactivities of resveratrol have been studied in detail and some mechanisms of pharmacology have been clarified recently.However,in vivo pharmacological effects of resveratrol in some cases do not meet the perfect results in vitro,owing to influences deriving from a variety of structural feature on bioavailability.In order to overcome shortcomings in the structure of resveratrol,many endeavors are contributed to modify the structure resveratrol,and a series of library composing of novel resveratrol derivatives is set up for investigating pharmacological activities.The derivation of resveratrol mainly focuses on the following three aspects:1.The variety of functional groups attaching to benzene ring.A commonly used protocol is to vary the position and the number of hydroxyl group in stilbene or substitute hydroxyl groups by other ones.In addition,other natural molecules or medicinal molecules are employed to etherize or esterify the phenolic hydroxyl groups in order to obtain pro-drugs or twin drugs2.The derivation of C=C bond.The linear or cyclic moieties are applied to substitute trans-configuration of C=C in order to enlarge or decrease the conjugation system in resveratrol.The oligomers of resveratrol achieving either from natural resource or from synthetic protocol are based on the reaction of C=C in resveratrol.Thus,the aforementioned modifications on the structure of resveratrol provide with abundant structural features of resveratrol.3.Substitution of benzene ring.On the basis of bioisosterism,the application of a bioisostere to replace a benzene ring in the resveratrol leads to a variety of derivatives with C=C being the linkage for the conjugation system,in order to clarify the influence of conjugation system on bioactivities of resveratrol derivatives.The aforementioned results differ from the resveratrol itself.Increasing bioavailability by introducing active groups,producing novel structural features,generating hybrid with other structural features are still hot topics in the derivation of resveratrol.Presented herein are studies on the introduction of functional groups into resveratrol,the derivation on C=C,and formation of hybrid with resveratrol,aiming at exploring the pathway to enhancing activities of resveratrol derivatives toward DNA oxidation,and enlarging the application scale of resveratrol by the recognition on structure-activity relationship of resveratrol in protecting DNA against radicalinduced oxidation.The contents of this dissertation are composed of three facets:1.Introduction of functional groups into resveratrol skeleton and characterization of antioxidant propertiesOwing to a variety of reactive sites and susceptibility toward oxidation,the reaction with resveratrol being reagent is still a challengeable work.Formylation of resveratrol was reacted through Vilsmeier-Hacck reaction direct,and resveratrol aldehyde was reduced to resveratrol-2-benzyl alcohol.The Schiff base derivatives were formed by reacting with the aldehyde group of resveratrol aldehyde,and the imines were further reduced to the corresponding amines.The hydroxyl groups of the resveratrol-2-benzyl alcohol are used to form the ester derivatives.These derivatives can guarantee the integrity of the molecular skeleton of resveratrol.2 Schiff bases,1 amines,1 esters and 1 glycosides were synthesized.The antioxidant capacity of these compounds were evaluated by the method of the oxidation of DNA caused by free radicals generation by 2,2’-azobis(2-amidinopropane hydrochloride)(AAPH)and HO·,Cu2+ / glutathione(GSH).The results show that the activity of direct functionalization products is lower than that of resveratrol due to the phenolic hydroxyl groups were affected by hydrogen bonds.The derivatives of direct functionalization products is higher than that of direct functionalization products.In the target compounds,the stoichiometric factor of the imide and the amine formed by resveratrol and glucosamine were significantly higher than that of resveratrol and glucoside of resveratrol.Based on above result,phenolic hydroxyl group is essential in the antioxidant properties,changed the shape of the molecule,introducted a group with larger steric effect in the molecule to increase the surface area of the molecular,so then,enhancing the formation of hydrophobic interaction or hydrogen bonds with DNA can be used as a design ideas of new antioxidant molecules.2.Study on the cycloaddition reaction based on the double bond of resveratrol and the characterization of antioxidant activity.The 1,3-dipolar cycloaddition is performed on double bond in resveratrol,affording the tetrahydropyrrolation product of resveratrol.The antioxidant activity of tetrahydropyrrolation resveratrol was tested in the experimental system of AAPH-induced oxidation of DNA.It is found that the stoichiometric factor of tetrahydropyrrolation resveratrol is higher than that of resveratrol itself.Whether this conclusion is also available for other stilenes should be taken into consideration.A series of stilenes is synthesized by Wittig-Horner reaction,and tetrahydropyrroles are achieved by 1,3-dipolar cycloaddition in the case of azomethine ylide generated in situ.Not all of the stilenes can be tetrahydropyrrolized by using the same azomethine ylide,which is synthesized under the condition of lithium diisopropylamide and trimethylamine oxide.As for the stilenes with electron-withdrawing-group,the corresponding tetrahydropyrroles are produced with azomethine ylide resulting from trifluoroacetic acid and silane.By comparing the antioxidant activities of all stilene compounds and those of the corresponding tetrahydropyrrole derivatives,we found that the stoichiometric factors of tetrahydropyrrole products are all higher than those of the corresponding stilene substrates.The introduction of electron donating groups and the bromine atom are beneficial for the improvement of the stoichiometric factor of the tetrahydropyrrole products.It is owing to aromatization of tetrahydropyrroles under the action of free radicals in addition to the impact of phenolic hydroxyl groups and steric effect.The aforementioned research works indicate that introducing electron-donatinggroups and bromine atom into two benzene rings,the stoichiometric factor of tetrahydropyrrolation of stilene is improved obviously.The aromatization of non-conjugated structure in the target molecules plays important role in the enhancement of antioxidant activity,which provides new ideas for the further design of antioxidant molecular.3.The synthetic exploration of resveratrol derivatives based on fullerene.The antioxidant effect is not as good as expected by hydrophobic interaction(the introduction of amantadine);the introduction of larger steric hindrance group and seeking for the intramolecularly oxidation-reduction relationship between the introduced molecular fragment and resveratrol molecular fragment are new idea for the design of antioxidant molecules.C60 has the properties of antioxidant and large molecular volume.In this part,we tried to introduce C60 fragments into the resveratrol molecule.Prato reaction is a common cycloaddition reaction of C60.It is the reaction of aldehyde,sarcosine and C60 to form tetrahydropyrrole rings under heating conditions.We tried to introduce the aldehyde or sarcosine fragment into resveratrol molecule,unfortunately,part of the reaction was failed due to solubility and steric factors,other part of these reactions,We introduced functional groups that can participate in the Prato reaction successefully,but these intermediate can not occue Prato reactionhad,or did not form the desired target molecules.Bingel reaction is another common reaction of C60,This reaction needs to be completed with malonic ester in the presence of DBU and halogen to form a three membered ring,we tried to connect the resveratrol fragment with the C60 fragment through the Bingel reaction,but failed again.Based on above,we found some key factors that affect the reaction of resveratrol and C60,it is important to maintain the proper distance between the two compounds and to protect the phenolic hydroxyl groups of resveratrol to avoid the poor stability of the reaction substrate.