Featured Article: Inhibition of diabetic cataract by glucose tolerance factor extracted from yeast.

Diabetes leads to many complications; among them is the development of cataract. Hyperglycemia brings to increased polyol concentration in the lens, to glycation of lens proteins, and to elevated level of ROS (Reactive Oxygen Species) causing oxidative stress. The glucose tolerance factor (GTF) was found by several groups to decrease hyperglycemia and oxidative stress both in diabetic animals and humans. The aim of our study was to explore the damages induced by high glucose to the eye lens and to assess the protective effects of GTF both in vivo and in vitro The in vivo study included control healthy rats, streptozotocin (STZ) diabetic untreated rats, and STZ diabetic rats orally treated with 15 doses of GTF. The diabetic untreated rats developed cataracts, whereas the development of cataract was totally or partially prevented in GTF treated animals. In vitro studies were done on bovine lenses incubated for 14 days. Half of the lenses were incubated in normal glucose conditions, and half in high glucose conditions (450 mg%). To one group of the normal or high glucose condition GTF was added. The optical quality of all the lenses was measured daily by an automated scanning laser system. The control lenses, whether with or without GTF addition, did not show any reduction in their quality. High glucose conditions induced optical damage to the lenses. Addition of GTF to high glucose conditions prevented this damage. High glucose conditions affected the activity of aldose reductase and sodium potassium ATPase in lens epithelial cell. Addition of GTF decreased the destructive changes induced by high glucose conditions. The amount of soluble cortical lens proteins was decreased and structural changes were detected in lenses incubated in high glucose medium. These changes could be prevented when GTF was added to high glucose medium. Our findings demonstrate the anticataractogenic potential of GTF.

Improving bioavailability and stability of genistein by complexation with high-amylose corn starch.

Genistein, like other phytochemicals, has beneficial health effects, but its bioavailability is limited. This research studied the effect of complexation of genistein with starch on genistein bioavailability. Genistein release from these complexes was tested in vitro under simulated intestinal conditions and in vivo in rats fed high-amylose corn starch (HACS)-genistein complexes (experimental group) as compared to those fed a physical mixture of HACS and genistein (controls). In vitro results showed that genistein release is sustained and fits the normal transit time of food in the intestine. The genistein concentration in the plasma was twice as high in the experimental group versus controls; the genistein concentration in the urine was also higher in the experimental group but lower in the feces. These results indicate that starch-genistein complexes increase genistein bioavailability and suggest that starch can affect the bioavailability of additional food components.

On the unexpected stability of the dianion of perylene diimide in water--a computational study.

It was recently reported (Shirman, J. Phys. Chem. B, 2008, 112, 8855) that the stable dianion of perylene diimide can be prepared in water. Herein, a computational study (using DFT at the M06-2X/6-31++G** level of theory) of this species is presented. It is shown that this dianion is aromatic and that its reaction with water is highly endergonic. The primary cause for this is the stabilization provided by the enhanced aromaticity of the dianion relative to its neutral counterpart. Comparison with other aromatic dianions is also presented.

Curdlan complexes as a potential food-grade delivery system: genistein case study.

Complexes of curdlan and genistein were prepared using four different methods. The total amount of genistein in curdlan-genistein complexes prepared at 40 degrees C (system I) was significantly higher (2.3 mg/100 mg dry matter) than that in other systems studied: curdlan-genistein complexes prepared at 60 degrees C (system II; 1.8 mg/100 mg dry matter); curdlan-genistein gel complexes (system III; 1.0 mg/100 mg dry matter); and curdlan-genistein dimethyl sulfoxide complexes (system IV; 1.8 mg/100 mg dry matter). x-ray diffraction results indicate that complexation of curdlan with genistein changes the crystalline nature of the pure components. Particle size analysis, atomic force microscopy and scanning electron microscopy imaging of curdlan-genistein complexes showed strong difference in particle size, surface and distribution in comparison with pure curdlan, confirming our assumption of a molecular interaction between curdlan and genistein and the formation of a new structure, which was revealed at the nanoscale level. All the curdlan-genistein complexes showed prolonged genistein release of up to 72 h, enhanced upon enzymatic digestion of curdlan by lyticase, thus opening the possibility of release regulation by the incorporation of lyticase in the delivery system. It is therefore suggested that the complexes could be used as a delivery system for the protection and slow release of genistein in the digestive tract.

Effect of CO on the oxidative addition of arene C-H bonds by cationic rhodium complexes.

Sequential addition of CO molecules to cationic aryl-hydrido Rh(III) complexes of phosphine-based (PCP) pincer ligands was found to lead first to C-H reductive elimination and then to C-H oxidative addition, thereby demonstrating a dual role of CO. DFT calculations indicate that the oxidative addition reaction is directly promoted by CO, in contrast to the commonly accepted view that CO hinders such reactions. This intriguing effect was traced to repulsive pi interactions along the aryl-Rh-CO axis, which are augmented by the initially added CO ligand (due to antibonding interactions between occupied Rh d(pi) orbitals and occupied pi orbitals of both CO and the arene moiety), but counteracted by the second CO ligand (due to significant pi back-donation). These repulsive interactions were themselves linked to significant weakening of the pi-acceptor character of CO in the positively charged rhodium complexes, which is concurrent with an enhanced sigma-donating capability. Replacement of the phosphine ligands by an analogous phosphinite-based (POCOP) pincer ligand led to significant changes in reactivity, whereby addition of CO did not result in C-H reductive elimination, but yielded relatively stable mono- and dicarbonyl aryl-hydrido POCOP-Rh(III) complexes. DFT calculations showed that the stability of these complexes arises from the higher electrophilicity of the POCOP ligand, relative to PCP, which leads to partial reduction of the excessive pi-electron density along the aryl-Rh-CO axis. Finally, comparison between the effects of CO and acetonitrile on C-H oxidative addition revealed that they exhibit similar reactivity, despite their markedly different electronic properties. However, DFT calculations indicate that the two ligands operate by different mechanisms.

Metal-ligand cooperation in the trans addition of dihydrogen to a pincer Ir(I) complex: a DFT study.

DFT calculations on the hydrogenation of a (PNP)Ir(I) complex, to give the trans--rather then the cis--dihydride isomer, show that the reaction proceeds via a deprotonation/protonation of the ligand arm with concomitant dearomatization/aromatization of the pyridine core. Thus, the actual H(2) activation step occurs by an Ir(III) complex and not by the Ir(I) starting complex, as supported by experimental observations. This ligand participation allows for products that would otherwise be inaccessible. In addition, trace amounts of water, which are likely to be present in the solvent, facilitate proton transfer reaction steps.

The impact of weak C-H...Rh interactions on the structure and reactivity of trans-[Rh(CO)2(phosphine)2]+: an experimental and theoretical examination.

The crystal structure of the new cationic Rh(I) complex trans-[Rh(CO)(2)(L)(2)]BF(4) (L=alpha(2)-(diisopropylphosphino)isodurene) was found to exhibit a nonlinear OC-Rh-CO fragment and weak intramolecular C-H...Rh interactions. These interactions, which have also been shown to occur in solution, have been examined by density functional theory calculations and found to be inextricably linked to the presence of the distorted OC-Rh-CO fragment. This linkage has also been demonstrated by comparison with a highly similar Rh(I) complex, in which these C-H...Rh interactions are absent. Furthermore, the presence of these weak interactions has been shown to have a significant effect on the reactivity of the metal center.

Stable aromatic dianion in water.

Perylene diimide (PDI) bearing polyethylene glycol substituents at the imide positions was reduced in water with sodium dithionite to produce an aromatic dianion. The latter is stable for months in deoxygenated aqueous solutions, in contrast to all known aromatic dianions which readily react with water. Such stability is due to extensive electron delocalization and the aromatic character of the dianion, as evidenced by spectroscopic and theoretical studies. The dianion reacts with oxygen to restore the parent neutral compound, which can be reduced again in an inert atmosphere with sodium dithionite to give the dianion. Such reversible charging renders PDIs useful for controlled electron storage and release in aqueous media. Simple preparation of the dianion, reversible charging, high photoredox power, and stability in water can lead to development of new photofunctional and electron transfer systems in the aqueous phase.

Structural and functional properties of amylose complexes with genistein.

Complexes of amylose or high-amylose corn starch (HACS) with genistein were prepared by the acidification of an alkali solution to yield a V 6IotaIotaIota structure. The amylose-genistein complexes exhibited significantly higher genistein content (11 mg/100 mg of complex) than HACS-genistein complexes (9 mg/100 mg of complex). The effect of genistein on the amylose complexes was examined in different genistein-amylose ratios, and a model for genistein organization in the amylose complexes was suggested. The complexes were stable at different pH values, with <10% of the complexed genistein released, and were stable at 30 and 50 degrees C. Lower stability was observed at 80 degrees C as shown by the extensive release of genistein. All complexes showed high retention of genistein in simulated stomach conditions and released genistein upon digestion in pancreatin solution. It is therefore suggested that the complexes can be used as carriers for the slow release of genistein.

Mechanism of thermal unimolecular decomposition of TNT (2,4,6-trinitrotoluene): a DFT study.

The widespread and long-term use of TNT has led to extensive study of its thermal and explosive properties. Although much research on the thermolysis of TNT and polynitro organic compounds has been undertaken, the kinetics and mechanism of the initiation and propagation reactions and their dependence on the temperature and pressure are unclear. Here, we report a comprehensive computational DFT investigation of the unimolecular adiabatic (thermal) decomposition of TNT. On the basis of previous experimental observations, we have postulated three possible pathways for TNT decomposition, keeping the aromatic ring intact, and calculated them at room temperature (298 K), 800, 900, 1500, 1700, and 2000 K and at the detonation temperature of 3500 K. Our calculations suggest that at relatively low temperatures, reaction of the methyl substituent on the ring (C-H alpha attack), leading to the formation of 2,4-dinitro-anthranil, is both kinetically and thermodynamically the most favorable pathway, while homolysis of the C-NO(2) bond is endergonic and kinetically less favorable. At approximately 1250-1500 K, the situation changes, and the C-NO(2) homolysis pathway dominates TNT decomposition. Rearrangement of the NO(2) moiety to ONO followed by O-NO homolysis is a thermodynamically more favorable pathway than the C-NO(2) homolysis pathway at room temperature and is the most exergonic pathway at high temperatures; however, at all temperatures, the C-NO(2) --> C-ONO rearrangement-homolysis pathway is kinetically unfavorable as compared to the other two pathways. The computational temperature analysis we have performed sheds light on the pathway that might lead to a TNT explosion and on the temperature in which it becomes exergonic. The results appear to correlate closely with the experimentally derived shock wave detonation time (100-200 fs) for which only the C-NO(2) homolysis pathway is kinetically accessible.

Selective bromination of perylene diimides under mild conditions.

A novel method for the bromination of perylene diimides, PDI (1), under mild conditions is reported. Variation of the reaction conditions allows mono- and dibromination of PDIs to afford 2 and 3 (these can be separated through standard procedures) or exclusive dibromination to afford 3. Pure 1,7 regioisomers are obtained through repetitive crystallization. The structure of 1,7-3b was elucidated by a single-crystal X-ray analysis. The facility of the bromination reaction, which decreases in the order 1a > 1b > 1c, depends on PDI aggregation propensities. Monobrominated PDIs were utilized for the syntheses of novel unsymmetrical piperidinyl (4a and 4b) and trimethylsilylethynyl derivatives (5a and 5b). Computational studies (DFT) on imide substituent rotation in PDIs reveal that in the case of bulky groups there is a restricted rotation leading to isomers, in agreement with our experimental results. An aromatic core twist in PDIs bearing one and two bromine substituents was also investigated by DFT.

Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Antidepressant treatments that achieve a higher remission rate than those currently available are urgently needed. The thyroid hormone triiodothyronine may potentiate antidepressant effects. OBJECTIVE: To determine the antidepressant efficacy and safety of liothyronine sodium (triiodothyronine) when administered concurrently with the selective serotonin reuptake inhibitor sertraline hydrochloride to patients with major depressive disorder. DESIGN: Double-blind, randomized, 8-week, placebo-controlled trial. SETTING: Outpatient referral centers. PATIENTS: A total of 124 adult outpatients meeting unmodified DSM-IV criteria for major depressive disorder without psychotic features. INTERVENTIONS: Patients were randomized to receive sertraline hydrochloride (50 mg/d for 1 week; 100 mg/d thereafter) plus liothyronine sodium (20-25 microg/d for 1 week; 40-50 microg/d thereafter) or sertraline plus placebo for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was categorical response to treatment (> or =50% decrease in scores on the 21-item Hamilton Rating Scale for Depression from baseline to study end point). Remission rate (final Hamilton Rating Scale for Depression score, < or =6) was a secondary outcome measure. RESULTS: Intent-to-treat Hamilton Rating Scale for Depression response rates were 70% and 50% in the sertraline-liothyronine and sertraline-placebo groups, respectively (P = .02; odds ratio, 2.93; 95% confidence interval, 1.23-7.35); remission rates were 58% with sertraline-liothyronine and 38% with sertraline-placebo (P = .02; odds ratio, 2.69; 95% confidence interval, 1.16-6.49). Baseline T(3) values were lower in patients treated with sertraline-liothyronine who had remissions than in those without remissions (t(48) = 3.36; P<.002). Among patients treated with sertraline-liothyronine, remission was associated with a significant decrease in serum thyrotropin values (F(1,73) = 4.00; P<.05). There were no significant effects of liothyronine supplementation on frequency of adverse effects. CONCLUSIONS: These results demonstrate enhancement of the antidepressant effect of sertraline by concurrent treatment with liothyronine without a significant increase in adverse effects. The antidepressant effect of liothyronine may be directly linked to thyroid function.

Palladium complexes of perylene diimides: strong fluorescence despite direct attachment of late transition metals to organic dyes.

We prepared the first sigma-bonded metal complexes of widely utilized organic dyes, perylene tetracarboxylic acid diimides (PDIs). These 1,7-dipalladium PDI complexes were synthesized by C-Br oxidative addition of 1,7-dibromo-N,N'-dicyclohexyl PDI (Br2PDI) to Pd(0) phosphine complexes bearing triphenylphosphine and bischelating 1,2-bis(diphenylphosphino)ethane (dppe). The structures of Pd-PDI complexes were elucidated by single-crystal X-ray analysis. Surprisingly, despite direct attachement of two late transition metal centers, Pd-PDI systems are highly fluorescent (Phi=0.65 and 0.22 for triphenylphosphine and dppe systems, respectively). This is rationalized in terms of weak electronic interactions between the metal centers and PDI pi-system, as revealed by TD-DFT calculations.

Single molecule electron transport junctions: charging and geometric effects on conductance.

A p-benzenedithiolate (BDT) molecule covalently bonded between two gold electrodes has become one of the model systems utilized for investigating molecular transport junctions. The plethora of papers published on the BDT system has led to varying conclusions with respect to both the mechanism and the magnitude of transport. Conductance variations have been attributed to difficulty in calculating charge transfer to the molecule, inability to locate the Fermi energy accurately, geometric dispersion, and stochastic switching. Here we compare results obtained using two transport codes, TRANSIESTA-C and HUCKEL-IV, to show that upon Au-S bond lengthening, the calculated low bias conductance initially increases by up to a factor of 30. This increase in highest occupied molecular orbital (HOMO) mediated conductance is attributed to charging of the terminal sulfur atom and a corresponding decrease in the energy gap between the Fermi level and the HOMO. Addition of a single Au atom to each terminal of the extended BDT molecule is shown to add four molecular states near the Fermi energy, which may explain the varying results reported in the literature.

The mechanism of aluminum-catalyzed Meerwein-Schmidt-Ponndorf-Verley reduction of carbonyls to alcohols.

The mechanistic details of the Meerwein-Schmidt-Ponndorf-Verley (MSPV) reduction of ketones to the corresponding alcohols were investigated both experimentally and computationally. Density functional theory (DFT) was used to assess the energetics of several proposed pathways (direct hydrogen transfer, hydridic, and radical). Our results demonstrate that a direct hydrogen transfer mechanism involving a concerted six-membered ring transition state is the most favorable pathway for all calculated systems starting from a small model system and concluding with the experimentally investigated BINOLate/Al/(i)PrOH/MePhC=O system. Experimental values for the activation parameters of acetophenone reduction using the BINOLate/Al/(i)PrOH system (DeltaG# = 21.8 kcal/mol, DeltaH# = 18.5 kcal/mol, DeltaS# = -11.7 au) were determined on the basis of kinetic investigation of the reaction and are in good agreement with the computational findings for this system. Calculated and experimental kinetic isotope effects support the concerted mechanism.

Aromatic vs aliphatic C-H bond activation by rhodium(I) as a function of agostic interactions: catalytic H/D exchange between olefins and methanol or water.

The aryl-PC type ligand 3, benzyl(di-tert-butyl)phosphane, reacts with [Rh(coe)(2)(solv)(n)()]BF(4) (coe = cyclooctene, solv = solvent), producing the C-H activated complexes 4a-c (solv = (a). acetone, (b). THF, (c). methanol). Complexes 4a-c undergo reversible arene C-H activation (observed by NMR spin saturation transfer experiments, SST) and H/D exchange into the hydride and aryl ortho-H with ROD (R = D, Me). They also promote catalytic H/D exchange into the vinylic C-H bond of olefins, with deuterated methanol or water utilized as D-donors. Unexpectedly, complex 2, based on the benzyl-PC type ligand 1 (analogous to 3), di-tert-butyl(2,4,6-trimethylbenzyl)phosphane, shows a very different reversible C-H activation pattern as observed by SST. It is not active in H/D exchange with ROD and in catalytic H/D exchange with olefins. To clarify our observations regarding C-H activation/reductive elimination in both PC-Rh systems, density functional theory (DFT) calculations were performed. Both nucleophilic (oxidative addition) and electrophilic (H/D exchange) C-H activation proceed through eta(2)-C,H agostic intermediates. In the aryl-PC system the agostic interaction causes C-H bond acidity sufficient for the H/D exchange with water or methanol, which is not the case in the benzyl PC-Rh system. In the latter system the C-H coordination pattern of the methyl controls the reversible C-H oxidative addition leading to energetically different C-H activation processes, in accordance with the experimental observations.

Metallacarbenes from diazoalkanes: an experimental and computational study of the reaction mechanism.

PCP ligand (1,3-bis-[(diisopropyl-phosphanyl)-methyl]-benzene), and PCN ligand ([3-[(di-tert-butyl-phosphanyl)-methyl]-benzyl]-diethyl-amine) based rhodium dinitrogen complexes (1 and 2, respectively) react with phenyl diazomethane at room temperature to give PCP and PCN-Rh carbene complexes (3 and 5, respectively). At low temperature (-70 degrees C), PCP and PCN phenyl diazomethane complexes (4 and 6, respectively) are formed upon addition of phenyl diazomethane to 1 and 2. In these complexes, the diazo moiety is eta(1) coordinated through the terminal nitrogen atom. Decomposition of complexes 4 and 6 at low temperatures leads only to a relatively small amount of the corresponding carbene complexes, the major products of decomposition being the dinitrogen complexes 1 and 2 and stilbene. This and competition experiments (decomposition of 6 in the presence of 1) suggests that phenyl diazomethane can dissociate under the reaction conditions and attack the metal center through the diazo carbon producing a eta(1)-C bound diazo complex. Computational studies based on a two-layer ONIOM model, using the mPW1K exchange-correlation functional and a variety of basis sets for PCP based systems, provide mechanistic insight. In the case of less bulky PCP ligand bearing H-substituents on the phosphines, a variety of mechanisms are possible, including both dissociative and nondissociative pathways. On the other hand, in the case of i-Pr substituents, the eta(1)-C bound diazo complex appears to be a critical intermediate for carbene complex formation, in good agreement with the experimental results. Our results and the analysis of reported data suggest that the outcome of the reaction between a diazoalkane and a late transition metal complex can be anticipated considering steric requirements relevant to eta(1)-C diazo complex formation.