Biological evaluation of water soluble arene Ru(II) enantiomers with amino-oxime ligands

Abstract

New water soluble, enantiopure arene ruthenium compound SS-(1R,4S)-[(η-p-cymene)Ru{ĸNH(Bn),ĸNOH}Cl]Cl (Bn = benzyl, 1a') has been synthesized. The novel compound along with that previously described RR-(1S,4R)-[(η-p-cymene)Ru{ĸNH(Bn),ĸNOH}Cl]Cl (1a) was evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of novel ruthenium derivative 1a' was determined by single crystal X-ray crystallography. Both enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3, lung A-549, pancreas MIA PaCa-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. Both enantiomers are active and versatile cytotoxic agents, showing IC values from 2 to 12 times lower than those found for cisplatin in the different cell lines evaluated. The mechanism of cell death induced by the metal compounds was analyzed in A-549 and Jurkat cell lines. Derivatives 1a and 1a' induced apoptotic cell death of A-549 cells while dose-dependent cell death mechanisms have been found in the Jurkat cell line. Compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, revealing moderate binding affinity of 1a and 1a' towards duplex DNA. Finally, the efficacy of 1a in a preliminary in vivo assay of PC-3 xenografts in nude mice has been evaluated, resulting in a promising inhibition of tumor growth by 45%. Analysis of tumor tissue also showed a significant decrease of levels of crucial molecules in the invasive phenotype of PC-3 cells.

Piano-Stool Ruthenium(II) Complexes with Delayed Cytotoxic Activity: Origin of the Lag Time

“…It can be pointed out that the observed IC 50 values, ranging from 1.72 to 5.82 μM, are comparable to data reported in the literature for various types of piano-stool ruthenium­(II) complexes. − However, it can be stressed that the IC 50 values for 3 Cl iPr , 3 I iPr and 3 dmso iPr , given in Table , were determined after 24 h of incubation with cells, whereas most of the IC 50 values found in the literature were obtained after a drug-exposure time of 48, 72, or 96 h; − hence, the low-micromolar IC 50 values achieved after 24 h of incubation with 3 CI iPr , 3 I iPr , and 3 dmso iPr indicate that they are highly cytotoxic. Notable activities after 24 h of incubation have been described for tethered, acylpyrazolonato-containing, or amino-oxime-based half-sandwich ruthenium­(II) complexes, but 3 Cl iPr , 3 I iPr , and 3 iPr dmso are comparatively more efficient.…”

“…IC 50 values were then determined for compounds 3 Cl indicate that they are highly cytotoxic. Notable activities after 24 h of incubation have been described for tethered, 69 acylpyrazolonato-containing, 70 or amino-oxime-based halfsandwich ruthenium(II) complexes, 71 Dimethyl(1-pyrenyl)phosphane versus Diisopropyl-(1-pyrenyl)phosphane. As mentioned in the Introduction, the use of the new ligand diisopropyl(1-pyrenyl)phosphane (L) originates from previous studies, which have shown that Pligands of the type PR 1 R 2 (1-pyrenyl), which give rise to [RuX 2 (η 6 -arene)(PR 1 R 2 (1-pyrenyl))] compounds, exhibit remarkable cytotoxic properties; in particular, the chlorido Ru complex with the ligand dimethyl(1-pyrenyl)phosphane and η 6 -methyl benzoate, namely [RuCl 2 (η 6 -methyl benzoate)-(dimethyl(1-pyrenyl)phosphane)], exhibited IC 50 values in the low micromolar range for various cancer cell lines.…”

Chirality in Anticancer Agents

“…Cuvea-Alique and co-workers [67] evaluated the anticancer activities of arene Ru(II) enantiomers witzzh aminooxime ligands-Figure 10. The oxime-containing Ru(II) compounds have shown potent anticancer activities against a broad range of different cancer cell lines, with no significant differences between the two enantiomers.…”

PC-3 İnsan Prostat Kanser Hücre Hattı Üzerine [1-(2-Metil-2-Propenil)-3-(2-Metilbenzil)Benzimidazolyum Klorür Ligandı ve Bu Ligandın Gümüş(I) Kompleksinin Sitotoksik Aktivitesi

“…IC 50 değerindeki düşüş sitotoksik aktivitedeki artışı göstermektedir. Kompleks (2a), her üç uygulama zamanı için de günümüzde hali hazırda kullanılan kemoterapötik bir ajan olan cisplatinden daha yüksek sitotoksik aktivite göstermiştir [18][19][20] . Kompleksin (2a), PC-3 insan prostat kanser hücrelerinde 24, 48 ve 72 saat için elde edilen IC 50 değerleri WI-38 insan sağlıklı akciğer fibroblast hücreleri için elde edilen IC 50 değerinden daha küçüktür.…”