Anticancer Potential of Diruthenium Complexes with Bridging Hydrocarbyl Ligands from Bioactive Alkynols

Diruthenacyclopentenone complexes of the general composition [Ru2Cp2(CO)2{μ-η1:η3-CH═C(C(OH)(R))C(═O)}] (2a-c; Cp = η5-C5H5) were synthesized in 94-96% yields from the reactions of [Ru2Cp2(CO)2{μ-η1:η3-C(Ph)═C(Ph)C(═O)}] (1) with 1-ethynylcyclopentanol, 17α-ethynylestradiol, and 17-ethynyltestosterone, respectively, in toluene at reflux. Protonation of 2a-c by HBF4 afforded the corresponding allenyl derivatives [Ru2Cp2(CO)3{μ-η1:η2-CH═C═R}]BF4 (3a-c) in 85-93% yields. All products were thoroughly characterized by elemental analysis, mass spectrometry, and IR, UV-vis, and nuclear magnetic resonance spectroscopy. Additionally, 2a and 3a were investigated by cyclic voltammetry, and the single-crystal diffraction method was employed to establish the X-ray structures of 2b and 3a. The cytotoxicity in vitro of 2b and 3a-c was evaluated against nine human cancer cell lines (A2780, A2780R, MCF-7, HOS, A549, PANC-1, Caco-2, PC-3, and HeLa), while the selectivity was assessed on normal human lung fibroblast (MRC-5). Overall, complexes exert stronger cytotoxicity than cisplatin, and 3b (comprising 17α-estradiol derived ligand) emerged as the best-performing complex. Inductively coupled plasma mass spectrometry cellular uptake studies in A2780 cells revealed a higher level of internalization for 3b and 3c compared to 2b, 3a, and the reference compound RAPTA-C. Experiments conducted on A2780 cells demonstrated a noteworthy impact of 3a and 3b on the cell cycle, leading to the majority of the cells being arrested in the G0/G1 phase. Moreover, 3a moderately induced apoptosis and oxidative stress, while 3b triggered autophagy and mitochondrial membrane potential depletion

Synthesis and studies of aqueous-stable diruthenium aminocarbyne complexes uncovered an N-indolyl derivative as a prospective anticancer agent

We conducted a systematic study on the reactivity of [Ru2Cp2(CO)(4)] (Cp = eta(5)-C5H5) with isocyanides and the subsequent methylation reaction to produce [Ru2Cp2(CO)(2)(mu-CO){mu-CNMe(R)}]+ complexes as CF3SO3- salts, [2a-h]+ [R = Me, cyclohexyl (Cy), 2,6-C6H3Me2 (Xyl), 1H-indol-5-yl, 2-naphthyl, 4-C6H4OMe, (S)-CHMe(Ph), CH2Ph (Bn)]. The resulting products, including five novel ones, underwent structural characterization by IR and multinuclear NMR spectroscopy, with five of them further confirmed via single crystal X-ray diffraction. Compounds [2a-e,h]CF(3)SO(3 )exhibit appreciable water solubility, substantial amphiphilic character and outstanding stability in physiological-like solutions (negligible degradation after 72 hours in DMEM at 37(degrees)C). Representative complexes [2b](+) and [2c](+ )were additionally characterized through cyclic voltammetry in CH2Cl2 and in aqueous phosphate buffer solution. Compounds [2a-d]CF3SO3 were assessed for in vitro cytotoxicity against A2780, A2080R and MCF-7 human cancer cell lines, and [2a-c]CF3SO3 revealed significant-to-moderate cytotoxicity, outperforming cisplatin in several cases. The most favourable IC50 values were observed for [2d]CF3SO3, ranging from 3.7 to 13.0 mu M. Experiments on the noncancerous human cell line MRC-5 highlighted a reasonable selectivity for [2b-d]CF3SO3, with the highest selectivity indexes (SI) calculated as 10.1 (ratio of IC(50 )on MRC-5/IC50 on A2780) and 8.5 (ratio of IC50 on MRC-5/IC(50 )on A2780R) for [2d]CF3SO3. Subsequently, [2d]CF3SO3 was tested across a panel of HOS, A549, PANC1, CaCo2, PC3 and HeLa cancer cells, showing variable cytotoxicity with IC50 values in the range of 9.7 to 20.3 mu M. The cellular effects of [2d](+ )on A2780 cells were investigated using flow cytometry assays, focusing on the cell cycle modification, time-resolved cellular uptake, intracellular ROS production, mitochondrial membrane depolarization, induction of cell death through apoptosis, activation of caspases 3/7 and induction of autophagy. Overall, the results suggest a diphasic mechanism of action for [2d]+, inducing metabolic stress and arresting proliferation in the first/fast phase, followed by the induction of apoptosis and autophagy in the second/slower phase