In Vitro and in Vivo Evaluation of Ruthenium(II)−Arene PTA Complexes

Abstract

The antitumor activity of the organometallic ruthenium(II)-arene complexes, RuCl(2)(eta(6)-arene)(PTA), (arene = p-cymene, toluene, benzene, benzo-15-crown-5, 1-ethylbenzene-2,3-dimethylimidazolium tetrafluoroborate, ethyl benzoate, hexamethylbenzene; PTA = 1,3,5-triaza-7-phosphaadamantane), abbreviated RAPTA, has been evaluated. In vitro biological experiments demonstrate that these compounds are active toward the TS/A mouse adenocarcinoma cancer cell line whereas cytotoxicity on the HBL-100 human mammary (nontumor) cell line was not observed at concentrations up to 0.3 mM, which indicates selectivity of these ruthenium(II)-arene complexes to cancer cells. Analogues of the RAPTA compounds, in which the PTA ligand is methylated, have also been prepared, and these prove to be cytotoxic toward both cell lines. RAPTA-C and the benzene analogue RAPTA-B were selected for in vivo experiments to evaluate their anticancer and antimetastatic activity. The results show that these complexes can reduce the growth of lung metastases in CBA mice bearing the MCa mammary carcinoma in the absence of a corresponding action at the site of primary tumor growth. Pharmacokinetic studies of RAPTA-C indicate that ruthenium is rapidly lost from the organs and the bloodstream.

Iron(III) Pincer Complexes as a Strategy for Anticancer Studies

“…Among them, a series of arene-ruthenium complexes such as RM175, RAPTA-C, RAED-C, and UNICAM-1 have shown very promising therapeutic effects. [8][9][10][11][12] Additionally, a class of cyclometalated ruthenium complexes known as RDCs (ruthenium-derived compounds) has shown particularly good activity as anticancer agents, for both in vitro and in vivo studies. [8,13] Various reports have shown that the mechanisms by which phenylpyridine derivatives exert their anticancer effects are presumably not through DNA interaction, as in the case of cisplatin, but in part through redox reactions with oxidoreductases.…”

Synthesis, Characterization, and Biological Evaluation of New Ru(II) Polypyridyl Photosensitizers for Photodynamic Therapy

“…[13][14][15][16][17][18] They have gained widespread attention since two complexes, namely NAMI-A and KP1019 (and the respective sodium salt KP1339), passed early clinical trials. [19][20][21] The use of ruthenium in PDT however, has been quite limited so far.…”

Exploring metallodrug–protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound

“…Among them, ruthenium(II)-arene complexes bearing 1,3,5-triaza-7-phosphaadamantane (pta) ligands-named 'RAPTA' [7]-have been found to exhibit promising antimetastatic properties in vivo, and appear to function in a way different from cisplatin. [8][9][10] Indeed, ruthenium complexes could prove to be effective alternatives to those based on platinum, and trans-[tetrachloro(dimethyl sulphoxide)(imidazole) ruthenate(III)] (NAMI-A) [11] and trans-[tetrachlorobis (1H-indazole)ruthenate(III)] (KP1019) [12] have both completed phase I clinical trials.…”