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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

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2018
Disertacija.pdf (3.414Mb)
IzvestajKomisije17023.pdf (223.4Kb)
Author
Gagić, Žarko P.
Mentor
Nikolić, Katarina
Committee members
Agbaba, Danica
Ivković, Branka
Srdić-Rajić, Tatjana
Metadata
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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...

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 hea...lthy 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 PLS statistical method...

Faculty:
Универзитет у Београду, Фармацеутски факултет
Date:
13-04-2018
Projects:
  • Synthesis, Quantitative Structure and Activity Relationship, Physico-Chemical Characterisation and Analysis of Pharmacologically Active Substances (RS-172033)
Keywords:
estri vitamina E / esters of vitamin E / sinteza / aminokiseline / tumor / antitumorska aktivnost / virtuelni skrining / QSAR / farmakofora / dizajn lekova / synthesis / amino acids / cancer / antitumor activity / virtual screening / QSAR / pharmacophore / drug design
[ Google Scholar ]
Handle
https://hdl.handle.net/21.15107/rcub_nardus_9555
URI
https://nardus.mpn.gov.rs/handle/123456789/9555
http://eteze.bg.ac.rs/application/showtheses?thesesId=5848
https://fedorabg.bg.ac.rs/fedora/get/o:17751/bdef:Content/download
http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=2048262242

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