Kompleks Pt (II) i Pt(IV) sa novim diaminskim ligandima: sinteza, karakterizacija i antitumorska aktivnost

Abstract

U ovom radu opisana je sinteza, karakterizacija i biološka aktivnost sedam organskihjedinjenja edda-tipa, šest kompleksa platine(IV) i pet kompleksa platine(II) sa ovimorganskim molekulima kao ligandima.Sintetisana su jedinjenja: (S,S)-etilendiamin-N,N'-di-2-amino-(3-cikloheksil)propanskakiselina dihidrohlorid, njoj odgovarajući metil, etil, n-propil, n-butil, izobutil i izopentilestri i njima odgovarajući kompleksi platine(IV) i platine(II). Ligandi su sintetisanipolazeći od neesencijalne aminokiseline, S-2-amino-3-cikloheksilpropanske kiselinehidrohlorida, iz koje je sintetisana diamindikarboksilna kiselina i njeni estri. U reakcijikalijum-tetrahalogenidoplatinata(II), odnosno kalijum-heksahalogenidoplatinata(IV) iodgovarajućeg dehidrohlorovanog liganda dobijeni su diamindihalogenidoplatina(II) idiamintetrahalogenidoplatina(IV) kompleksi. Strukture svih sintetisanih jedinjenjautvrđene su standardnim spektroskopskim metodama: infracrvenom spektroskopijom,NMR spektroskopijom, masenom spektrometrijom dok je pretpostavljena molekulskaformula potvrđena elementalnom analizom. DFT i MM proračuni u saglasnosti su sarezultatima ovih metoda i dali su mogućnost pretpostavke najstabilnijih geometrijskihizomera oktaerdaskih platina(IV) kompleksa.Biološka istraživanja zasnovana su na ispitivanju in vitro aktivnosti sintetisanih liganadai kompleksa na nekoliko tumorskih ćelijskih linija: C6 i U251 glioma, L929fibrosarkoma i B16 melanoma, ćelije humanog melanoma A375, kancera debelog crevaHCT116, ćelije humanog karcinoma pluća A549 i adenokarcinoma dojki MCF7.Rezultati su pokazali veoma dobru antitumorsku aktivnost ovih jedinjenja. Od svihsintetisanih liganada ističe se ligand O,O'-dietil-(S,S)-etilendiamin-N,N'-di-2-amino-(3-cikloheksil)propanoat dihidrohlorid, L3, koji je pokazao izuzetno dejstvo na izabranimtumorskim ćelijskim linijama, koje je istog reda veličine ili bolje od cisplatine.Najaktivniji među sintetisanim kompleksima, tetrahlorido(O,O'-dietil-(S,S)-etilendiamin-N,N'-di-2-amino-(3-cikloheksil)propanoato)platina(IV) kompleks, K3,...

In this thesis is described synthesis, characterization and biological activity of sevenorganic molecules edda-type, six platinum(IV) complexes and five platinum(II)complexes with those molecules as ligands.Here were synthesized: (S,S)-ethylendiamine-N,N'-di-2-amino-(3-cyclohexyl)propanoatacid dihidrochloride and its methyl, ethyl, n-propyl, n-butyl, isobutyl and isopentylesters, as well as their platinum(IV) and platinum(II) complexes. Ligands weresynthesized starting from nonessential aminoacid S-2-amino-3-cyclohexylpropanoateacid hydrochloride via diaminodicarboxylic acid and its esters.Diamindichalogenidoplatinum(II) and diamintetrachalogenidoplatinum(IV) complexeswere synthesized in the reaction of potassium-tetrachalogenidoplatinum(II) orpotassium-hexachalogenidoplatinum(IV) and corresponding ligands. Structures ofsynthesized molecules were confirmed by standard spectroscopic methods: infraredspectroscopy, NMR spectroscopy, mass spectrometry and molecular formulas wereconfirmed by elemental analysis. DFT and MM calculations were in agreement with allspectroscopic methods and were used for determination of the most stable geometricisomers for two octahedral platinum(IV) complexes.Results of biological tests showed in vitro activity of synthesized ligands and complexesagainst wide spectrum of tumor cell lines: C6 and U251 glioma, L929 fibrosarcoma andB16 melanoma, human melanoma A375, colon cancer cells HCT116, human lungcarcinom A549 and breast adenocarcinoma MCF7. Results indicated very goodantitumor activity of those compounds. Ligand, O,O'-diethyl-(S,S)-ethylendiamine-N,N'-di-2-amino-(3-cyclohexyl)propanoate dihidrochloride, L3, was very effectiveagainst all tumor cell lines, comparable or superior to the antitumor action of cisplatin.The most active complex was tetrachlorido(O,O'-diethyl-(S,S)-ethylendiamine-N,N'-di-2-amino-(3-cyclohexyl)propanoato)platinum(IV) complex, K3, and it was used forexamination the most possible way of cell death, on the chosen U251 cell line.Platinum(II) complexes showed good antitumor activity against all cell lines...