Interweaving catalysis and cancer using Ru- and Os-arene complexes to alter cellular redox state: A structure-activity relationship (SAR) review

Half-Sandwich Iridium(III), Rhodium(III), and Ruthenium(II) Complexes Chelating Hybrid sp2-N/sp3-N Donor Ligands to Achieve Improved Anticancer Selectivity

“…The perturbations of NADH/NAD + balance through catalytic anticancer complexes may lead to the enhancement of the selectivity toward cancer over that of normal cells. Recently, this concept of using hydride transfer catalysis for the design of cancer drugs has been widely studied . As aforementioned, the Sadler group and our group have shown that the half-sandwich Ir­(III) and Ru­(II) complexes increased the ROS levels through catalytic oxidation of NADH to NAD + , thus affording the oxidative stress mechanism of cell death (Scheme , I - III ). ,,,, …”

“…The production of excessive ROS levels by various anticancer complexes can cause the disruption of the cell redox balance and lead to oxidative stress and cell death. − Since the cancer cells are usually under the enhanced oxidative stress in comparison with the normal cells, further increase of the ROS level by the anticancer complexes would have a smaller impact on the redox status in the normal cells, which may provide a basis for the selectivity of the anticancer agents. ,, Encouraged by the fact that some half-sandwich complexes that were able to promote the oxidation of NADH to NAD + can also cause the increase of the ROS level in cancer cells, , the ROS levels in A549 cancer cells and BEAS-2B normal cells induced by complexes Ir1 , Rh1 , and Ru1 at various concentrations were determined by fluorescence microscope using DCFH-DA as the probe (Figures and S81–S83). It should be noted that this assay showed total oxidative stress rather than the accurate determination of specific reactive oxygen species.…”

“…For example, phenylpyridine C∧N chelating half-sandwich Ir­(III) complexes were able to induce the increase of the reactive oxygen species (ROS) level in A2780 cancer cells, which was associated with the generation of H 2 O 2 by catalytic reaction of hydride transfer from coenzymes nicotinamide adenine dinucleotide (NADH) to oxygen (Scheme , I ). , Generally, since cancer cells are under constant oxidative stress owing to the generation of high ROS levels, they are much more sensitive to the change of cell’s redox state . The changes in the NADH/NAD + ratio can also lead to apoptosis in cancer cells while having little influence on normal cells. − Sadler and co-workers also showed that the combination of redox modulators could allow Os­(II) complex FY-26 to increase the selectivity toward cancer cells over normal cells with redox MoAs . Our group has continuously been committed to develop organometallic half-sandwich Ir­(III), Rh­(III), and Ru­(II) complexes bearing an N∧N chelating ligand system.…”

Green Light-Triggered Photocatalytic Anticancer Activity of Terpyridine-Based Ru(II) Photocatalysts

“…NADH, a crucial molecule for cellular redox balance maintenance, serves as an electron carrier and coenzyme in several metabolic pathways. − Its pivotal involvement in electron transfer, energy production, and enzyme regulation makes it necessary for the normal functioning of cells and overall cellular health. − Any unnatural alteration in the intracellular NADH concentration can disrupt the mitochondrial ETC, intracellular redox harmony, and energy production, ultimately leading to cell death. − This concept has been used by Sadler and co-workers to achieve light-triggered anticancer activity with an Ir­(III) complex . Further, Huang's group and our group generalized this concept with both Ir­(III) and Ru­(II) complexes to produce synergistic oxygen-based ROS generation and NADH oxidation to obtain light-triggered anticancer effects against different cancer cell lines. − Henceforth, the NADH photo-oxidation ability of Ru1 – Ru3 was investigated using UV–vis spectroscopy by monitoring the intensity of the NADH characteristic band at 339 nm and the NAD + characteristic band at 259 nm in a PBS-DMSO (99:1 v/v) solution. ,, Ru1 – Ru3 (10 μM) did not show any changes in the absorption spectra of NADH (240 μM) in the dark (Figure S19b–d in the Supporting Information).…”

“…In metal-based photocatalytic cancer drug development, NADH is one of the target molecules for in-cell catalysis, as it has been discovered that the NADH coenzyme level in cancer cells is higher than that of normal cells. − NADH is also very crucial for many intracellular biochemical processes such as (i) functions of ca. 400 oxidoreductases, (ii) ATP generation, (iii) maintenance of in-cell redox balance and cellular metabolism, (iv) main electron donor in the mitochondrial electron transfer chain, etc. − Thus, systematic oxidation of NADH to NAD + in cancer cells using a low nontoxic catalytic amount of the drug can present an alternative cancer cell death mechanism. , In metal-based photocatalytic cancer drug development research, Ir­(III) photocatalysts dominated mostly due to their excited state photochemistry. − In 2019, for the first time, Sadler and co-workers achieved blue light-triggered in-cell NADH oxidation with an Ir­(III) photocatalyst, which induced immunogenic apoptosis in cancer cells by altering the intracellular NAD + /NADH ratio .…”