Derivati etilendiamin-N,N'-di-2-(3-cikloheksil) propanske kiseline sa potencijalnim citotoksičnim dejstvom - in silico/in vitro fizičko-hemijska i ADME karakterizacija
Derivatives of ethylendiamine N,N'-di-2-(3-cyclohexyl) propanoic acid with potential cytotoxic activity - in silico/in vitro physicochemical and ADME characterization
Author
Tubić, Biljana K.Mentor
Marković, Bojan
Committee members
Vladimirov, Sote
Sabo, Tibor

Stojisavljević Šatara, Svjetlana
Dobričić, Vladimir

Metadata
Show full item recordAbstract
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-ED...CP 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 (U...HPLC-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...