Novi rutenijum–arenski kompleksi sa antiinflamatornim lekovima

Abstract

U ovom radu sintetisano je četiri nova arenska kompleksa Ru(II) sa dva nesteroidna antiimflamatorna leka, indometacin i mefenaminskom kiselininom. Kompleksi su sintetisani polazeći od metanolnog rastvora polaznog Ru(II) polusendvič jedinjenja i baznog metanolnog rastvora odgovarajućeg liganda. Strukture novih kompleksa određene su NMR i IC spektroskopijom, kao i masenom spektrometrijom. Pokazano je da se ligandi koordinuju monodentatno preko karboksilnih kiseonika. Citotoksična aktivnost liganada i kompleksa ispitana je na tri ćelijske linije humanog kancera i zdravih humanih fibroblastnih ćelija, korišćenjem MTT metode. IC50 vrednosti dobijene na ćelijama leukemije K562 bile su uporedive sa onim za cisplatinu (10.3 µM (cisplatina), 11.9 µM (kompleks 1) i 13.2 µM (kompleks 3)). Korišćenjem protočne citometrije pokazano je da ovi kompleksi pri IC50 koncentracijama zaustavljaju ćelijski ciklus u S fazi. Merenje produkcije reaktivnih kiseoničnih DCFH-DA metodom potvrdilo je njihov potencijal da povećavaju ROS više od cisplatine.

Two non-steroidal antiinflammatory drugs, indomethacin and mefenamic acid, were coordinated to Ru(II)-arenes to give four new complexes. These four complexes were synthesized by mixing methanolic solution of starting half-sandwich Ru complexes with base solution of ligand in methanol. Structures of complexes were determinated by NMR, IR spectroscopy and mass spectrometry. It was shown that they coordinates monodentatly via carboxylic oxygen. The cytotoxic activity of the ligands and ruthenium complexes was tested in three human cancer cell lines and non-tumour human fetal lung fibroblast cells by MTT assay. The IC50 values obtained in leukemia K562 cells, were comparable to cisplatin (10.3 µM (CDDP), 11.9 µM (1) and 13.2 µM (3)). Flow cytometric analysis of these conplexes, showed that at IC50 concentrations, they arrested cell cycle progression in the S phase. Measurement of reactive oxygen species (ROS) production, by DCFH-DA staining, confirmed their potential to increase ROS even more than cisplatin.