Derivati etilendiamin-N,N'-di-2-(3-cikloheksil) propanske kiseline sa potencijalnim citotoksičnim dejstvom - in silico/in vitro fizičko-hemijska i ADME karakterizacija

Abstract

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...