Sinteza, karakterizacija i citotoksična aktivnost rutenijum (II)-arenskih kompleksa sa piridinskim derivatima

Abstract

Sposobnost rutenijum(II)–arenskih vrsta da koordinuju različite klase liganada, čini ihpogodnim za fino podešavanje hemijskih i farmaceutskih svojstava. Novosintetisanirutenijum(II)–arenski kompleksi dobijeni su u reakciji polaznog jedinjenja[RuCl2(η6–p–cimen)]2 sa odgovarajućim ligandom u 1 : 2 ili 1 : 2,2 molskom odnosu umetanolu, etanolu ili izopropanolu uz blago zagrevanje. Komercijalno dostupni ligandikorišćeni za pripremu kompleksa mogu se smatrati piridinskim derivatima sa acetilgrupama, amino i hlor supstituentima ili sa jednom ili dve karboksilne grupe. Drugagrupa liganada uključivala je kaprilni hidrazid (hidrazid sa dugim ugljovodoničnimlancem), hidrazid izonikotinske kiseline (hidrazid sa aromatičnim piridinskimprstenom), tiosemikarbazone i semikarbazone (dobijene u reakciji 3– i 4–acetilpiridinasa tiosemikarbazidom ili kaprilnim hidrazidom). Treća grupa liganada može se smatratiderivatima pikolinske kiseline sa fluor, hlor, brom ili metil supstituentima ilipripojenom fenil grupom dajući izohinolin–3–karboksilnu kiselinu. Sintetisanajedinjenja okarakterisana su elementalnom analizom, masenom spektrometrijom, IC iNMR spektroskopijama. Na osnovu dobijenih spektroskopskih podataka zaključeno jeda molekuli imaju takozvanu „three–leg piano–stool“ geometriju koja je uobičajena zaovaj tip jedinjenja, sa bidentatno ili monodentatno koordinovanim ligandima. Strukturerutenijum(II)–arenskih jedinjenja sa 3–acetilpiridinom, 2,4–piridindikarboksilnomkiselinom, 2,6–piridindikarboksilnom kiselinom, pikolinskom kiselinom, kaprilnimhidrazidom, 6–fluorpikolinskom i 6–brompikolinskom kiselinom potvrđene surendgenskom strukturnom analizom. Ispitivanjem citotoksične aktivnosti otkriven jeslab antiproliferativni efekat kompleksa na ispitivane tumorske ćelijske linije, saizuzetkom dva jedinjenja, prvog sa pikolinskom kiselinom i drugog sa izohinolin–3–karboksilnom kiselinom. Poslednje pomenuto jedinjenje pokazalo je značajno nižucitotoksičnu aktivnost prema normalnim ćelijama (MRC–5) u odnosu na visokuaktivnost primećenu na linijama tumorskih ćelija, kao i značajnu selektivnost međuispitivanim ćelijama tumora. Hidroliza [RuCl(2,3–piridindikarboksilato)(η6–p–cimen)]kompleksa i njegova interakcija sa 9–metiladeninom proučavana je 1H NMR, 1H–1H...

Ability of ruthenium(II)–arene species to coordinate to different classes of ligands,makes them suitable for fine–tuning chemical and pharmaceutical properties. Novelsynthesized ruthenium(II)–arene complexes were obtained in the reaction of startingcompound [RuCl2(η6–p–cymene)]2 with the corresponding ligand in a 1 : 2 or 1 : 2.2molar ratio in methanol, ethanol or isopropanol with mild heating. Commerciallyavailable ligands used for preparation of complexes could be considered as pyridinederivatives with acetyl grups, amino and chloro substituents, or with one or twocarboxylic groups. Second group of ligands included caprylic hydrazide (hydrazide withlong hydrocarbon chain), isonicotinic acid hydrazide (hydrazide with aromatic pyridinering), thiosemicarbazones and semicarbazones (derived from reaction of 3– and4–acethylpyridine with thiosemicarbazide or caprylic hydrazide). Third group of ligandscould be considered as derivatives of picolinic acid with fluoro, chloro, bromo andmethyl substituents or fused phenyl group giving isoquinoline–3–carboxylic acid.Synthesized compounds were characterized by elemental analysis, mass spectrometry,IR and NMR spectroscopies. According to the obtained spectroscopic data themolecules adopt the usual „three–leg piano–stool“ geometry which is common for thistype of complexes, with ligands coordinated in a bidentate or monodentate manner. Thestructures of ruthenium(II)–arene compounds with coordinated 3–acetylpyridine, 2,4–pyridinedicarboxylic acid, 2,6–pyridinedicarboxylic acid, picolinic acid, caprylichydrazide, 6–fluoropicolinic acid and 6–bromopicolinic acid were determined by X–raycrystallography. Examination of the cytotoxic activity revealed low antiproliferativeeffect of complexes in investigated tumor cell lines, with exception of two compounds,the one with picolinic acid and the other with isoquinoline–3–carboxylic acid. Latercompound exhibited significantly lower cytotoxic activity in normal cells (MRC–5)against high activity observed in panel of tumor cells and prominent cell type selectivityamong tumor cells. Hydrolysis of [RuCl(2,3–pyridinedicarboxylato)(η6–p–cimen)]complex and its interaction with 9–methyladenin was studied by 1H NMR,1H–1H COSY and 1H–1H NOESY spectroscopy. Interaction of complex...