Pt (II) and Pt(IV)complexes with new diamine ligands: synthesis, characterization and antitumor activity

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..

Supplementary data for article: Poljarević, J.; Grgurić-Šipka, S.; Kaluđerović, G. N.; Sabo, T. Dibromido[(S,S)-Ethylenediamine-N,N ’-Di-2-(3-Cyclohexyl)Propanoato]Platinum(IV): Synthesis, Characterization, and DFT Calculations. Journal of Coordination Chemistry 2011, 64 (6), 1016–1022. https://doi.org/10.1080/00958972.2011.560940

Supplementary material for: [https://doi.org/10.1080/00958972.2011.560940]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1160

In vivo ispitivanje enzimske aktivnosti nekih Ru(II) jedinjenja sa N-alkilfenotiazinima

The purpose of the present study was to investigate and compare the effects of two ruthenium complexes with trifl uoperazine on acethylcholinesterase enzyme activity and lactate dehydrogenase levels in vivo under physiological conditions in rats blood. Complexes 1 and 2 showed positive effects on acethylcholinesterase at all doses and did not disturb its normal activity. Total LDH activity was inhibited in the presence of both complexes, but Ru(II) complexes showed different effects on the activity of LDH isoenzymes. The activities of LDH1 and LDH2 isoenzymes were decreased in all applied doses of the complex 2, while the activity of LDH2 reduced using complex 1 in the same doses. Results of the present study suggest the neuro-and cardio protective potential of oral administration of complexes 1 and 2, as non-toxic compounds under physiological conditions. These protective effects are the result of their potent antioxidant activity.Cilj ovog rada je da se ispitaju i uporede efekti dva kompleksa rutenijuma sa trifluoperazinom na aktivnost enzima acetilholinesteraze i laktat-dehidrogenase in vivo pod fiziološkim uslovima u krvi pacova. Kompleksi 1 i 2 pokazali su pozitivan efekat na aktivnost acetiholinesteraze u svim primenjenim dozama. Ukupna aktivnost LDH je inhibirana u prisustvu oba kompleksa, ali kompleksi Ru(II) pokazuju različite rezultate na izoenzimske oblike ovog enzima. Aktivnosti izoenzima LDH1 i LDH2 su smanjene u svim primenjenim dozama kompleksa 2, dok kompleks 1 smanjuje aktivnost samo izoenzima LDH2 u tim istim koncentracijama. Rezultati prikazanog istraživanja ukazuju na neuro - i kardio zaštitni potencijal oralne primene kompleksa 1 i 2, kao netoksičnih jedinjenja pod fiziološkim uslovima, indukovano preko njihovog snažnog antioksidativnog efekta

Supplementary data for article: Misirlić Denčić, S.; Poljarević, J.; Isakovic, A. M.; Marković, I.; Sabo, T. J.; Grgurić-Šipka, S. Antileukemic Action of Novel Diamine Pt(II) Halogenido Complexes: Comparison of the Representative Novel Pt(II) with Corresponding Pt(IV) Complex. Chemical Biology and Drug Design 2017, 90 (2), 262–271. https://doi.org/10.1111/cbdd.12945

Supporting information for: [https://doi.org/10.1111/cbdd.12945]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2483]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3120

Supplementary data for article: Poljarević, J.; Krstić, M.; Grgurić-Šipka, S.; Sovilj, S. P.; Misic, D. R.; Sabo, T. Platinum(IV) Complexes with N-Alkylphenothiazines: Synthesis, Characterization, and Antibacterial Activity. Journal of Coordination Chemistry 2013, 66 (21), 3760–3769. https://doi.org/10.1080/00958972.2013.851788

Supplementary material for: [https://doi.org/10.1080/00958972.2013.851788]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1452

Supplementary data for the article: Meszaros, J. P.; Poljarević, J.; Gal, T. G.; May, N. V.; Spengler, G.; Enyedy, E. A. Comparative Solution and Structural Studies of Half-Sandwich Rhodium and Ruthenium Complexes Bearing Curcumin and Acetylacetone. Journal of Inorganic Biochemistry 2019, 195, 91–100. https://doi.org/10.1016/j.jinorgbio.2019.02.015

Supplementary material for: [https://doi.org/10.1016/j.jinorgbio.2019.02.015]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2873

Comparative solution and structural studies of half-sandwich rhodium and ruthenium complexes bearing curcumin and acetylacetone

Half-sandwich organometallic complexes of curcumin are extensively investigated as anticancer compounds.Speciation studies were performed to explore the solution stability of curcumin complexes formed with [Rh(η5- C5Me5)(H2O)3]2+. Acetylacetone (Hacac), as the simplest β-diketone ligand bearing (O,O) donor set, was involved for comparison and its Ru(η6‑p‑cymene), Ru(η6‑toluene) complexes were also studied. 1H NMR, UV–visible and pH-potentiometric titrations revealed a clear trend of stability constants of the acac complexes: Ru(η6‑p‑cymene) > Ru(η6‑toluene) > Rh(η5-C5Me5). Despite this order, the highest extent of complex formation is seen for the Rh(η5-C5Me5) complexes at pH 7.4. Formation constant of [Rh(η5-C5Me5)(H2curcumin) (H2O)]+ reveals similar solution stability to that of the acac complex. Additionally, structures of two complexes were determined by X-ray crystallography. The in vitro cytotoxicity of curcumin was not improved by the complexation with these organometallic cations.Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/2875]This is the peer-reviewed version of the following article: Meszaros, J. P.; Poljarević, J.; Gal, T. G.; May, N. V.; Spengler, G.; Enyedy, E. A. Comparative Solution and Structural Studies of Half-Sandwich Rhodium and Ruthenium Complexes Bearing Curcumin and Acetylacetone. Journal of Inorganic Biochemistry 2019, 195, 91–100. [https://doi.org/10.1016/j.jinorgbio.2019.02.015

Supplementary data for article: Poljarević, J.; Grgurić-Šipka, S.; Kaluđerović, G. N.; Sabo, T. Dibromido[(S,S)-Ethylenediamine-N,N ’-Di-2-(3-Cyclohexyl)Propanoato]Platinum(IV): Synthesis, Characterization, and DFT Calculations. Journal of Coordination Chemistry 2011, 64 (6), 1016–1022. https://doi.org/10.1080/00958972.2011.560940

Supplementary material for: [https://doi.org/10.1080/00958972.2011.560940]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1160