Sinteza, karakterizacija i potencijalni antitumorski efekti mononuklearnih 5,6- epoksi-5,6-dihidro-1,10-fenantrolinskih kompleksa platine(II)

Abstract

Uvod: Četiri Pt(II) kompleksa opšte formule [Pt(L)(5,6-epoxy-1,10-phen)], gde je L anjon malonske kiseline (mal, Pt1), 2-metilmalonske kiseline (Me-mal, Pt2), 2,2- dimetilmalonske kiseline (Me2-mal, Pt3) i 1,1-ciklobutandikarboksilne kiseline (CBDCA, Pt4) i 5,6-epoksi-1,10-fen je 5,6-epoksi-5,6-dihidro-1,10-fenantrolin. Materijal i metode: Kompleksi su sintetizovani i okarakterisani elementalnom mikroanalizom i različitim spektroskopskim tehnikama. Kristalna struktura anhidrovanog kompleksa Pt3 određena je difrakcijom rendgenskih zraka monokristala. Antikancerogena aktivnost kompleksa platine(II) je ispitivana u ljudskim i mišjim ćelijskim linijama karcinoma dojke i kolorektuma, kao i u zdravoj liniji mezenhimalnihn matičnih ćelija miša, korišćenjem MTT testa. Rezultati: Ispitivani kompleksi platine(II) pokazuju snažnu citotoksičnu aktivnost protiv ćelija karcinoma dojke miša (4T1), humanih (HCT116) i mišjih (CT26) ćelija kolorektalnog karcinoma. Pt3 kompleks pokazuje jaču selektivnost protiv tumorskih ćelija u poređenju sa drugim ispitivanim kompleksima platine(II) i na taj način pokazuje korisnu antitumorsku aktivnost, uglavnom indukujući apoptozu i inhibiciju proliferacije i migracije tumorskih ćelija. Pt3 kompleks, takođe pokazuje značajnu in vivo antitumorsku aktivnost u ortotopskom modelu tumora dojke, bez toksičnosti za jetru, bubrege, pluća i srce. Zaključak: Svi rezultati ukazuju da novosintetisani kompleksi platine(II) imaju dobru antitumorsku aktivnost na tumorske ćelije karcinoma dojke i kolorektalnog karcinoma i imaju potencijal da postanu mogući kandidati u antikancerskoj terapiji.

Introduction: Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is an anion of either malonic acid (mal, Pt1), 2-methylmalonic acid (Me-mal, Pt2), 2,2-dimethylmalonic acid (Me2-mal, Pt3) or 1,1-cyclobutanedicarboxylic acid (CBDCA, Pt4) and 5,6-epoxy-1,10-phen is 5,6-epoxy-5,6-dihydro-1,10-phenanthroline. Material and methods: Complexes were synthesized and characterized by elemental microanalysis and different spectroscopic techniques. The crystal structure of anhydrous Pt3 complex was determined by single crystal X-ray diffraction. The in vitro anticancer activity of the platinum(II) complexes was investigated in human and murine cancer cell lines as well as in a normal murine cell line by MTT assay. Results: The results show that the investigated platinum(II) complexes exhibit potent cytotoxic activity against murine breast carcinoma cells (4T1), human (HCT116) and murine (CT26) colorectal carcinoma cells. The Pt3 complex shows stronger selectivity against cancer cells compared to other platinum(II) complexes tested and thus exhibits beneficial antitumor activity, mainly by inducing apoptosis and inhibiting cell proliferation and migration. The Pt3 complex also exhibits significant in vivo antitumor activity in the orthotopical 4T1 tumor model without detected liver, kidney, lung, and heart toxicity. Conclusion: All the results indicate that these novel platinum(II) complexes have good antitumor activity on breast and colorectal cancer and have the potential to become possible candidates for cancer treatment.