o:17453 Derivati etilendiamin-N,N'-di-2-(3-cikloheksil) propanske kiseline sa potencijalnim citotoksičnim dejstvom - in silico/in vitro fizičko-hemijska i ADME karakterizacija doktorska disertacija Derivatives of ethylendiamine N,N'-di-2-(3-cyclohexyl) propanoic acid with potential cytotoxic activity - in silico/in vitro physicochemical and ADME characterization : doctoral dissertation sr Estri (S,S)-1,2-etandiamin-N,N'-di-2-(3-cikloheksil)propanske kiseline (EDCP) sa metanolom (DM-EDCP), etanolom (DE-EDCP), propanolom (DPEDCP), butanolom (DB-EDCP) i izobutanolom (DIB-EDCP) i estri (S,S)-1,3- propandiamin-N,N'-di-2-(3-cikloheksil)propanske kiseline (PDCP) sa metanolom (DM-PDCP), etanolom (DE-PDCP), propanolom (DP-PDCP), butanolom (DB-PDCP), izobutanolom (DIB-PDCP), pentanolom (DPE-PDCP) i izopentanolom (DIPE-PDCP) dizajnirani su kao ligandi za Pt(IV) komplekse. U in vitro ispitivanjima utvrđena je značajna citotoksična aktivnost za navedene komplekse, ali i za ligande u nevezanom obliku. Ispitivana supstanca DE-EDCP pokazala je najveću citotoksičnu aktivnost. U ovoj doktorskoj disertaciji opisan je razvoj i validacija savremene bioanalitičke metode - ultra visoko efikasne tečne hromatografije u sprezi sa masenom detekcijom (UHPLC-MS/MS). Metoda je razvijena i validirana za potrebe pretkliničkih ispitivanja, odnosno za određivanje ispitivane supstance DE-EDCP u biološkom materijalu, kao i njenog potencijalnog metabolita EDCP. Kao interni standard primenjen je strukturni analog DB-PDCP. Tokom in vitro fizičko-hemijske biofarmaceutske karakterizacije ispitivanih supstanci određena je i ocenjena njihova rastvorljivost u vodenom rastvoru, lipofilnost i permeabilnost na veštačkim membranama. Profili rastvorljivosti kiselina i njihovih estara se značajno razlikuju, dok su profili rastvorljivosti obe kiseline (EDCP i PDCP) slični, kao i profili rastvorljivosti svih estara. Kiseline se dobro rastvaraju u izrazito kiseloj sredini i u izrazito baznoj sredini, dok je rastvorljivost estara najveća u izrazito kiseloj sredini... Esters of (S,S)-1,2-ethanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid (EDCP) with methyl alcohol (DM-EDCP), ethyl alcohol (DE-EDCP), n-propyl alcohol (DP-EDCP), n-butyl-alcohol (DB-EDCP) and isobutyl-alcohol (DIBEDCP), and esters of (S,S)-1,3-propanediamine-N,N'-di-2-(3- cyclohexyl)propanoic acid (PDCP) with methyl alcohol (DM-PDCP), ethyl alcchol (DE-PDCP), n-propyl alcohol (DP-PDCP), n-butyl alcohol (DB-PDCP), and isobutyl alcohol (DIB-PDCP), n-pentyl alcohol (DPE-PDCP) and isopentyl alcohol (DIPE-PDCP) were designed as ligand of Pt(IV) complexes. During the in vitro investigation it was found significantly cytotoxic activity of these complexes, and also it was found cytotoxic activity of ligand without complexes. Investigated substance DE-EDCP was exerted the strongest cytotoxic activity. In this doctoral dissertation, there is presented a development and validation of a new ultra-high-performance liquid chromatography tandem mass spectrometry bioanalytical method (UHPLC-MS/MS). The developed method is supposed for determination of DE-EDCP and its potential metabolit EDCP in biological materials during non-clinical and clinical studies. The structural analogue DB-PDCP was used as an internal standard. During the in vitro biopharmaceutical characterization of the investigated substances, there was performed a determination of solubility, lipophilicity and membrane permeability. Profiles of solubility of the observed acids and their corresponding esters are significantly different, while the profiles of solubility for two acids (EDCP and PDCP) are similar as well as the profiles of solubility for all the esters... Farmacija - Farmaceutska-medicinska hemija i strukturna analiza / Pharmacy- Pharmaceutical-medicinal chemistry and structural analysis Datum odbrane: 09.03.2018. derivati 1,2-etandiamin-N,N'-di-2-(3-cikloheksil)propanskekiseline, derivati 1,3-propandiamin-N,N'-di-2-(3-cikloheksil)propanske kiseline,bioanalitička metoda, tečna hromatografija pod ultra visokim pritiskom u sprezisa masenom spektrometrijom (UHPLC-MS/MS), rastvorljivost, lipofilnost,membranska permeabilnost, docking, ADME(T) predviđanje, predviđanjemetaboličkih reakcija i metabolita - Metabolizer derivatives of (S,S)-1,2-ethanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid and (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid, bioanalytical method, ultra-high performance liquidchromatography tandem mass spectrometry-UHPLC-MS/MS), solubility,lipophilicity, membrane permeability, docking study, ADME(T) prediction,prediction of metabolic reactions and metabolites - Metabolizer 547.415.1:[543.544.5:004.94(043.3) yes 49966863 91552101 5707 91552100 49966863 2018-04-16T15:54:48.053Z 45 no 46 mentor Biljana K., 1974- Tubić 2018 63 mentor Bojan, 1978- Marković 2018 63 član komisije Sote, 1951- Vladimirov 2018 63 član komisije Tibor, 1958- Sabo 2018 63 član komisije Svjetlana Stojisavljević Šatara 2018 63 član komisije Vladimir Dobričić 2018 201 list 6894405 http://phaidrabg.bg.ac.rs/o:17453 no yes 4 2018-04-16T15:54:48.320Z 70 11 1067094 1067100 derivati 1,2-etandiamin-N,N'-di-2-(3-cikloheksil)propanskekiseline, derivati 1,3-propandiamin-N,N'-di-2-(3-cikloheksil)propanske kiseline,bioanalitička metoda, tečna hromatografija pod ultra visokim pritiskom u sprezisa masenom spektrometrijom (UHPLC-MS/MS), rastvorljivost, lipofilnost,membranska permeabilnost, docking, ADME(T) predviđanje, predviđanjemetaboličkih reakcija i metabolita - Metabolizer derivatives of (S,S)-1,2-ethanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid and (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid, bioanalytical method, ultra-high performance liquidchromatography tandem mass spectrometry-UHPLC-MS/MS), solubility,lipophilicity, membrane permeability, docking study, ADME(T) prediction,prediction of metabolic reactions and metabolites - Metabolizer 547.415.1:[543.544.5:004.94(043.3) 1738 11A13 2018