Study On The Property Of Antioxidants Prepared By Multicomponent Reactions

In recent years, multicomponent reaction (MCR) has been widely used in thefields of synthetic and medicinal chemistry because it can be used to constructcomplicated compounds with multi-functional groups.In the past decade, the investigations on antioxidant were mainly focused on thestructure-activity relationship of conjugated molecules, in which hydroxyl wassupposed as an essential group. However, the studies on antioxidants withnon-conjugated structure or new antioxidantive functional group were relatively rate.Therefore, in this thesis, we synthesized furanquinoline and dihydropyrimidinederivatives involving conjugated structure by domino-reaction and Biginelli-3CR,respectively, as well as a series of non-conjugated-acetoxycarboxamides anddiamides by Passerini-3CR and Ugi-4CR, respectively. The antioxidative abilities ofthese compounds were evaluated by scavenging2,2’-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS+·),2,2’-diphenyl-1-picrylhydrazyl radical (DPPH) and Galvinoxyl radical, and byinhibiting radical-induced oxidation of DNA. The major contents in this thesis is asthe following:1. Furoquinoline synthesized by domino reaction and effects on radical-induced oxidation of DNA.In this part,4-methyl-2,3-dihydrofuro[2,3-b]quinolin-6-ol,4-methyl-2,3-di-hydrofuro[2,3-b]quinolin-8-ol, and4-methyl-2,3-dihydrofuro[2,3-b]quinolin-7-olwere synthesized by a domino recyclization reaction of1-acetyl-N-phenyl-cyclopropanecarboxamide in the presence of SnCl4as the catalyst. Moreover, thefuroquinoline without hydroxyl group was also synthesized to serve as the referencecompound. The antioxidant capacity of these four compouds were evaluated in theexperimental system of the oxidation of DNA caused by OH, Cu2+/glutathione(GSH), and2,2’-azobis(2-amidinopropane hydrochloride)(AAPH). The aim of thispart was to clarify the influences of the position of hydroxyl group and furo[2,3-b]moiety on the antioxidative effectiveness of conjugated structural furoquinoline. Inprotecting DNA against AAPH-induced oxidation, only the hydroxy substitutedfuranquinoline derivative exhibited antioxidant activity, and the hydrogen radicalformed by the reaction of the hydroxyl group in the furanquinoline with the radicalswas able to be transfered to the furo[2,3-b] group via resonance structures, whichwere beneficial for stabilizing the corresponding radical, and this interaction inducedthe antioxidant ability of6-and8-position hydroxy-substituted furo[2,3-b]quinolinederivatives were more active than that of7-substituted furo[2,3-b]quinoline. Thisphenomenon was also found when these hydroxy-substituted furo[2,3-b]quinolineinhibited Cu2+/GSH-induced oxidation of DNA. Moreover, the chelation offuroquinoline with Cu2+, and the hydroxylation reaction between furan and OH madethe furo[2,3-b]quinolone also exhibited weak activities on both protecting DNAagainst OH and Cu2+/GSH-induced oxidation even in the absence of hydroxyl group.In summary, for the aromaticity ring fused heterocycles, the conjugating effectcould stabilize free radicals originated from the functional group, which was asignificant factor for affecting the antioxidant activity of the compound. Therefore,the activities of conjugated compounds on DNA oxidation was dependent upon theposition of hydroxyl group.2. Synthesis and antioxidant activities of dihydropyrimidine by Biginelli3-CR Thirteen dihydropyrimidines (DHPM) were synthesized in modest yields viacatalyst-free and solvent-free Biginelli-3CR. The antioxidant abilities of theseDHPMs were evaluated by quenching ABTS+., DPPH and Galvinoxyl radical, and byprotecting DNA against AAPH-induced oxidation.The N-H group and the phenolic hydroxyl at the4-position ofdihydropyrimidines were antioxidative functional groups in DHPMs. In scavengingradicals, C=S group and more phenolic hydroxyl groups were both beneficial forenhancing the antioxidant effect of DHPM. Moreover, the ferrocene moiety alsoplayed a key role in scavenging ABTS+.and Galvinoxyl radical. In protecting DNAagainst AAPH-induced oxidation, the ferrocene group can also enhance the N-Hactivity through conjugated electronic-donating effects. This conclusion can besupported by comparing the antioxidant activities of benzoyl and furanyl substitutedferrocenoyl dihydropyrimidine. The C=S group played the same role with ferrocenoylgroup in improving the antioxidant activity of DHPMs. Moreover, increase thenumber of hydroxyl group is also beneficial for the activity of DHPMs in preventingAAPH-induced oxidation of DNA.In summary, increase the number of hydroxyl group and introducingelectron-donating group were two important ways toward of improving theantioxidant activities of the conjugated compounds.3. Synthesis and antioxidant activities of coumarin-involved-acetoxycarboxamide via Passerini3-CRIn this part, coumarins were modified by gallic acid, ferulic acid and caffeic acidto afford18non-conjugated-acyloxycarboxamides via Passerini-3CR. Then, theeffects of the obtained-acyloxycarboxamides on quenching radicals and inhibitingDNA oxidation were estimated. The aim of this part was to study the structure-activityrelationships of various functional groups in non-conjugated compounds.In scavenging radicals, the antioxidant activity of-acyloxycarboxamides wasgenerated by the hydroxyl groups on carboxylic acid moiety, and increasing the number of hydroxyl groups was beneficial for enhancing the activities of-acyloxycarboxamides to scavenge ABTS+.. However, the increase in the number ofhydroxyl groups was not conducive to-acyloxycarboxamides in scavenging DPPHand Galvinoxyl radical. In protecting DNA against AAPH-induced oxidation, theantioxidant activity of-acyloxycarboxamides was also associated with the number ofhydroxyl group. In addition, the steric effect rather than the electronic effect ofterminal moiety of-acyloxycarboxamides was an important factor for influencingthe inhibitory effects of phenolic hydroxyl groups derived from carboxylic acid onAAPH-induced of DNA oxidation.In summary, the hydroxyl groups on different substituents in the non-conjugatedstraight chain molecule can enhance antioxidantive capacities. Moreover, thesterically effect among different substituents of non-conjugated compound became anovel factor for enhancing antioxidative effectiveness.4. Synthesis and antioxidant activities of biamides by Ugi4-CRIn this part,19bisamides with a long carbon chain and different groups at theterminal moiety were synthesized via Ugi-4CR. The effects of the obtained19bisamides on scavenging radicals and inhibiting AAPH-induced oxidation of DNAwere estimated.Increasing the number of hydroxyl groups was still beneficial for enhancing theactivities of diamides in scavenging radicals and inhibiting AAPH-induced of DNAoxidation. In protecting DNA against AAPH-induced oxidation, the steric effect ofterminal moiety was also able to enhance the activities of biamides, the stronginhibitory effects of ferrocenyl-contained acyloxycarboxamides on DNA oxidationwas owing to the special recognition effect of ferrocenyl group on biologicalexperimental materials. The conclusions as aforementioned were the same as theresults on-acyloxycarboxamides. Furthermore, the OH at the different parts ofdiamide existed intramolecular effect with each other both on protecting DNA andscavenging radical. In addition, we also found that the distance between the active groups and terminal moiety of diamides was another important factor for bisamidesinhibiting DNA oxidation.In summary, a mutual antioxidant effects of phenolic hydroxyl groups existedamong different parts of the non-conjugated molecule with long carbon chain.