Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η5-Cpxbiph)Ir(phpy)(Cl)] (1-Cl), which contains π-bonded biphenyltetramethylcyclopentadienyl (Cpxbiph) and C∧N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η5-Cpxbiph)Ir(phpy)(py)]+ (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H2O2 by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.

Artificial enzymes: Half‐sandwich arene ruthenium(II) and cyclopentadienyl iridium(III) complexes containing N,N‐chelated ligands can use NADH as a source of hydride for the reduction of ketones (see picture). Moreover, cyclopentadienyl phenanthroline iridium(III) derivatives at micromolar concentrations are robust catalysts for the production of H2 from NADH in water and can raise the NAD+/NADH ratio in cancer cells.

Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(h 5 -Cp xbiph )Ir-(phpy)(Cl)] (1-Cl), which contains p-bonded biphenyltetramethylcyclopentadienyl (Cp xbiph ) and C^N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(h 5 -Cp xbiph )Ir(phpy)(py)] + (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H 2 O 2 by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands.

A wide variety of steric and electronic features can be incorporated into transition metal coordination complexes, offering the prospect of rationally-designed therapeutic agents with novel mechanisms of action. Here we compare the chemical reactivity and anticancer activity of organometallic Os II complexes [Os(h 6 -arene)(XY)Z]PF 6 where arene ¼ p-cymene or biphenyl, XY ¼ N,N 0 -chelated phenyliminopyridine or phenylazopyridine derivatives, and Z ¼ Cl or I. The X-ray crystal structure of [Os(h 6 -p-cym)(Impy-OHLike the azopyridine complexes we reported recently (Dalton Trans., 2011, 40, 10553-10562), some iminopyridine complexes are also potently active towards cancer cells (nanomolar IC 50 values). However we show that, unlike the azopyridine complexes, the iminopyridine complexes can undergo aquation, bind to the nucleobase guanine, and oxidize coenzyme nicotine adenine dinucleotide (NADH). We report the first detection of an Os-hydride adduct in aqueous solution by 1 H NMR (À4.2 ppm). Active iminopyridine complexes induced a dramatic increase in the levels of reactive oxygen species (ROS) in A549 lung cancer cells. The anticancer activity may therefore involve interference in the redox signalling pathways in cancer cells by a novel mechanism.

Künstliche Enzyme: Aren‐Ruthenium(II)‐ und Cyclopentadienyl‐Iridium(III)‐Halbsandwichkomplexe mit N,N‐Chelatliganden nutzen NADH als Hydridquelle bei der Reduktion von Ketonen (siehe Bild). Cyclopentadienyl‐Iridium(III)‐Phenanthrolinderivate in mikromolaren Konzentrationen sind stabile Katalysatoren für die Erzeugung von H2 aus NADH in Wasser und können in Krebszellen das Verhältnis von NAD+ zu NADH steigern.

We aimed to examine the association between soft drink consumption and asthma and lung function among Qatari adults. In the cross-sectional study, we used data from 986 Qatari participants aged 20 years and above attending the Qatar Biobank Study. Usual consumption of soft drink was assessed using a food frequency questionnaire. Lung function was measured by spirometry and asthma was based on self-report. The associations between soft drink consumption and asthma and lung function were assessed using multivariable logistic and linear regression, respectively. In total, 65 participants out of 986 (6.6%) reported having asthma. A clear dose-response relationship between soft drink consumption and asthma was found. High soft drink consumers (≥7 times/week) were 2.60 (95% CI 1.20–5.63) times more likely to have asthma as compared to non-consumers. The association was partly mediated by BMI and inflammation. Diet soft drink consumption was positively associated with asthma (OR 1.12 (95% CI 1.02–1.23)) but not with lung function. Regular soft drink consumption was inversely associated with FEV1, but not with FVC. In conclusion, soft drink consumption is positively associated with asthma in Qatari adults. The association is partly mediated by obesity and inflammation. Limiting soft drink consumption should be taken into consideration for asthma prevention.

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