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 organskih jedinjenja edda-tipa, šest kompleksa platine(IV) i pet kompleksa platine(II) sa ovim organskim molekulima kao ligandima. Sintetisana su jedinjenja: (S,S)-etilendiamin-N,N'-di-2-amino-(3-cikloheksil)propanska kiselina dihidrohlorid, njoj odgovarajući metil, etil, n-propil, n-butil, izobutil i izopentil estri i njima odgovarajući kompleksi platine(IV) i platine(II). Ligandi su sintetisani polazeći od neesencijalne aminokiseline, S-2-amino-3-cikloheksilpropanske kiseline hidrohlorida, iz koje je sintetisana diamindikarboksilna kiselina i njeni estri. U reakciji kalijum-tetrahalogenidoplatinata(II), odnosno kalijum-heksahalogenidoplatinata(IV) i odgovarajućeg dehidrohlorovanog liganda dobijeni su diamindihalogenidoplatina(II) i diamintetrahalogenidoplatina(IV) kompleksi. Strukture svih sintetisanih jedinjenja utvrđene su standardnim spektroskopskim metodama: infracrvenom spektroskopijom, NMR spektroskopijom, masenom spektrometrijom dok je pretpostavljena molekulska formula potvrđena elementalnom analizom. DFT i MM proračuni u saglasnosti su sa rezultatima ovih metoda i dali su mogućnost pretpostavke najstabilnijih geometrijskih izomera oktaerdaskih platina(IV) kompleksa. Biološka istraživanja zasnovana su na ispitivanju in vitro aktivnosti sintetisanih liganada i kompleksa na nekoliko tumorskih ćelijskih linija: C6 i U251 glioma, L929 fibrosarkoma i B16 melanoma, ćelije humanog melanoma A375, kancera debelog creva HCT116, ćelije humanog karcinoma pluća A549 i adenokarcinoma dojki MCF7. Rezultati su pokazali veoma dobru antitumorsku aktivnost ovih jedinjenja. Od svih sintetisanih 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 izabranim tumorskim 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 seven organic 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)propanoat acid dihidrochloride and its methyl, ethyl, n-propyl, n-butyl, isobutyl and isopentyl esters, as well as their platinum(IV) and platinum(II) complexes. Ligands were synthesized starting from nonessential aminoacid S-2-amino-3-cyclohexylpropanoate acid hydrochloride via diaminodicarboxylic acid and its esters. Diamindichalogenidoplatinum(II) and diamintetrachalogenidoplatinum(IV) complexes were synthesized in the reaction of potassium-tetrachalogenidoplatinum(II) or potassium-hexachalogenidoplatinum(IV) and corresponding ligands. Structures of synthesized molecules were confirmed by standard spectroscopic methods: infrared spectroscopy, NMR spectroscopy, mass spectrometry and molecular formulas were confirmed by elemental analysis. DFT and MM calculations were in agreement with all spectroscopic methods and were used for determination of the most stable geometric isomers for two octahedral platinum(IV) complexes. Results of biological tests showed in vitro activity of synthesized ligands and complexes against wide spectrum of tumor cell lines: C6 and U251 glioma, L929 fibrosarcoma and B16 melanoma, human melanoma A375, colon cancer cells HCT116, human lung carcinom A549 and breast adenocarcinoma MCF7. Results indicated very good antitumor activity of those compounds. Ligand, O,O'-diethyl-(S,S)-ethylendiamine- N,N'-di-2-amino-(3-cyclohexyl)propanoate dihidrochloride, L3, was very effective against 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 for examination the most possible way of cell death, on the chosen U251 cell line. Platinum(II) complexes showed good antitumor activity against all cell lines...