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Hydrolysis of the Os–Cl bond for complexes 1–13. The bars represent the percentage of remaining open-tether chlorido complexes 1–13 over time in unbuffered D2O as determined by ¹H NMR. Equilibrium is mostly reached in the first 24 h. Complex 13 is fully hydrolysed from the first data recording (t ≤ 15 min upon dissolution)
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Aquation is often acknowledged as a necessary step for metallodrug activity inside the cell. Hemilabile ligands can be used for reversible metallodrug activation. We report a new family of osmium(ii) arene complexes of formula [Os(η6-C6H5(CH2)3OH)(XY)Cl]+/0 (1-13) bearing the hemilabile η6-bound arene 3-phenylpropanol, where XY is a neutral N,N or...
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Synthetic anticancer catalysts offer potential for low-dose therapy and the targeting of biochemical pathways in novel ways. Chiral organo-osmium complexes, for example, can catalyse the asymmetric transfer hydrogenation of pyruvate, a key substrate for energy generation, in cells. However, small-molecule synthetic catalysts are readily poisoned an...
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... As such, the η 6 -bound ring is strongly anchored to the metal, while the σbond between the pendant functionality and the metal centre can be dissociated under specific stimuli. [6] The chelate effect of the tether ring can be advantageous in terms of stability, and beneficial in the stereo-differentiation processes of asymmetric catalysis. [7] Hemilability in this type of complexes -whereby a vacancy in the first coordination sphere of the metal can be purposely created-is particularly attractive for both catalytic and biological applications, since it allows for controlled metalcentred reactivity inside the cell. ...
... [7] Hemilability in this type of complexes -whereby a vacancy in the first coordination sphere of the metal can be purposely created-is particularly attractive for both catalytic and biological applications, since it allows for controlled metalcentred reactivity inside the cell. [6,8] Despite the impact of the arene on the chemistry of halfsandwich metal-arene compounds, versatility on arene functionalisation has been modest. This is particularly critical in the case of osmium complexes, with just a few reported examples different from the well-known [Os(η 6 -p-cymene)XYZ] complexes. ...
... Among these examples, there are Os-arenes bearing alcohols and acids reported by us, [6,9] and those bearing η 6 -biphenyl ligand, reported by Sadler. [10] The lack of structural variation is undoubtedly attributed to the limitations imposed by the synthetic methodology to attach the arene to the Os(II) core, most of which are not shared by Ru(II). ...
Half‐sandwich Ru(II)‐ and Os(II)‐arene complexes have great potential for catalytic and biological applications. The possibility of fine‐tuning their chemical reactivity by including modifications in the ligands around the metal adds to their many advantages. However, structural modifications at the η⁶‐bound arene have had significant synthetic limitations, particularly in the design of Os(II)‐tethered complexes. For the first time, we have employed a practical C(sp³)‐C(sp²) coupling to obtain 28 new Ru(II) and Os(II) η⁶‐arene half‐sandwich complexes with a wide variety of arene functionalities, including those that enable the formation of tether rings, such as quinoline, and coumarin. The introduction of novel functional groups at the arene in Ru(II)‐ and Os(II) half‐sandwich complexes can broaden the synthetic scope of this type of organometallic complexes, and help to take full advantage of their structural diversity, for example, in intracellular catalysis.
... Expanding on this concept, Pizarro and coworkers designed a series of organoiridium catalysts bearing a pyridine ring tethered to Cp* (Cat2, Chart 1B). [16][17][18] The investigators showed that the pyridine-tethered catalysts were substantially more potent against cancer cells than their non-tethered variants. The enhanced effects were attributed to the tethered pyridine being able to shield the Ir center from external nucleophiles and minimize premature catalyst activation. ...
Organoiridium picolinamidate complexes are promising for intracellular applications because of their biocompatibility, activity in living systems, and ease of derivatization. To shield their metal centers from inhibition by biological nucleophiles (e.g., glutathione), attempts were made to increase the steric bulk of the supporting N-(2,6-R 2-phenyl)picolinamidate ligand. It was found that when R = H (Ir1) or methyl (Ir2), the ligand adopts N,N′-coordination to iridium, whereas when R = isopropyl (Ir3) or phenyl (Ir4), N,O-coordination was observed. Based on experimental measurements and density functional theory calculations, it was revealed that the carbon chemical shift of the C(O)NR group can be used as a diagnostic handle to distinguish between the N,N′-and N,O-isomers in solution. Computational studies indicate that the former is favored thermodynamically but the latter is preferred when the R group is overly bulky. Complexes Ir1-Ir4 exhibit differences in lipophilicity, cellular uptake, cytotoxicity, and the propensity to generate reactive oxygen species in living cells. Reaction studies showed that Ir1/Ir2 are more efficient than Ir3/Ir4 in promoting the reduction of aldehydes to alcohols via transfer hydrogenation but both isomer types were susceptible to catalyst poisoning by glutathione. This work has led to new insights into structural isomerism in organoiridium picolinamidate complexes and suggests that steric tuning alone is insufficient to protect the Ir center from poisoning by biological nucleophiles.
... However, several challenges must be addressed before osmium nanoparticles can be considered for breast cancer treatment [155]. These include toxicity issues, particularly the oxidation of osmium to the highly toxic OsO 4 compound, and techno-economic concerns to ensure affordability and accessibility [156]. ...
Despite various methods currently used in cancer therapy, breast cancer remains the leading cause of morbidity and mortality worldwide. Current therapeutics face limitations such as multidrug resistance, drug toxicity and off-target effects, poor drug bioavailability and biocompatibility, and inefficient drug delivery. Nanotechnology has emerged as a promising approach to cancer diagnosis, imaging, and therapy. Several preclinical studies have demonstrated that compounds and nanoparticles formulated from platinum group metals (PGMs) effectively treat breast cancer. PGMs are chemically stable, easy to functionalise, versatile, and tunable. They can target hypoxic microenvironments, catalyse the production of reactive oxygen species, and offer the potential for combination therapy. PGM nanoparticles can be incorporated with anticancer drugs to improve efficacy and can be attached to targeting moieties to enhance tumour-targeting efficiency. This review focuses on the therapeutic outcomes of platinum group metal nanoparticles (PGMNs) against various breast cancer cells and briefly discusses clinical trials of these nanoparticles in breast cancer treatment. It further illustrates the potential applications of PGMNs in breast cancer and presents opportunities for future PGM-based nanomaterial applications in combatting breast cancer.
... Antimicrobial [35] activities were found for the complexes 48-51. Complexes 67-74 have been tested for the production of lactate inside the cells [44]. ...
... Interestingly, Pizarro et al. reported on Os(II) complexes bearing picolinate N,O-chelates and studied their reactivity toward catalytic TH of pyruvate, producing quantifiable excess lactate inside cancer cells when using formate as the hydride source. 24 Finally, in 2022, Yoon et al. described a water-soluble carbene rhodium complex of formula [(η 5 -Cp*)Rh(MDI)Cl] + [MDI = 1,1′methylenebis(3,3′-dimethylimidazolium)] ( Figure 1) as a catalyst for the reduction of NAD + to NADH, highlighting the evidence for the formation of a stable metal-hydride intermediate upon its isolation and characterization. 25 When studying the catalytic activity and cycle of [(Cp*)-Rh(bipy)Cl] + , Fish et al. described the possibility of a reverse reaction, where NADH is oxidized to NAD + via the formation of a hydride complex. ...
... This substrate selectivity is not uncommon, and previous studies on osmium-arene complexes have shown that this may be modulated by the type of non-arene ligand bound to the metal center. 24 Comparing the performance of complex 2A to the rest of the series revealed that a kinetic labilization of the acetate ligands is crucial for good catalyst performance beyond simple thermodynamic considerations. ...
With the aim to design water-soluble organometallic Ru(II) complexes acting as anticancer agents catalyzing transfer hydrogenation (TH) reactions with biomolecules, we have synthesized four Ru(II) monocarbonyl complexes (1−4), featuring the 1,4-bis(diphenylphosphino)butane (dppb) ligand and different bidentate nitrogen (N ∧ N) ligands, of general formula [Ru(OAc)-CO(dppb)(N ∧ N)] n (n = +1, 0; OAc = acetate). The compounds have been characterized by different methods, including 1 H and 31 P NMR spectroscopies, electrochemistry, as well as single-crystal X-ray diffraction in the case of 1 and 4. The compounds have also been studied for their hydrolysis in an aqueous environment and for the catalytic regioselective reduction of nicotinamide adenine dinucleotide (NAD +) to 1,4-dihydronicotinamide adenine dinucleotide (1,4-NADH) in aqueous solution with sodium formate as a hydride source. Moreover, the stoichiometric and catalytic oxidation of 1,4-NADH have also been investigated by UV−visible spectrophotometry and NMR spectroscopy. The results suggest that the catalytic cycle can start directly from the intact Ru(II) compound or from its aquo/hydroxo species (in the case of 1−3) to afford the hydride ruthenium complex. Overall, initial structure−activity relationships could be inferred which point toward the influence of the extension of the aromatic N ∧ N ligand in the cationic complexes 1−3 on TH in both reduction/oxidation processes. While complex 3 is the most active in TH from NADH to O 2 , the neutral complex 4, featuring a picolinamidate N ∧ N ligand, stands out as the most active catalyst for the reduction of NAD + , while being completely inactive toward NADH oxidation. The compound can also convert pyruvate into lactate in the presence of formate, albeit with scarce efficiency. In any case, for all compounds, Ru(II) hydride intermediates could be observed and even isolated in the case of complexes 1−3. Together, insights from the kinetic and electrochemical characterization suggest that, in the case of Ru(II) complexes 1−3, catalytic NADH oxidation sees the H-transfer from 1,4-NADH as the rate-limiting step, whereas for NAD + hydrogenation with formate as the H-donor, the rate-limiting step is the transfer of the ruthenium hydride to the NAD + substrate, as also suggested by density functional theory (DFT) calculations. Compound 4, stable with respect to hydrolysis in aqueous solution, appears to operate via a different mechanism with respect to the other derivatives. Finally, the anticancer activity and ability to form reactive oxygen species (ROS) of complexes 1−3 have been studied in cancerous and nontumorigenic cells in vitro. Noteworthy, the conversion of aldehydes to alcohols could be achieved by the three Ru(II) catalysts in living cells, as assessed by fluorescence microscopy. Furthermore, the formation of Ru(II) hydride intermediate upon treatment of cancer cell extracts with complex 3 has been detected by 1 H NMR spectroscopy. Overall, this study paves the way to the application of non-arene-based organometallic complexes as TH catalysts in a biological environment.
... In fact, this was the first report of 18 e − osmium-arene species showing TH of pyruvate to lactate. Complex C59 increased lactate concentration in MCF-7 cells when coincubated with formate, whereas not much concentration was seen for MDA-MB-231 cells; this could be due to the readiness of the former to internalize pyruvate [130]. Very recently, Chu et al. reported the poor activity of triazolebased (N,N ′ ) ruthenium and osmium(II)-p-cymene complexes in both human cancer and normal cell lines which had nothing to do with their poor ability to reduce pyruvate to lactate [131]. ...
The field of bioorganometallic chemistry has expanded significantly in the recent past. Organometallic complexes have offered up new opportunities as efficient catalysts (such as those for transfer hydrogenation and olefin metathesis) and anticancer drug prospectives. The thermodynamic and kinetic properties of ligand substitution and redox processes involving these complexes, particularly those of ruthenium(II) and osmium(II), are seen to be governed by electronic and steric factors. The complexes of these metal ions are popular as versatile precursors and have been used in an array of half-sandwich complexes for biological and catalytic applications. These piano-stool complexes can indirectly influence cellular redox homeostasis via catalytic transfer hydroge-nation, which is an emerging concept in the field of anticancer therapy. These include the oxidation of NADH to NAD + , the reduction of NAD + to NADH, and the conversion of pyruvate to lactate. The next generation of catalytic cancer drugs may be developed as a result of these unnatural intracellular alterations caused by catalytic and non-toxic dosages of these organometallic complexes. In this article, we attempt to correlate the design, structure, and functionality of organometallic complexes of ruthenium(II) and osmium(II) reported in the past years (2010 onwards) conceptualized for utilizing transfer hydrogenation catalysis for cancer therapy.
... Reductive stress can be promoted in cancer cells by selenium-containing metabolites [26][27][28] or ruthenium complexes [29] and examples with other metals have also been reported. [30][31][32][33] Glutathione (GSH) is the most abundant intracellular antioxidant, and its levels are often increased in reductive stress. [34] Consistently, we found increased intracellular GSH levels in two selected cancer cell lines upon incubation with compound 6, but not in HEK293 cells ( Figure 5G). ...
Platinum(II) complexes bearing N‐heterocyclic carbenes based guanosine and caffeine have been synthesized by unassisted C−H oxidative addition, leading to the corresponding trans‐hydride complexes. Platinum guanosine derivatives bearing triflate as counterion or bromide instead of hydride as co‐ligand were also synthesized to facilitate correlation between structure and activity. The hydride compounds show high antiproliferative activity against all cell lines (TC‐71, MV‐4‐11, U‐937 and A‐172). Methyl Guanosine complex 3, bearing a hydride ligand, is up to 30 times more active than compound 4, with a bromide in the same position. Changing the counterion has no significant effect in antiproliferative activity. Increasing bulkiness at N7, with an isopropyl group (compound 6), allows to maintain the antiproliferative activity while decreasing toxicity for non‐cancer cells. Compound 6 leads to an increase in endoplasmic reticulum and autophagy markers on TC71 and MV‐4‐11 cancer cells, induces reductive stress and increases glutathione levels in cancer cells but not in non‐cancer cell line HEK‐293.
... The toxicity of the compounds was greatly enhanced upon addition of formate to the cell culture media. Interestingly, Pizarro et al reported on Os(II) complexes bearing picolinate N,Ochelates and studied their reactivity toward catalytic TH of pyruvate, producing quantifiable excess lactate inside cancer cells when using formate as hydride-source 17 18 When studying the catalytic activity and cycle of [(Cp*)Rh(bipy)Cl] + , Fish et al. described the possibility of a reverse reaction, where NADH is oxidized to NAD + via formation of a hydride complex 3 . Later in 2012, Ru(II)-arene complexes containing bipyridyl bidentate ligands ( Figure 1) were shown to oxidize NADH to generate NAD + 19 . ...
With the aim to design new water-soluble organometallic Ru(II) complexes acting as anticancer agents catalysing transfer hydrogenation (TH) reactions with biomolecules, we have synthesized four Ru(II) monocarbonyl complexes (1-4) featuring the 1,4-bis(diphenylphosphino)butane (dppb) ligand and different bidentate nitrogen (N^N) ligands, of general formula [Ru(OAc)CO(dppb)(N^N)] n (n = +1, 0; OAc = acetate). The compounds have been characterised by different methods, including 1 H and 31 P NMR spectroscopy, electrochemistry as well as single crystals X-ray diffraction in the case of 1 and 4. The compounds have also been studied for their hydrolysis in aqueous environment, and for the catalytic regioselective reduction of NAD + to 1,4-NADH in aqueous solution with sodium formate as hydride source. Moreover, the stoichiometric and catalytic oxidation of 1,4-NADH have also been investigated by UV-Visible spectrophotometry and NMR spectroscopy. Overall, initial structure-activity relationships could be inferred which point towards the influence of the extension of the aromatic N^N ligand in the cationic complexes 1-3 on the TH in both reduction/oxidation processes. The neutral complex 4, featuring a picolinamidate N^N ligand, stands out as the most active catalyst for the reduction of NAD + , while being completely inactive towards NADH oxidation. The compound can also convert pyruvate into lactate in the presence of formate, albeit with scarce efficiency. In any case, for all compounds, Ru(II) hydride intermediates could be observed and even isolated in the case of complexes 1-3. Together, insight from the kinetic and electrochemical characterization suggests that, in the case of Ru(II) complexes 1-3, catalytic NADH oxidation sees the H-transfer from 1,4-NADH as the rate limiting step, whereas for NAD + hydrogenation with formate as the H-donor, the rate limiting step is the transfer of the ruthenium hydride to the NAD + substrate. The latter is further modulated by the presence of di-cationic aquo-or mono-2 cationic hydroxo-species of complexes 1-3. Instead, compound 4, stable with respect to hydrolysis in aqueous solution, appears to operate via a different mechanism. Finally, the anticancer activity and ability to form reactive oxygen species (ROS) of complexes 1-3 have been studied in cancerous and non-tumorigenic cells in vitro. Noteworthy, the conversion of aldehydes to alcohols could be achieved by the three Ru(II) catalysts in living cells, as assessed by fluorescence microscopy. Furthermore, the formation of Ru(II) hydride intermediate upon treatment of cancer cell extracts with complex 3 has been detected by 1 H NMR spectroscopy. Overall, this study paves the way to the application of non-arene based organometallic complexes as TH catalysts in biological environment. 3
... 14 Optimization of catalytic systems for transfer hydrogenation requires a particular attention to their stability and activity in an aqueous environment and compatibility with hydrogen donors, auxiliaries, and other species possibly present in solution. Promising results have been obtained with organometallic η 6 -arene complexes of Os(II) 25 and Ru(II), 11,26 and η 5 -Cp* species of Ir(III) 1,27−29 and Rh(III), 1,30 which combine robustness, solubility in water, and pH-triggered activity. ...
... Contrasting the performance of catalysts 1−3 with that of previously reported catalysts is rather complicated because most of the data in the literature are concerned with the hydrogenation of different substrates 21−24 and/or reactions carried out under completely different experimental conditions (not in pure water, in the presence of auxiliaries/additives, at different temperature). 25,27,84 To the best of our knowledge, only Sadler and co-workers reported an example of ATH of pyruvate to D-lactate in water, 85 It can be deduced that the turnover limiting step of the process is the hydrogenation of the substrate rather than the formation of the iridium-hydride. Ogo, Fukuzumi, and coworkers showed that the transfer hydrogenation rate of an acetophenone derivative containing an electron-withdrawing group (trifluoroacetophenone), mediated by [Cp*Ir(bpy)H] using HCOOH as H-donor, is higher than that of the acetophenone itself. ...
... A variety of promising candidates have been found to be potent against platinum-drug resistant cancer cells and can interact with non-nucleic acid targets. Some studies have shown that half-sandwich metal complexes could engage in catalytic reactions inside living cells [4][5][6][7], such as those that promote allyl carbamate cleavage [8,9] or transfer hydrogenation processes [10][11][12]. These complexes are currently being explored as potential catalytic drugs. ...
In this work, we report on the development of fluorescent half-sandwich iridium complexes using a fluorophore attachment strategy. These constructs consist of pentamethylcyclopentadienyl (Cp*) iridium units ligated by picolinamidate donors conjugated to green-emitting boron-dipyrromethene (bodipy) dyes. Reaction studies in H2O/THF mixtures showed that the fluorescent Ir complexes were active as catalysts for transfer hydrogenation, with activities similar to that of their non-fluorescent counterparts. The iridium complexes were taken up by NIH-3 T3 mouse fibroblast cells, with 50% inhibition concentrations ranging from ~20–70 μM after exposure for 3 h. Visualization of the bodipy-functionalized Ir complexes in cells using fluorescence microscopy revealed that they were localized in the mitochondria and lysosome but not the nucleus. These results indicate that our fluorescent iridium complexes could be useful for future biological studies requiring intracellular catalyst tracking.
