Metal–Ligand Cooperation in H₂ Activation with Iron Complexes Bearing Hemilabile Bis(diphenylphosphino)amine Ligands

The octahedral transition-metal complex [(dppa)­Fe­(Ph₂P–N–PPh₂)₂] (<b>1</b>) [dppa = bis­(diphenylphosphino)­amine] with homofunctional bidentate ligands is described. The ligand exhibits hemilability due to its small bite angle and the steric repulsion of the coordinated donor groups. As the {Ph₂P–N–PPh₂}⁻ ligand can act as an internal base, heterolytic cleavage of dihydrogen by complex <b>1</b> leads to the formation of the hydride complex [(dppa)­(Ph₂P–N–PPh₂)­Fe­(H)­(κ¹-Ph₂P–NH–PPh₂)₂] (<b>2</b>), representing an example of cooperative bond activation with a homofunctional hemilabile ligand. This study demonstrates that hemilability of homofunctionalized ligands can be affected by careful adjustment of geometric parameters

A Novel Mechanism Is Involved in Cationic Lipid-Mediated Functional siRNA Delivery

A key challenge for therapeutic application of RNA interference is to efficiently deliver synthetic small interfering RNAs (siRNAs) into target cells that will lead to the knockdown of the target transcript (functional siRNA delivery). To facilitate rational development of nonviral carriers, we have investigated by imaging, pharmacological and genetic approaches the mechanisms by which a cationic lipid carrier mediates siRNA delivery into mammalian cells. We show that ∼95% of siRNA lipoplexes enter the cells through endocytosis and persist in endolysosomes for a prolonged period of time. However, inhibition of clathrin-, caveolin-, or lipid-raft-mediated endocytosis or macropinocytosis fails to inhibit the knockdown of the target transcript. In contrast, depletion of cholesterol from the plasma membrane has little effect on the cellular uptake of siRNA lipoplexes, but it abolishes the target transcript knockdown. Furthermore, functional siRNA delivery occurs within a few hours and is gradually inhibited by lowering temperatures. These results demonstrate that although endocytosis is responsible for the majority of cellular uptake of siRNA lipoplexes, a minor pathway, probably mediated by fusion between siRNA lipoplexes and the plasma membrane, is responsible for the functional siRNA delivery. Our findings suggest possible directions for improving functional siRNA delivery by cationic lipids

Manganese(I) Tricarbonyl Complexes with Bidentate Pyridine-Based Actor Ligands: Reversible Binding of CO₂ and Benzaldehyde via Cooperative C–C and Mn–O Bond Formation at Ambient Temperature

We report manganese(I) tricarbonyl complexes decorated with imino- and amino-pyridine ligands [Mn(impy)(CO)3Br] and [Mn(ampy)(CO)3Br], respectively. Both compounds can be transformed either via two-electron reduction for the former or double deprotonation for the latter into anionic species with a disturbed (“dearomatized”) π-electron system of the pyridine ring M[Mn(amidopy*)(CO)3] (M = alkali metal). The newly formed five-coordinated complex is anionic and encompasses a nucleophilic carbon center within its metalla cycle. This leads to noteworthy reactivity: [Mn(amidopy*)(CO)3]− readily reacts with CO double bonds. Specifically, CO2 and benzaldehyde can bind to the complex via a metal–ligand cooperative [1,3]-addition under C–C and Mn–O bond formation and concomitant rearomatization of the pyridine ring. Remarkably, we found that this addition is reversible. Exchange reactions using isotopically labeled 13CO2 indicate reversible C–C and Mn–O bond formation at ambient temperature. Likewise, bonded benzaldehyde is exchanged from the complex under a CO2 atmosphere. Density functional theory calculations suggest a significant role for the cationic counter ion in the bond activation reactions that can make this bond activation feasible

Manganese(I) Tricarbonyl Complexes with Bidentate Pyridine-Based Actor Ligands: Reversible Binding of CO₂ and Benzaldehyde via Cooperative C–C and Mn–O Bond Formation at Ambient Temperature

We report manganese(I) tricarbonyl complexes decorated with imino- and amino-pyridine ligands [Mn(impy)(CO)3Br] and [Mn(ampy)(CO)3Br], respectively. Both compounds can be transformed either via two-electron reduction for the former or double deprotonation for the latter into anionic species with a disturbed (“dearomatized”) π-electron system of the pyridine ring M[Mn(amidopy*)(CO)3] (M = alkali metal). The newly formed five-coordinated complex is anionic and encompasses a nucleophilic carbon center within its metalla cycle. This leads to noteworthy reactivity: [Mn(amidopy*)(CO)3]− readily reacts with CO double bonds. Specifically, CO2 and benzaldehyde can bind to the complex via a metal–ligand cooperative [1,3]-addition under C–C and Mn–O bond formation and concomitant rearomatization of the pyridine ring. Remarkably, we found that this addition is reversible. Exchange reactions using isotopically labeled 13CO2 indicate reversible C–C and Mn–O bond formation at ambient temperature. Likewise, bonded benzaldehyde is exchanged from the complex under a CO2 atmosphere. Density functional theory calculations suggest a significant role for the cationic counter ion in the bond activation reactions that can make this bond activation feasible

The biocompatibility of mesoporous silicates

Micro- and nano-mesoporous silicate particles are considered potential drug delivery systems because of their ordered pore structures, large surface areas and the ease with which they can be chemically modified. However, few cytotoxicity or biocompatibility studies have been reported, especially when silicates are administered in the quantities necessary to deliver low-potency drugs. The biocompatibility of mesoporous silicates of particle sizes similar to 150 nm, similar to 800 nm and similar to 4 mu m and pore sizes of 3 nm, 7 nm and 16 nm, respectively, is examined here. In vitro, mesoporous silicates showed a significant degree of toxicity at high concentrations with mesothelial cells. Following subcutaneous injection of silicates in rats, the amount of residual material decreased progressively over 3 months, with good biocompatibility on histology at all time points. In contrast, intra-peritoneal and intra-venous injections in mice resulted in death or euthanasia. No toxicity was seen with subcutaneous injection of the same particles in mice. Microscopic analysis of the lung tissue of the mice indicated that death may be due to thrombosis. Although local tissue reaction to mesoporous silicates was benign, they caused severe systemic toxicity. This toxicity might be mitigated by modification of the materials. (C) 2008 Elsevier Ltd. All rights reserved

Injectable in situ cross-linking hydrogels for local antifungal therapy

Invasive fungal infections can be devastating, particularly in immunocompromised patients, and difficult to treat with systemic drugs. Furthermore, systemic administration of those medications can have severe side effects. We have developed an injectable local antifungal treatment for direct administration into existing or potential sites of fungal infection. Amphotericin B (AmB), a hydrophobic, potent, and broad-spectrum antifungal agent, was rendered water-soluble by conjugation to a dextran-aldehyde polymer. The dextranaldehyde-AmB conjugate retained antifungal efficacy against Candida albicans. Mixing carboxymethylcellulose-hydrazide with dextran-aldehyde formed a gel that cross-linked in situ by formation of hydrazone bonds. The gel provided in vitro release of antifungal activity for 11 days. and contact with the gel killed Candida for three weeks. There was no apparent tissue toxicity in the murine peritoneum and the gel caused no adhesions. Gels produced by entrapment of a suspension of AmB in CMC-dextran without conjugation of drug to polymers did not release fungicidal activity, but did kill on contact Injectable systems of these types, containing soluble or insoluble drug formulations, could be useful for treatment of local antifungal infections, with or without concurrent systemic therapy. (C) 2009 Elsevier Ltd. All rights reserved

Automated ARGET ATRP Accelerates Catalyst Optimization for the Synthesis of Thiol-Functionalized Polymers

Conventional synthesis of polymers by ATRP is relatively low throughput, involving iterative optimization of conditions in an inert atmosphere. Automated, high-throughput controlled radical polymerization was developed to accelerate catalyst optimization and production of disulfide-functionalized polymers without the need of an inert gas. Using ARGET ATRP, polymerization conditions were rapidly identified for eight different monomers, including the first ARGET ATRP of 2-(diethylamino)­ethyl methacrylate and di­(ethylene glycol) methyl ether methacrylate. In addition, butyl acrylate, oligo­(ethylene glycol) methacrylate 300 and 475, 2-(dimethylamino)­ethyl methacrylate, styrene, and methyl methacrylate were polymerized using bis­(2-hydroxyethyl) disulfide bis­(2-bromo-2-methylpropionate) as the initiator, tris­(2-pyridylmethyl)­amine as the ligand, and tin­(II) 2-ethylhexanoate as the reducing agent. The catalyst and reducing agent concentration was optimized specifically for each monomer, and then a library of polymers was synthesized systematically using the optimized conditions. The disulfide-functionalized chains could be cleaved to two thiol-terminated chains upon exposure to dithiothreitol, which may have utility for the synthesis of polymer bioconjugates. Finally, we demonstrated that these new conditions translated perfectly to conventional batch polymerization. We believe the methods developed here may prove generally useful to accelerate the systematic optimization of a variety of chemical reactions and polymerizations

Selective Hydrogenation of Amides to Amines and Alcohols Catalyzed by Improved Iron Pincer Complexes

A comparative study on the synthesis, stability, and catalytic activity of various iron pincer complexes with the general formula [(R-PN^<i>H</i>P)­Fe­(H) (CO) (BH₄)] is reported, where R denotes the substituent of the terminal PR₂-groups (R = ^<i>t</i>Bu, Cy, ^<i>i</i>Pr, Ph, Et). By the example of the synthesized precatalysts, it is shown that the nature of the ligands has a surprising influence on the catalytic properties of the complexes. Bulky ligands and less electron donating ligands affect the stability of the complexes, which preferably react under the loss of CO or H₂ to deactivated products. In return, the reduced steric demand and the strong σ-donating properties of the Et-substituted precatalyst (<b>2a</b>) lead to an improved activity in the hydrogenation of esters to alcohols, compared to that of the previously reported ^<i>i</i>Pr-substituted complexes. The improved activity of complex <b>2a</b> is clearly demonstrated in the direct hydrogenation of amides to alcohols and amines under mild conditions

Photoswitchable Nanoparticles for Triggered Tissue Penetration and Drug Delivery

We report a novel nanoparticulate drug delivery system that undergoes reversible volume change from 150 to 40 nm upon phototriggering with UV light. The volume change of these monodisperse nanoparticles comprising spiropyran, which undergoes reversible photoisomerization, and PEGylated lipid enables repetitive dosing from a single administration and enhances tissue penetration. The photoswitching allows particles to fluoresce and release drugs inside cells when illuminated with UV light. The mechanism of the light-induced size switching and triggered-release is studied. These particles provide spatiotemporal control of drug release and enhanced tissue penetration, useful properties in many disease states including cancer

<i>In Vivo</i> Compatibility of Graphene Oxide with Differing Oxidation States

Graphene oxide (GO) is suggested to have great potential as a component of biomedical devices. Although this nanomaterial has been demonstrated to be cytocompatible <i>in vitro</i>, its compatibility <i>in vivo</i> in tissue sites relevant for biomedical device application is yet to be fully understood. Here, we evaluate the compatibility of GO with two different oxidation levels following implantation in subcutaneous and intraperitoneal tissue sites, which are of broad relevance for application to medical devices. We demonstrate GO to be moderately compatible <i>in vivo</i> in both tissue sites, with the inflammatory reaction in response to implantation consistent with a typical foreign body reaction. A reduction in the degree of GO oxidation results in faster immune cell infiltration, uptake, and clearance following both subcutaneous and peritoneal implantation. Future work toward surface modification or coating strategies could be useful to reduce the inflammatory response and improve compatibility of GO as a component of medical devices