C-H, N-H, and O-H Bond Activations to Prepare Phosphorescent Hydride-Iridium(III)-Phosphine Emitters with Photocatalytic Achievement in C-C Coupling Reactions.

Complex IrH5(PiPr3)2 (1) activates two different σ-bonds of 3-phenoxy-1-phenylisoquinoline, 2-(1H-benzimidazol-2-yl)-6-phenylpyridine, 2-(1H-indol-2-yl)-6-phenylpyridine, 2-(2-hydroxyphenyl)-6-phenylpyridine, N-(2-hydroxyphenyl)-N'-phenylimidazolylidene, and 1,3-di(2-pyridyl)-4,6-dimethylbenzene to give IrH{κ3-C,N,C-[C6H4-isoqui-O-C6H4]}(PiPr3)2 (2), IrH{κ3-N,N,C-[NBzim-py-C6H4]}(PiPr3)2 (3), IrH{κ3-N,N,C-[Ind-py-C6H4]}(PiPr3)2 (4), IrH{κ3-C,N,O-[C6H4-py-C6H4O]}(PiPr3)2 (5), IrH{κ3-C,C,O-[C6H4-Im-C6H4O]}(PiPr3)2 (6), and IrH{κ3-N,C,C-[py-C6HMe2-C5H3N]}(PiPr3)2 (7), respectively. The activations are sequential, with the second generally being the slowest. Accordingly, dihydride intermediates IrH2{κ2-C,N-[C6H4-isoqui-O-C6H5]}(PiPr3)2 (2d), IrH2{κ2-N,N-[NBzim-py-C6H5]}(PiPr3)2 (3d), IrH2{κ2-N,N-[Ind-py-C6H5]}(PiPr3)2 (4d), and IrH2{κ2-N,C-[py-C6HMe2-py]}(PiPr3)2 (7d) were characterized spectroscopically. Complexes 3 and 5 are green phosphorescent emitters upon photoexcitation, exhibiting good absorption over a wide range of wavelengths, emission quantum yields about 0.70 in solution, long enough lifetimes (10-17 µs), and reversible electrochemical behavior. In agreement with these features, complex 3 promotes the photocatalytic α-amino C(sp3)-H arylation of N,N-dimethylaniline and N-phenylpiperidine with 1,4-dicyanobenzene and 4-cyanopyridine under blue LED light irradiation. The C-C coupling products are isolated in high yields with only 2 mol % of photocatalyst after 24 h.

In Cellulo Bioorthogonal Catalysis by Encapsulated AuPd Nanoalloys: Overcoming Intracellular Deactivation.

Bioorthogonal metallocatalysis has opened up a xenobiotic route to perform nonenzymatic catalytic transformations in living settings. Despite their promising features, most metals are deactivated inside cells by a myriad of reactive biomolecules, including biogenic thiols, thereby limiting the catalytic functioning of these abiotic reagents. Here we report the development of cytocompatible alloyed AuPd nanoparticles with the capacity to elicit bioorthogonal depropargylations with high efficiency in biological media. We also show that the intracellular catalytic performance of these nanoalloys is significantly enhanced by protecting them following two different encapsulation methods. Encapsulation in mesoporous silica nanorods resulted in augmented catalyst reactivity, whereas the use of a biodegradable PLGA matrix increased nanoalloy delivery across the cell membrane. The functional potential of encapsulated AuPd was demonstrated by releasing the potent chemotherapy drug paclitaxel inside cancer cells. Nanoalloy encapsulation provides a novel methodology to develop nanoreactors capable of mediating new-to-life reactions in cells.

Ligand Design and Preparation, Photophysical Properties, and Device Performance of an Encapsulated-Type Pseudo-Tris(heteroleptic) Iridium(III) Emitter.

The organic molecule 2-(1-phenyl-1-(pyridin-2-yl)ethyl)-6-(3-(1-phenyl-1-(pyridin-2-yl)ethyl)phenyl)pyridine (H3L) has been designed, prepared, and employed to synthesize the encapsulated-type pseudo-tris(heteroleptic) iridium(III) derivative Ir(κ6-fac-C,C',C″-fac-N,N',N″-L). Its formation takes place as a result of the coordination of the heterocycles to the iridium center and the ortho-CH bond activation of the phenyl groups. Dimer [Ir(µ-Cl)(η4-COD)]2 is suitable for the preparation of this compound of class [Ir(9h)] (9h = 9-electron donor hexadentate ligand), but Ir(acac)3 is a more appropriate starting material. Reactions were carried out in 1-phenylethanol. In contrast to the latter, 2-ethoxyethanol promotes the metal carbonylation, inhibiting the full coordination of H3L. Complex Ir(κ6-fac-C,C',C″-fac-N,N',N″-L) is a phosphorescent emitter upon photoexcitation, which has been employed to fabricate four yellow emitting devices with 1931 CIE (x:y) ∼ (0.52:0.48) and a maximum wavelength at 576 nm. These devices display luminous efficacies, external quantum efficiencies, and power efficacies at 600 cd m-2, which lie in the ranges 21.4-31.3 cd A-1, 7.8-11.3%, and 10.2-14.1 lm W1-, respectively, depending on the device configuration.

A 1-week sleep and light intervention improves mood in premenstrual dysphoric disorder in association with shifting melatonin offset time earlier.

To test the hypothesis that 1 week of combined sleep and light interventions (SALI), which phase-advance (shift earlier) melatonin circadian rhythms, improves mood significantly more than phase-delay (shift later) SALI. After a 2-month diagnostic evaluation for premenstrual dysphoric disorder (PMDD per DSM-5 criteria) in a university clinical research setting, 44 participants enrolled in baseline studies were randomized in the luteal phase at home to (A) a phase-advance intervention (PAI): 1 night of late-night wake therapy (LWT: sleep 9 pm-1 am) followed by 7 days of the morning (AM) bright white light (BWL), or (B) a phase-delay intervention (PDI): 1 night of early-night wake therapy (EWT: sleep 3-7 am) plus 7 days of the evening (PM) BWL. After a month of no intervention, participants underwent the alternate intervention. Outcome measures were mood, the melatonin metabolite, 6-sulfatoxymelatonin (6-SMT), and actigraphy (to assess protocol compliance). At baseline, atypical depression correlated positively with phase delay in 6-SMT offset time (r = .456, p = .038). PAI advanced 6-SMT offset from baseline more than PDI (p < .05), and improved raw mood scores more than PDI (p < .05). As hypothesized, percent improvement in mood correlated positively with a phase advance from baseline in 6-SMT offset time (p < .001). Treatment with 1 night of advanced/restricted sleep followed by 7 days of AM BWL (PAI) was more efficacious in reducing PMDD depression symptoms than a PDI; mood improvement occurred in association with phase advance in 6-SMT offset time. Combined SALIs offer safe, efficacious, rapid-acting, well-tolerated, non-pharmacological, non-hormonal, affordable, repeatable home interventions for PMDD. Clinical Trials.gov NCT # NCT01799733.

Homogeneous catalysis with polyhydride complexes.

Roles of the hydrogen atoms attached to the metal center of transition metal polyhydride complexes, LnMHx (x ≥ 3), are analyzed for about forty types of organic reactions catalyzed by such class of species. Reactions involve nearly every main organic functional group and represent friendly environmental procedures of synthesis of relevant and necessary molecules in several areas ranging from energy and environment to medicine or pharmacology. Catalysts are mainly complexes of group 8 metals, along with rhenium and iridium, and manganese and cobalt to a lesser extent. Their MHx units can be formed by Kubas-type dihydrogen, elongated dihydrogen, or hydride ligands, which facilitate both the homolytic and heterolytic σ-bond activation reactions and hydrogen transfer processes from the metal center to unsaturated organic molecules. As a consequence of the ability of polyhydride complexes to activate σ-bonds, the vast majority of the reactions catalyzed by derivatives of this class involve at least one σ-bond activation elemental step, whereas two sequential ruptures of σ-bonds and the cross-coupling of the resulting fragments take place in a variety of reactions of C-H functionalization and hydrodefluorination. The hydrogen transfer processes usually generate highly unsaturated metal fragments, which are very reactive and extremely active in interesting C-C coupling reactions. Polyhydride complexes bearing Kubas-type dihydrogen ligands are the last intermediates in dehydrogenation processes, while they can be the first ones in hydrogenation reactions. Polyhydrides coordinating elongated dihydrogen ligands are acidic, while classical hydride complexes behave as Brønsted bases. The combination of the properties of both types of species in a catalytic cycle gives rise to interesting outer-sphere processes. The basic character of the classical hydride ligands also confers them the ability of cooperating in the coordination of acidic molecules such as boranes, which is of great relevance for reactions involving the activation of a B-H bond. Multiple bonds of unsaturated organic molecules also undergo insertion into the M-H bond of the catalysts. Such insertions are a key step in many processes.

Effect of Lidocaine 2% Versus Bupivacaine 0.5% and 1 Versus 2 Dual Separate Injections on Onset and Duration of Ultrasound-Guided Wrist Blocks: A Blinded 2 × 2 Factorial Randomized Clinical Trial.

BACKGROUND: Local anesthetics are often selected or mixed to accomplish faster onset of anesthesia. However, with ultrasound guidance, local anesthetics are delivered with greater precision, which may shorten the onset time with all classes of local anesthetics. In this study, we compared onset time and duration of ultrasound-guided wrist blocks with a fast onset versus a longer lasting local anesthetic administered via single or dual (spatially separate) injections at the level of the midforearm. METHODS: In this randomized clinical trial, 36 subjects scheduled for carpal tunnel release were randomly assigned to receive ultrasound-guided median and ulnar nerve blocks with lidocaine 2% or bupivacaine 0.5% via single or dual injections (n = 9 in each group). Subjects fulfilled the study requirements. The main outcome variables were onset and duration of sensory blockade, which were tested separately in 2 (drug) × 2 (injection) analysis of variances (ANOVAs) with interaction terms. RESULTS: Sensory block onset time did not differ significantly between subjects given lidocaine 2% (9.2 ± 3.4 minutes) or bupivacaine 0.5% (9.5 ± 3.1 minutes) (P = .76; mean difference, -0.3 ± 1.1 minutes [95% confidence interval {CI}, -2.5 to 1.9]) or between the single- (9.6 ± 2.8 minutes) and dual- (9.1 ± 3.6 minutes) injection groups (P = .69; mean difference, -0.4 ± 1.1 minutes [95% CI, -1.8 to 2.6]). Sensory duration was longer for subjects in the bupivacaine 0.5% group (27.3 ± 11.6 hours) than for subjects in the lidocaine 2% group (8.4 ± 4.1 hours) (P < .001; 95% CI, 12.7-25.1). However, sensory duration in the single- (15.7 ± 12.5 hours) and dual- (19.4 ± 13.1 hours) injection groups did not differ significantly (P = .28; mean difference, -3.7 ± 4.3 hours [95% CI, -12.6 to 5.1]). CONCLUSIONS: No significant effect was found for onset time between lidocaine 2% and bupivacaine 0.5% used in ultrasound-guided wrist blocks. Dual injections did not shorten onset time. Since mean nerve block duration was longer with bupivacaine 0.5%, our results suggest that the selection of local anesthetic for the median and ulnar nerves at the level of the midforearm should be based on the desired duration of the block and not on its speed of onset.

Athlete Heart in Children and Young Athletes. Echocardiographic Findings in 331 Cases.

The changes of the athlete's heart are not well defined and characterized in children. We aimed to describe the morphological changes of the heart related to sport in young athletes. We evaluated a group of 331 young athletes under 18 years (mean 11.9 ± 3.2) who practice tennis: 58 (16.52%), football: 118 (33.62%), basketball: 16 (4.56%), athletics: 40 (11.4%), and swimming: 99 (28.21%). Type of sport, years of practice, and duration of the training were collected. All children underwent echocardiography with the following M-mode parameters: left atrium diameter (LAD), interventricular septum (IVS), and left ventricle posterior Wall (LVPW), diastolic diameter of the left ventricle (LVDD), and right ventricle outflow tract (RVOT). The major finding of our study was that 20% of the children had a Z score > 2 for the IVS and that increased to 30% for the children playing tennis or swimming. Also, other changes like LA and RVOT dilatation were observed in about 10 and 14% of the cases, respectively. Taken together, these figures indicate that cardiac remodeling is frequent in children. Further studies are needed to establish consensus-based criteria of athlete's heart in young children.

Metathesis between E-C(spn ) and H-C(sp3 ) σ-Bonds (E=Si, Ge; n=2, 3) on an Osmium-Polyhydride.

The silylation of a phosphine of OsH6 (Pi Pr3 )2 is performed via net-metathesis between Si-C(spn ) and H-C(sp3 ) σ-bonds (n=2, 3). Complex OsH6 (Pi Pr3 )2 activates the Si-H bond of Et3 SiH and Ph3 SiH to give OsH5 (SiR3 )(Pi Pr3 )2 , which yield OsH4 {κ1 -P,η2 -SiH-[i Pr2 PCH(Me)CH2 SiR2 H]}(Pi Pr3 ) and R-H (R=Et, Ph), by displacement of a silyl substituent with a methyl group of a phosphine. Such displacement is a first-order process, with activation entropy consistent with a rate determining step occurring via a highly ordered transition state. It displays selectivity, releasing the hydrocarbon resulting from the rupture of the weakest Si-substituent bond, when the silyl ligand bears different substituents. Accordingly, reactions of OsH6 (Pi Pr3 )2 with dimethylphenylsilane, and 1,1,1,3,5,5,5-heptamethyltrisiloxane afford OsH5 (SiR2 R')(Pi Pr3 )2 , which evolve into OsH4 {κ1 -P,η2 -GeH-[i Pr2 PCH(Me)CH2 SiR2 H]}(Pi Pr3 ) (R=Me, OSiMe3 ) and R'-H (R'=Ph, Me). Exchange reaction is extended to Et3 GeH. The latter reacts with OsH6 (Pi Pr3 )2 to give OsH5 (GeEt3 )(Pi Pr3 )2 , which loses ethane to form OsH4 {κ1 -P,η2 -GeH-[i Pr2 PCH(Me)CH2 GeEt2 H]}(Pi Pr3 ).

Hydration of Aliphatic Nitriles Catalyzed by an Osmium Polyhydride: Evidence for an Alternative Mechanism.

The hexahydride OsH6(PiPr3)2 competently catalyzes the hydration of aliphatic nitriles to amides. The main metal species under the catalytic conditions are the trihydride osmium(IV) amidate derivatives OsH3{κ2-N,O-[HNC(O)R]}(PiPr3)2, which have been isolated and fully characterized for R = iPr and tBu. The rate of hydration is proportional to the concentrations of the catalyst precursor, nitrile, and water. When these experimental findings and density functional theory calculations are combined, the mechanism of catalysis has been established. Complexes OsH3{κ2-N,O-[HNC(O)R]}(PiPr3)2 dissociate the carbonyl group of the chelate to afford κ1-N-amidate derivatives, which coordinate the nitrile. The subsequent attack of an external water molecule to both the C(sp) atom of the nitrile and the N atom of the amidate affords the amide and regenerates the κ1-N-amidate catalysts. The attack is concerted and takes place through a cyclic six-membered transition state, which involves Cnitrile···O-H···Namidate interactions. Before the attack, the free carbonyl group of the κ1-N-amidate ligand fixes the water molecule in the vicinity of the C(sp) atom of the nitrile.

Pseudo-Tris(heteroleptic) Red Phosphorescent Iridium(III) Complexes Bearing a Dianionic C,N,C',N'-Tetradentate Ligand.

1-Phenyl-3-(1-phenyl-1-(pyridin-2-yl)ethyl)isoquinoline (H2MeL) has been prepared by Pd(N-XantPhos)-catalyzed "deprotonative cross-coupling processes" to synthesize new phosphorescent red iridium(III) emitters (601-732 nm), including the carbonyl derivative Ir(κ4-cis-C,C'-cis-N,N'-MeL)Cl(CO) and the acetylacetonate compound Ir(κ4-cis-C,C'-cis-N,N'-MeL)(acac). The tetradentate 6e-donor ligand (6tt') of these complexes is formed by two different bidentate units, namely, an orthometalated 2-phenylisoquinoline and an orthometalated 2-benzylpyridine. The link between the bidentate units reduces the number of possible stereoisomers of the structures [6tt' + 3b] (3b = bidentate 3e-donor ligand), with respect to a [3b + 3b' + 3b″] emitter containing three free bidentate units, and it permits a noticeable stereocontrol. Thus, the isomers fac-Ir(κ4-cis-C,C'-cis-N,N'-MeL){κ2-C,N-(C6H4-py)}, mer-Ir(κ4-cis-C,C'-cis-N,N'-MeL){κ2-C,N-(C6H3R-py)}, and mer-Ir(κ4-trans-C,C'-cis-N,N'-MeL){κ2-C,N-(C6HR-py)} (R = H, Me) have also been selectively obtained. The new emitters display short lifetimes (0.7-4.6 µs) and quantum yields in a doped poly(methyl methacrylate) film at 5 wt % and 2-methyltetrahydrofuran at room temperature between 0.08 and 0.58. The acetylacetonate complex Ir(κ4-cis-C,C'-cis-N,N'-MeL)(acac) has been used as a dopant for a red PhOLED device with an electroluminescence λmax of 672 nm and an external quantum efficiency of 3.4% at 10 mA/cm2.

A minimally-masked inactive prodrug of panobinostat that is bioorthogonally activated by gold chemistry.

The recent incorporation of Au chemistry in the bioorthogonal toolbox has opened up new opportunities to deliver biologically independent reactions in living environments. Herein we report that the O-propargylation of the hydroxamate group of the potent HDAC inhibitor panobinostat leads to a vast reduction of its anticancer properties (>500-fold). We also show that this novel prodrug is converted back into panobinostat in the presence of Au catalysts in vitro and in cell culture.

Role of regional anesthesia in Enhanced Recovery After Surgery (ERAS) protocols.

PURPOSE OF REVIEW: Enhanced Recovery After Surgery (ERAS) protocols and interventional locoregional anesthesia (LRA) techniques continuously evolve. This review outlines the latest recommendations for the use of regional anesthesia in ERAS protocols and emerging interventional analgesia techniques. RECENT FINDINGS: Research in ultrasound-guided regional anesthesia has led to a refinement of the traditional techniques and the introduction of a number of new approaches to complement ERAS strategies. The efficacy and versatility of LRA enable its use in an increasing number of ERAS indications. SUMMARY: The implementation of ERAS protocols in different surgical procedures reduces overall complications and recovery time. Multimodal analgesia strategies with regional anesthesia techniques are some of the key interventions contributing to the improvement in postoperative outcomes.

Insertion of Unsaturated C-C Bonds into the O-H Bond of an Iridium(III)-Hydroxo Complex: Formation of Phosphorescent Emitters with an Asymmetrical ß-Diketonate Ligand.

A synthetic methodology to prepare iridium(III) emitters of the class [3b+3b+3b'] with two ortho-metalated 1-phenylisoquinolines and an asymmetrical ß-diketonate has been discovered. The abstraction of the chloride ligands of the dimer [Ir(µ-Cl){κ2-C,N-(C6H4-isoqui)}2]2 (1, C6H5-isoqui = 1-phenylisoquinoline) with AgBF4 in acetone and the subsequent addition of water to the resulting solution affords the water solvate mononuclear complex [Ir{κ2-C,N-(C6H4-isoqui)}2(H2O)2]BF4 (2), which reacts with KOH to give the dihydroxo-bridged dimer [Ir(µ-OH){κ2-C,N-(C6H4-isoqui)}2]2 (3). Treatment of the latter with dimethyl acetylenedicarboxylate leads to Ir{κ2-C,N-(C6H4-isoqui)}2{κ2-O,O-[OC(CO2CH3)CHC(OCH3)O]} (4), as a result of the anti-addition of the O-H bond of a mononuclear [Ir(OH){κ2-C,N-(C6H4-isoqui)}2] fragment to the C-C triple bond of the alkyne and the coordination of one of the carboxylate substituents to the metal center. Complex 3 also reacts with α,ß-unsaturated ketones. The reaction with 3-(4-methylphenyl)-1-phenylprop-2-en-1-one affords Ir{κ2-C,N-(C6H4-isoqui)}2{κ2-O,O-[OC(C6H5)CHC(p-C6H4Me)O]} (5), whereas methyl vinyl ketone gives a mixture of Ir{κ2-C,N-(C6H4-isoqui)}2{κ2-O,O-[OC(CH3)CHCHO]} (6) and Ir{κ2-C,N-(C6H4-isoqui)}2{κ2-O,O-[OC(CH3)CHC(CH═CH2)O]} (7). Complexes 5 and 6 are the result of the addition of the O-H bond of the mononuclear [Ir(OH){κ2-C,N-(C6H4-isoqui)}2] fragment to the C-C double bond of the α,ß-unsaturated ketones and the coordination of the carbonyl group to the iridium center, to generate O,O-chelates which lose molecular hydrogen to aromatize into the asymmetrical ß-diketonate ligands. Complexes 4-7 are phosphorescent emitters in the red spectral region (599-672 nm) in doped poly(methyl methacrylate) (PMMA) film at 5 wt % at room temperature and 2-methyltetrahydrofuran at room temperature and 77 K. They display short lifetimes (0.8-2.5 µs) and quantum yields in both doped PMMA films and in 2-methyltetrahydrofuran at room temperature depending on the substituents of the ß-diketonate: about 0.6-0.5 for 4 and 6 and ca. 0.35 for 5 and 7.

Phosphorescent Iridium(III) Complexes with a Dianionic C,C',N,N'-Tetradentate Ligand.

To prepare new phosphorescent iridium(III) emitters, 2-phenyl-6-(1-phenyl-1-(pyridin-2-yl)ethyl)pyridine (H2L) has been designed and its reactions with [Ir(µ-Cl)(η4-COD)]2 (1, COD = 1,5-cyclooctadiene) have been studied. The products obtained depend on the refluxing temperature of the solvent. Thus, complexes Ir(κ4-C,C',N,N'-L)Cl(CO) (2), [Ir(η4-COD)(κ2-N,N'-H2L)][IrCl2(η4-COD)] (3), and [Ir(µ-Cl)(κ4-C,C',N,N'-L)]2 (4) have been formed in 2-ethoxyethanol, propan-2-ol, and 1-phenylethanol, respectively. Complex 4 reacts with K(acac) to give the acetylacetonate derivative Ir(κ4-C,C',N,N'-L)(acac) (5). Complexes 2 and 5 are efficient blue-green and green emitters of classes [6tt+1m+2m] and [6tt+3b], respectively. They display lifetimes in the range of 1.1-4.5 µs and high quantum yields (0.54-0.87) in both PMMA films and 2-MeTHF at room temperature.

Preparation and Photophysical Properties of Bis(tridentate) Iridium(III) Emitters: Pincer Coordination of 2,6-Di(2-pyridyl)phenyl.

The way to prepare molecular emitters [5t + 4t'] of iridium(III) with a 5t ligand derived from the abstraction of the hydrogen atom at position 2 of the aryl group of 1,3-di(2-pyridyl)benzene (dpybH) is shown. In addition, the photophysical properties of the new emitters are compared with those of their counterparts resulting from the deprotonation of 1,3-di(2-pyridyl)-4,6-dimethylbenzene (dpyMebH), at the same position, which are also synthesized. Treatment of 0.5 equiv of the dimer [Ir(µ-Cl)(η2-COE)2]2 (COE = cyclooctene) with 1.0 equiv of Hg(dpyb)Cl leads to the iridium(III) derivative IrCl2{κ3-N,C,N-(dpyb)}(η2-COE) (3), which reacts with 2-(1H-imidazol-2-yl)-6-phenylpyridine (HNImpyC6H5) and 2-(1H-benzimidazol-2-yl)-6-phenylpyridine (HNBzimpyC6H5) in the presence of Na2CO3 to give Ir{κ3-C,N,N-(NImpyC6H4)}{κ3-N,C,N-(dpyb)} (4) and Ir{κ3-C,N,N-(NBzimpyC6H4)}{κ3-N,C,N-(dpyb)} (5), respectively. Similar reactions of the Williams's dimer [IrCl(µ-Cl){κ3-N,C,N-(dpyMeb)}]2 with HNImpyC6H5 and HNBzimpyC6H5 in the presence of Na2CO3 afford the dimethylated counterparts Ir{κ3-C,N,N-(NImpyC6H4)}{κ3-N,C,N-(dpyMeb)} (6) and Ir{κ3-C,N,N-(NBzimpyC6H4)}{κ3-N,C,N-(dpyMeb)} (7), whereas 2-(6-phenylpyridine-2-yl)-1H-indole (HIndpyC6H5) initially gives IrH{κ2-N,N-(IndpyC6H5)}{κ3-N,C,N-(dpyMeb)} (8) and subsequently Ir{κ3-C,N,N-(IndpyC6H4)}{κ3-N,C,N-(dpyMeb)} (9). Complexes 4-7 are phosphorescent green emitters (λem 490-550 nm), whereas 9 is greenish yellow emissive (λem 547-624 nm). They display lifetimes in the range 0.5-9.7 µs and quantum yields in both doped poly(methyl)methacrylate films and in 2-methyltetrahydrofuran at room temperature depending upon the ligands: 0.5-0.7 for 6 and 7, about 0.4 for 4 and 5, and 0.3-0.2 for 9.

Reduction of Benzonitriles via Osmium-Azavinylidene Intermediates Bearing Nucleophilic and Electrophilic Centers.

The reduction of the N≡C bond of benzonitriles promoted by OsH6(PiPr3)2 (1) has been studied. Complex 1 releases a H2 molecule and coordinates 2,6-dimethylbenzonitrile to afford the tetrahydride OsH4{κ1- N-(N≡CC6H3Me2)}(PiPr3)2 (2), which is thermally stable toward the insertion of the nitrile into one of the Os-H bonds. In contrast to 2,6-dimethylbenzonitrile, benzonitrile and 2-methylbenzonitrile undergo insertion, via Os(η2-N≡CR) intermediates, to give the azavinylidene derivatives OsH3(═N═CC6H4R)(PiPr3)2 [R = H (3) or Me (4)]. The analysis by means of computational tools (EDA-NOCV) of the bonding situation in these compounds suggests that the donor-acceptor nature of the osmium azavinylidene bond dominates over the mixed electron-sharing/donor-acceptor and pure electron-sharing bonding modes. The N atom is strongly nucleophilic, whereas one of the hydrides is electrophilic. In spite of the different nature of these centers, the migration of the latter to the N atom is kinetically prevented. However, the use of water as a proton shuttle allows hydride migration, as a consequence of a significant decrease in the activation barrier. The resulting phenylaldimine intermediates evolve by means of orthometalation to give OsH3{κ2- N, C-(NH═CHC6H3R)}(PiPr3)2 [R = H (5) or Me (6)]. The presence of electrophilic and nucleophilic centers in 3 confers upon it the ability to activate σ-bonds, including H2 and pinacolborane (HBpin). The reaction with the latter gives OsH3{κ2- N, C-[N(Bpin)═CHC6H4]}(PiPr3)2 (7).

Microglial-induced Müller cell gliosis is attenuated by progesterone in a mouse model of retinitis pigmentosa.

Norgestrel, a progesterone analogue, has demonstrated neuroprotective effects in a mouse model of retinitis pigmentosa. Neuroprotection is achieved in part through Norgestrels anti-inflammatory properties, alleviating detrimental microglial activity. Gliosis is a feature of many neurodegenerative diseases of the retina, including retinitis pigmentosa. Müller glia, a type of macroglia found in the retina, are major contributors of gliosis, characterized by the upregulation of glial fibrillary acidic protein (GFAP). Microglia-Müller glia crosstalk has been implicated in the initiation of gliosis. In the rd10 retina, increased microglial activity and gliotic events are observed prior to the onset of photoreceptor loss. We hypothesized that Norgestrels dampening effects on harmful microglial activity would consequently impact on gliosis. In the current study, we explore the role of microglia-Müller glia crosstalk in degeneration and Norgestrel-mediated neuroprotection in the rd10 retina. Norgestrels neuroprotective effects in the rd10 retina coincide with significant decreases in both microglial activity and Müller cell gliosis. Using a Müller glial cell line, rMC-1, and isolated microglia, we show that rd10 microglia stimulate GFAP production in rMC-1 cells. Norgestrel attenuates gliosis through direct actions on both microglia and Müller glia. Norgestrel reduces the release of harmful stimuli from microglia, such as interferon-γ, which might otherwise signal to Müller glia and stimulate gliosis. We propose that Norgestrel also targets Müller cell gliosis directly, by limiting the availability of pSTAT3, a known transcription factor for GFAP. These findings highlight an important aspect to Norgestrels neuroprotective effects in the diseased retina, in combating Müller cell gliosis.

Drug "Clicking" on Cell-Penetrating Fluorescent Nanoparticles for In Cellulo Chemical Proteomics.

Chemical proteomics approaches are widely used to identify molecular targets of existing or novel drugs. This manuscript describes the development of a straightforward approach to conjugate azide-labeled drugs via click chemistry to alkyne-tagged cell-penetrating fluorescent nanoparticles as a novel tool to study target engagement and/or identification inside living cells. A modification of the Baeyer test for alkynes allows monitoring the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, guaranteeing the presence of the drug on the solid support. As a proof of concept, the conjugation of the promiscuous kinase inhibitor dasatinib to Cy5-labeled nanoparticles is presented. Dasatinib-decorated fluorescent nanoparticles efficiently inhibited its protein target SRC in vitro, entered cancer cells, and colocalized with SRC in cellulo.

Bioorthogonal Uncaging of the Active Metabolite of Irinotecan by Palladium-Functionalized Microdevices.

SN-38, the active metabolite of irinotecan, is released upon liver hydrolysis to mediate potent antitumor activity. Systemic exposure to SN-38, however, also leads to serious side effects. To reduce systemic toxicity by controlling where and when SN-38 is generated, a new prodrug was specifically designed to be metabolically stable and undergo rapid palladium-mediated activation. Blocking the phenolic OH of SN-38 with a 2,6-bis(propargyloxy)benzyl group led to significant reduction of cytotoxic activity (up to 44-fold). Anticancer properties were swiftly restored in the presence of heterogeneous palladium (Pd) catalysts to kill colorectal cancer and glioma cells, proving the efficacy of this novel masking strategy for aromatic hydroxyls. Combination with a Pd-activated 5FU prodrug augmented the antiproliferative potency of the treatment, while displaying no activity in the absence of the Pd source, which illustrates the benefit of achieving controlled release of multiple approved therapeutics-sequentially or simultaneously-by the same bioorthogonal catalyst to increase anticancer activity.

Evidence for a Bis(Elongated σ)-Dihydrideborate Coordinated to Osmium.

The formation and Atoms in Molecules (AIM) analysis of osmium(IV) and osmium(II) complexes containing dihydrideborate groups and primary aminoborane ligands are reported. Complex OsH6(P iPr3)2 (1) loses a hydrogen molecule and the resulting unsaturated OsH4(P iPr3)2 species coordinates 9-borabicycle[3.3.1]nonane (HBbn) and pinacolborane (HBpin) to give the dihydrideborate derivatives OsH3{κ2- H, H-(H2BR2)}(P iPr3)2 (BR2 = Bbn (2), Bpin (3)). The bonding situation in these compounds and in the related osmium(II) derivative Os(Bcat){κ2- H, H-(H2Bcat)}(CO)(P iPr3)2 (4) (HBcat = catecholborane) has been analyzed by the AIM method. The Laplacian distributions in the Os-H-B plane exhibit a four-membered cyclic topology possessing two Os-H and two B-H bond critical points associated with one OsHHB ring critical point, which resembles that found for B2H6. The tetrahydride OsH4(P iPr3)2 also coordinates catecholborane, which initially affords OsH3{κ2- H, H-(H2Bcat)}(P iPr3)2 (5). In contrast to 2 and 3, complex 5 reacts with a second molecule of HBcat to give the elongated σ-borane-{bis(elongated σ) -dihydrideborate}-osmium(II) derivative OsH(η3-H2Bcat)(η2-HBcat)(P iPr3)2 (6). Complexes 5 and 6 have been also analyzed via the AIM method. Complex 5 displays the same topology as complexes 2-4. However, the OsH2B unit of 6 shows, besides the Os-H and B-H bond critical points, an additional Os-B bond critical point, which is associated with a bond path running between these atoms. This double triangular topology is completed with the respective ring critical points. Reactions of 1 with dimethylamine-borane (H3B·NHMe2) and tert-butylamine-borane (H3B·NH2tBu) give OsH2(η2:η2-H2BNR2)(P iPr3)2 (NR2 = NMe2 (7), NH tBu (8)). The AIM analyses of 7 and 8 also reveal the occurrence of an Os-B bond critical point associated with a bond path running between those atoms. However, neither Os-H bond critical points nor bond paths are observed in the latter species.