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Pharmacophore structure determination, design, synthesis and antiproliferative activity of alpha-tocopherol and gama-tocotrienol derivatives

dc.contributor.advisorNikolić, Katarina
dc.contributor.otherAgbaba, Danica
dc.contributor.otherIvković, Branka
dc.contributor.otherSrdić-Rajić, Tatjana
dc.creatorGagić, Žarko P.
dc.date.accessioned2020-09-30T14:22:20Z
dc.date.available2020-09-30T14:22:20Z
dc.date.issued2018
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/9555
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=5848
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:17751/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=2048262242
dc.identifier.urihttps://farfar.pharmacy.bg.ac.rs/handle/123456789/3671
dc.description.abstractVitamin E je generičko ime koje obuhvata dve klase jedinjenja, tokoferole i tokotrienole, od kojih svaka klasa sadrži 4 izomera (α, β, γ, δ). Analozi vitamina E putem različitih mehanizama mogu ispoljiti snažnu citotoksičnu aktivnost na više tipova tumorskih ćelija, a da pritom ne remete u velikoj meri aktivnost zdravih ćelija.Ovu doktorsku disertaciju čine tri celine čiji će rezultati imati potencijalni značaj za primenu derivata vitamina E u terapiji malignih bolesti.Prva celina obuhvata studije kvantitativnog odnosa strukture i dejstva (Quantitative Structure-Activity Relationship, QSAR) derivata vitamina E i određivanje strukture farmakofore.U drugoj celini opisani su: (1) sinteza estara α-tokoferola sa aminokiselinama lizinom, prolinom, glutaminom, asparaginom i estara γ-tokotrienola sa lizinom, prolinom, glutaminom; (2) in vitro ispitivanja biološke aktivnosti sintetisanih estara na MCF-7 i MDA-MB 231 ćelijskim linijama tumora dojke, A549 ćelijskoj liniji tumora pluća i MRC-5 zdravoj ćelijskoj liniji fetalnih fibroblasta pluća; (3) ispitivanje ćelijskih mehanizama antiproliferativne aktivnosti i sinergističkog efekta najaktivnijeg sinetisanog jedinjenja sa doksorubicinom na multirezistentnoj MDA-MB 231 ćelijskoj liniji; (4) studije stabilnosti u humanoj plazmi; (5) pretraživanje ChEMBL baze bioaktivnih molekula primenom metode virtelnog skrininga zasnovanog na strukturi liganda.Treću celinu predstavlja dizajn novih analoga vitamina E sa potencijalno snažnijim antitumorskim dejstvom...sr
dc.description.abstractVitamin E is a generic name comprising of two classes of compounds, tocopherols and tocotrienols, each class containing 4 isomers (α, β, γ, δ). Analogs of vitamin E, via different mechanisms, may exhibit strong cytotoxic activity to many types of malignant cells, while not disrupting in a greater extent activity of healthy cells.This doctoral thesis includes three sections whose results will have potential importance for the use of vitamin E derivatives in the treatment of malignant diseases.The first section includes Quantitative Structure-Activity Relationship (QSAR) study of vitamin E analogues and pharmacophore structure determination.The second section covers: (1) synthesis of α-tocopherol esters with amino acids lysine, proline, glutamine, asparagine, and γ-tocotrienol esters with lysine, proline, glutamine; (2) in vitro testing of biological activities of the synthesized esters on the MCF-7 and MDA-MB 231 breast cancer cell lines, A549 lung cancer cell line, and the MRC-5 healthy fetal lung fibroblasts cell line; (3) testing of cellular mechanisms which underlie the antiproliferative activity and synergistic effect of the most active compound with doxorubicin on multidrug-resistant MDA-MB 231 cell line; (4) stability study in human plasma; (5) filtering of the ChEMBL database of bioactive molecules using the ligand based virtual screening protocol.The third section represents design of new analogues of vitamin E with enhanced antitumor activity.2D- and 3D-QSAR studies were conducted on a series of vitamin E analogues with experimentally determined antiproliferative activity on MCF7 cell line, using PLSstatistical method...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Фармацеутски факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172033/RS//
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectestri vitamina Esr
dc.subjectesters of vitamin Een
dc.subjectsintezasr
dc.subjectaminokiselinesr
dc.subjecttumorsr
dc.subjectantitumorska aktivnostsr
dc.subjectvirtuelni skriningsr
dc.subjectQSARsr
dc.subjectfarmakoforasr
dc.subjectdizajn lekovasr
dc.subjectsynthesisen
dc.subjectamino acidsen
dc.subjectcanceren
dc.subjectantitumor activityen
dc.subjectvirtual screeningen
dc.subjectQSARen
dc.subjectpharmacophoreen
dc.subjectdrug designen
dc.titleOdređivanje strukture farmakofore, dizajn, sinteza i ispitivanje antiproliferativne aktivnosti derivata alfa-tokoferola i gama-tokotrienolasr
dc.title.alternativePharmacophore structure determination, design, synthesis and antiproliferative activity of alpha-tocopherol and gama-tocotrienol derivativesen
dc.typedoctoralThesisen
dc.rights.licenseBY-NC-ND
dcterms.abstractНиколић, Катарина; Срдић-Рајић, Татјана; Aгбаба, Даница; Ивковић, Бранка; Гагић, Жарко П.; Одређивање структуре фармакофоре, дизајн, синтеза и испитивање антипролиферативне активности деривата алфа-токоферола и гама-токотриенола; Одређивање структуре фармакофоре, дизајн, синтеза и испитивање антипролиферативне активности деривата алфа-токоферола и гама-токотриенола;
dc.identifier.fulltexthttp://farfar.pharmacy.bg.ac.rs/bitstream/id/8113/IzvestajKomisije17023.pdf
dc.identifier.fulltexthttp://farfar.pharmacy.bg.ac.rs/bitstream/id/8112/Disertacija.pdf
dc.type.versionpublishedVersion


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