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

Abstract

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 provide a rare electrochemical description of diruthenium bis-cyclopentadienyl compounds. 36,37,62…”

“…73,74 Complex [ 2d ] + exerts a generally more potent antiproliferative effect compared to other cationic complexes based on the Ru 2 Cp 2 (CO) 3 scaffold, under analogous conditions. 36,37 We hypothesize that the higher performance of [ 2d ] + is consequent to its greater aqueous stability.…”

“…The interaction studies of [ 2a ]CF 3 SO 3 and [ 2d ]CF 3 SO 3 with bovine serum albumin were performed using the same method as reported previously. 36 In brief, bovine serum albumin (BSA, 30 μM in 50 mM NH 4 HCO 3 ) was incubated with the selected complexes ([ 2a ]CF 3 SO 3 and [ 2d ]CF 3 SO 3 , 1 mM) at 37 °C for 48 h. The resulting solutions underwent processing for MALDI-TOF MS analysis using the sinapinic acid matrix. Mass spectra were recorded using a Microflex LRF20 MALDI-TOF mass spectrometer and analysed with flexAnalysis 3.4 software (Bruker Daltonik).…”

“…We provide a rare electrochemical description of diruthenium bis-cyclopentadienyl compounds. 36,37,62 The ). In the negative potential range, one partially reversible monoelectronic reduction at the formal potential of −1.35 V (i b /i f = 0.5 at 0.2 V s −1 ) is followed by a second irreversible reduction at −1.68 V for [2b] + .…”

“…Note that the "diruthenium approach" has garnered increasing attention in medicinal chemistry, [28][29][30][31][32][33][34][35] nevertheless investigations on the anticancer potential of compounds with a Ru-Ru bonded core remain quite limited. Contributing to this field, we have recently unveiled the activity of [Ru 2 Cp 2 (CO) 4 ] derivatives containing bridging allenyl 36 and vinyl ligands. 37 In principle, the pathway illustrated in Scheme 1 can be extended to the homologous diruthenium compounds.…”