Neutral luminescent bis(bipyridyl) osmium(II) complexes with improved phosphorescent properties

A new class of neutral bis(isocyanoborato) bis(bipyridyl) Os(II) complexes with the general formula of [Os(N–N)2(CNBR3)2] (N–N = bpy, 4,4′-Me2bpy; R = C6F5, C6H5) were prepared with simple synthetic methodologies. One of these complexes was structurally characterized by X-ray crystallography. Unlike most of the neutral bis(bipyridyl) Os(II) complexes, which are very weakly emissive or nonemissive, these isocyanoborato complexes displayed intense orange to red phosphorescence with a luminescent quantum yield up to 0.09 in CH2Cl2 solution at room temperature. The photophysical and electrochemical properties of these complexes were also investigated. Detailed photophysical study showed that these complexes exhibited significantly enhanced emission properties over other reported neutral bis(bipyridyl) Os(II) complexes. In addition, it also revealed that the photophysics, electrochemistry, and excited state properties can be fine-tuned or modified through the functionalization of isocyanoborate ligands

Glycemic control in critically ill patients with or without diabetes

Abstract Background Early randomized controlled trials have demonstrated the benefits of tight glucose control. Subsequent NICE-SUGAR study found that tight glucose control increased mortality. The optimal glucose target in diabetic and nondiabetic patients remains unclear. This study aimed to evaluate the relationship between blood glucose levels and outcomes in critically ill patients with or without diabetes. Methods This was a retrospective analysis of the eICU database. Repeat ICU stays, ICU stays of less than 2 days, patients transferred from other ICUs, those with less than 2 blood glucose measurements, and those with missing data on hospital mortality were excluded. The primary outcome was hospital mortality. Generalised additive models were used to model relationship between glycemic control and mortality. Models were adjusted for age, APACHE IV scores, body mass index, admission diagnosis, mechanical ventilation, and use of vasopressor or inotropic agents. Results There were 52,107 patients in the analysis. Nondiabetes patients exhibited a J-shaped association between time-weighted average glucose and hospital mortality, while this association in diabetes patients was right-shifted and flattened. Using a TWA glucose of 100 mg/dL as the reference value, the adjusted odds ratio (OR) of TWA glucose of 140 mg/dL was 3.05 (95% confidence interval (CI) 3.03–3.08) in nondiabetes and 1.14 (95% CI 1.08–1.20) in diabetes patients. The adjusted OR of TWA glucose of 180 mg/dL were 4.20 (95% CI 4.07–4.33) and 1.49 (1.41–1.57) in patients with no diabetes and patients with diabetes, respectively. The adjusted ORs of TWA glucose of 80 mg/dL compared with 100 mg/dL were 1.74 (95% CI 1.57–1.92) in nondiabetes and 1.36 (95% CI 1.12–1.66) in patients with diabetes. The glucose ranges associated with a below-average risk of mortality were 80–120 mg/dL and 90–150 mg/dL for nondiabetes and diabetes patients, respectively. Hypoglycemia was associated with increased hospital mortality in both groups but to a lesser extent in diabetic patients. Glucose variability was positively associated with hospital mortality in nondiabetics. Conclusions Time-weighted average glucose, hypoglycemia, and glucose variability had different impacts on clinical outcomes in patients with and without diabetes. Compared with nondiabetic patients, diabetic patients showed a more blunted response to hypo- and hyperglycemia and glucose variability. Glycemic control strategies should be reconsidered to avoid both hypoglycemia and hyperglycemia

Platinated benzonaphthyridone is a stronger inhibitor of poly(ADP-ribose) polymerase-1 and a more potent anticancer agent than is the parent inhibitor

Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhibitors with enhanced biological activities by conjugating platinum moiety with an original inhibitor, e.g., benzonaphthyridone. Based on the structure activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as cisplatin and its spectrum of anticancer activity was identical to that of cisplatin. The complex was able to enter into cancer cells efficiently, bind to DNA well, and block cell cycle at G(2)/M phase, indicating that complex 3 is an effective anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent anticancer agents with improved biological activities. (C) 2013 Elsevier Masson SAS. All rights reserved

Multi-targeted organometallic ruthenium(II)-arene anticancer complexes bearing inhibitors of poly(ADP-ribose) polymerase-1: A strategy to improve cytotoxicity

Small-molecule inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have currently drawn much attention as promising chemotherapeutic drug candidates, and there is a need to develop more potent PARP inhibitors with improved bioavailability. Here we report a strategy to improve the cytotoxicity of PARP inhibitors by conjugation with organometallic ruthenium(II)-arene compounds. We also report a systematic study to reveal the mechanism of action of these ruthenium-PARP inhibitor conjugates. The complexes have been synthesized and characterized spectroscopically. The improved antiproliferative activity from the as-prepared complexes in four human cancer cell lines has indicated their potential for further development as antitumor drugs. Cellular uptake study reveals that the most active complex 3 easily entered into cells. Target validation assays show that the complexes inhibited PARP-1 slightly better than the original PARP inhibitors, that complex 3 strongly bound to DNA and inhibited transcription, and that this complex arrested the cell cycle at the G(0)/G(1) stage. This type of information could shed light on the design of the next generation of more active ruthenium-PARP inhibitor conjugates. (C) 2013 Elsevier Inc. All rights reserved

Reduction of RuVI(N) to RuIII-NH3 by Cysteine in Aqueous Solution

The reduction of metal nitride to ammonia is a key step in biological and chemical nitrogen fixation. We report herein the facile reduction of a ruthenium(VI) nitride complex [(L)RuVI(N)(OH2)]+ (1, L = N,N′-bis(salicylidene)- o-cyclohexyldiamine dianion) to [(L)RuIII(NH3)(OH2)]+ by Lcysteine (Cys), an ubiquitous biological reductant, in aqueous solution. At pH 1.0−5.3, the reaction has the following stoichiometry: [(L)RuVI(N)(OH2)]+ + 3HSCH2CH(NH3)CO2 → [(L)RuIII(NH3)(OH2)]+ + 1.5(SCH2CH(NH3)CO2)2. Kinetic studies show that at pH 1 the reaction consists of two phases, while at pH 5 there are three distinct phases. For all phases the rate law is rate = k2[1][Cys]. Studies on the effects of acidity indicate that both HSCH2CH(NH3 +)CO2 – and −SCH2CH(NH3 +)CO2 − are kinetically active species. At pH 1, the reaction is proposed to go through [(L)- RuIV(NHSCH2CHNH3CO2H)(OH2)]2+ (2a), [(L)RuIII(NH2SCH2CHNH3CO2H)(OH2)]2+ (3), and [(L)RuIV(NH2)(OH2)]+ (4) intermediates. On the other hand, at pH around 5, the proposed intermediates are [(L)RuIV(NHSCH2CHNH3CO2)- (OH2)]+ (2b) and [(L)RuIV(NH2)(OH2)]+ (4). The intermediate ruthenium(IV) sulfilamido species, [(L)- RuIV(NHSCH2CHNH3CO2H)(OH2)]2+ (2a) and the final ruthenium(III) ammine species, [(L)RuIII(NH3)(MeOH)]+ (5) (where H2O was replaced by MeOH) have been isolated and characterized by various spectroscopic methods

Reduction of RuVIºN to RuIII-NH3 by Cysteine in Aqueous Solution

The reduction of metal nitride to ammonia is a key step in biological and chemical nitrogen fixation. We report herein the facile reduction of a ruthenium(VI) nitrido complex [(L)RuVI(N)(OH2)]+ (1, L = N,N′-bis(salicylidene)-o-cyclohexyldiamine dianion) to [(L)RuIII(NH3)(OH2)]+ by l-cysteine (Cys), an ubiquitous biological reductant, in aqueous solution. At pH 1.0–5.3, the reaction has the following stoichiometry: [(L)RuVI(N)(OH2)]+ + 3HSCH2CH(NH3)CO2 → [(L)RuIII(NH3)(OH2)]+ + 1.5(SCH2CH(NH3)CO2)2. Kinetic studies show that at pH 1 the reaction consists of two phases, while at pH 5 there are three distinct phases. For all phases the rate law is rate = k2[1][Cys]. Studies on the effects of acidity indicate that both HSCH2CH(NH3+)CO2– and –SCH2CH(NH3+)CO2– are kinetically active species. At pH 1, the reaction is proposed to go through [(L)RuIV(NHSCH2CHNH3CO2H)(OH2)]2+ (2a), [(L)RuIII(NH2SCH2CHNH3CO2H)(OH2)]2+ (3), and [(L)RuIV(NH2)(OH2)]+ (4) intermediates. On the other hand, at pH around 5, the proposed intermediates are [(L)RuIV(NHSCH2CHNH3CO2)(OH2)]+ (2b) and [(L)RuIV(NH2)(OH2)]+ (4). The intermediate ruthenium(IV) sulfilamido species, [(L)RuIV(NHSCH2CHNH3CO2H)(OH2)]2+ (2a) and the final ruthenium(III) ammine species, [(L)RuIII(NH3)(MeOH)]+ (5) (where H2O was replaced by MeOH) have been isolated and characterized by various spectroscopic methods

Synthesis, characterization, photophysics and electrochemical study of luminescent iridium(III) complexes with isocyanoborate ligands

A new series of cyclometalated iridium(III) complexes with isocyanoborate ligands [Ir(R2ppy)2(L)(CNBR\u273)] (R = H or F ; L = CNC6H4Cl-4 or PPh3 ; R\u27 = Ph, C6F5 or C6H4Cl-4), [Ir(biqb)(ppy)(CNBR\u27\u273)] (R\u27\u27 = C6F5 or C6H4Cl-4) and {Ir(ppy)2(CN)n[CNB(C6F5)3]2-n}(-) (n = 0 or 1) have been synthesized and characterized. Three of these complexes have also been structurally characterized by X-ray crystallography. The photophysical and electrochemical properties of these complexes have been investigated. The effects of isocyanoborate ligands on the luminescence properties of these iridium(III) complexes are also described

Luminescent Rhenium(I) Phenanthroline Complexes with a Benzoxazol-2-ylidene Ligand: Synthesis, Characterization, and Photophysical Study

A series of luminescent rhenium­(I) phenanthroline complexes containing benzoxazol-2-ylidene ligands with the general formula {Re­(CO)₃(phen)­[CN­(X)­C₆H₄-2-O]}⁺ and <i>cis</i>,<i>trans</i>-{Re­(CO)₂(phen)­(L)­[CN­(H)­C₆H₄-2-O]}⁺ (X = H, methyl; phen = 1,10-phenanthroline; L = PPh₃, PPh₂Me, P­(OEt)₃) have been synthesized and characterized. The X-ray crystal structures of most of the carbene complexes and some of their synthetic precursors have also been determined. A new synthetic methodology for the preparation of dicarbonyl rhenium diimine synthetic precursors with a labile acetonitrile ligand, [Re­(CO)₂(phen)­(PR₃)­(MeCN)]⁺, was developed. Photophysical study shows that these carbene complexes display a green to red ³MLLCT [dπ­(Re) → π*­(N–N)] phosphorescence at room temperature. The N-deprotonations of the benzoxazol-2-ylidene ligand in these complexes were investigated