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Određivanje strukture farmakofore, dizajn, sinteza i ispitivanje antiproliferativne aktivnosti derivata alfa-tokoferola i gama-tokotrienola
Pharmacophore structure determination, design, synthesis and antiproliferative activity of alpha-tocopherol and gama-tocotrienol derivatives
dc.contributor.advisor | Nikolić, Katarina | |
dc.contributor.other | Agbaba, Danica | |
dc.contributor.other | Ivković, Branka | |
dc.contributor.other | Srdić-Rajić, Tatjana | |
dc.creator | Gagić, Žarko P. | |
dc.date.accessioned | 2020-09-30T14:22:20Z | |
dc.date.available | 2020-09-30T14:22:20Z | |
dc.date.issued | 2018 | |
dc.identifier.uri | http://nardus.mpn.gov.rs/handle/123456789/9555 | |
dc.identifier.uri | http://eteze.bg.ac.rs/application/showtheses?thesesId=5848 | |
dc.identifier.uri | https://fedorabg.bg.ac.rs/fedora/get/o:17751/bdef:Content/download | |
dc.identifier.uri | http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=2048262242 | |
dc.identifier.uri | https://farfar.pharmacy.bg.ac.rs/handle/123456789/3671 | |
dc.description.abstract | Vitamin 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.abstract | Vitamin 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.format | application/pdf | |
dc.language | sr | |
dc.publisher | Универзитет у Београду, Фармацеутски факултет | sr |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172033/RS// | |
dc.rights | openAccess | en |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.source | Универзитет у Београду | sr |
dc.subject | estri vitamina E | sr |
dc.subject | esters of vitamin E | en |
dc.subject | sinteza | sr |
dc.subject | aminokiseline | sr |
dc.subject | tumor | sr |
dc.subject | antitumorska aktivnost | sr |
dc.subject | virtuelni skrining | sr |
dc.subject | QSAR | sr |
dc.subject | farmakofora | sr |
dc.subject | dizajn lekova | sr |
dc.subject | synthesis | en |
dc.subject | amino acids | en |
dc.subject | cancer | en |
dc.subject | antitumor activity | en |
dc.subject | virtual screening | en |
dc.subject | QSAR | en |
dc.subject | pharmacophore | en |
dc.subject | drug design | en |
dc.title | Određivanje strukture farmakofore, dizajn, sinteza i ispitivanje antiproliferativne aktivnosti derivata alfa-tokoferola i gama-tokotrienola | sr |
dc.title.alternative | Pharmacophore structure determination, design, synthesis and antiproliferative activity of alpha-tocopherol and gama-tocotrienol derivatives | en |
dc.type | doctoralThesis | en |
dc.rights.license | BY-NC-ND | |
dcterms.abstract | Николић, 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.fulltext | https://farfar.pharmacy.bg.ac.rs/bitstream/id/8113/IzvestajKomisije17023.pdf | |
dc.identifier.fulltext | https://farfar.pharmacy.bg.ac.rs/bitstream/id/8112/Disertacija.pdf | |
dc.identifier.rcub | https://hdl.handle.net/21.15107/rcub_nardus_9555 | |
dc.type.version | publishedVersion |