Novel glutathione analogues and their antioxidant activity
Date
2011-07-27
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Abstract
Käesoleva dissertatsiooni raames disainiti ja sünteesiti rida GSH analooge ning mõõdeti ja võrreldi nende antioksüdantseid omadusi nii GSH-ga kui omavahel. Omaduste ja struktuuri omavaheliste seoste leidmiseks modifitseeriti glutatiooni struktuuri. Glutatiooni analoogide disainimisel kasutati järgmisi erinevaid võimalusi: neljanda aminohappe lisamine GSH molekulile, GSH ahelas -glutamüüljäägi asendamine -glutamüüljäägiga, L-aminohapete asemel D-aminohapete kasutamine ja C-terminaalse karboksüülrühma amiidimine. Neljanda aminohappena kasutati kõige enam O-metüül-L-türosiini, et suurendada ühendite antioksüdatiivseid omadusi.
-glutamüülrühma asendamine -glutamüülrühmaga parandas oluliselt UPF peptiidide hüdroksüülradikaali püüdmisomadusi, kusjuures teised struktuurimodifikatsioonid ei andnud nii häid efekte. DPPH radikaali elimineerimisel on glutatioonil veidi madalam EC50 väärtus kui kõikidel UPF peptiididel. Võrreldes aga antiradikaalseid efektiivsusi, mille arvutamisel on arvesse võetud ka radikaali elimineerimise kiirus, ületavad UPF peptiidid GSH, kusjuures UPF17 on uuritud peptiididest kõige efektiivsem. Kineetiliselt iseloomustati GSH ja selle -glutamüülderivaadi poolt DPPH radikaali püüdmise mehhanismi ja leiti, et selles protsessis ilmneb mittekovalentse kompleksi tekke staadium.
Antud töös on ka näidatud, et UPF peptiidid on suhteliselt stabiilsed. Saadud tulemused koos UPF peptiidide andmetega nende mittetoksilisusest lubavad pidada käesolevas dissertatsioonis uuritud ühendeid võimalikeks ravimeellasteks.
The aim this thesis was to design, synthesize and characterize a series of novel glutathione-like compounds of antioxidant activity. To analyze structure-activity relationships, different variations in structure of these ligands were made. These variations included: linking of fourth amino acid to GSH backbone, replacing the native -glutamyl moiety in the GSH backbone with α-glutamyl moiety, using D-amino acids instead of L-isomers and amidation of the terminal carboxyl group. O-methyl-L-tyrosine was mostly used as the fourth amino acid to increase antioxidant activity of the compounds. Substitution of the -glutamyl moiety by α-glutamyl group drastically improved the hydroxyl radical scavenging properties of UPF peptides; while other structural modifications had somewhat less pronounced effects. In assay with DPPH radical GSH had slightly lower EC50 value than all UPF peptides, but regarding antiradical efficiencies, UPF peptides exceeded GSH, whereas UPF17 was the most effective compound. The kinetic mechanism of scavenging of DPPH• with GSH and its α-glutamyl derivative was kinetically characterized and participation of a non-covalent complex in this process was discovered. It was found that UPF peptides were relatively stable. These results, together with data that the compounds of UPF series do not reveal toxicity in used model systems, makes the compounds studied in this dissertation rather promising candidates of potential drugs.
The aim this thesis was to design, synthesize and characterize a series of novel glutathione-like compounds of antioxidant activity. To analyze structure-activity relationships, different variations in structure of these ligands were made. These variations included: linking of fourth amino acid to GSH backbone, replacing the native -glutamyl moiety in the GSH backbone with α-glutamyl moiety, using D-amino acids instead of L-isomers and amidation of the terminal carboxyl group. O-methyl-L-tyrosine was mostly used as the fourth amino acid to increase antioxidant activity of the compounds. Substitution of the -glutamyl moiety by α-glutamyl group drastically improved the hydroxyl radical scavenging properties of UPF peptides; while other structural modifications had somewhat less pronounced effects. In assay with DPPH radical GSH had slightly lower EC50 value than all UPF peptides, but regarding antiradical efficiencies, UPF peptides exceeded GSH, whereas UPF17 was the most effective compound. The kinetic mechanism of scavenging of DPPH• with GSH and its α-glutamyl derivative was kinetically characterized and participation of a non-covalent complex in this process was discovered. It was found that UPF peptides were relatively stable. These results, together with data that the compounds of UPF series do not reveal toxicity in used model systems, makes the compounds studied in this dissertation rather promising candidates of potential drugs.
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Väitekirja elektrooniline versioon ei sisalda publikatsioone.
Keywords
glutatioon, antioksüdandid, bioaktiivsus, glutathione, antioxidants, bioactivity