Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C-C Bond Cleavage Reactions.

The ability to control the activation of prodrugs by transition metals has been shown to have great potential for controlled drug release in cancer cells. However, the strategies developed so far promote the cleavage of C-O or C-N bonds, which limits the scope of drugs to only those that present amino or hydroxyl groups. Here, we report the decaging of an ortho-quinone prodrug, a propargylated ß-lapachone derivative, through a palladium-mediated C-C bond cleavage. The reaction's kinetic and mechanistic behavior was studied under biological conditions along with computer modeling. The results indicate that palladium (II) is the active species for the depropargylation reaction, activating the triple bond for nucleophilic attack by a water molecule before the C-C bond cleavage takes place. Palladium iodide nanoparticles were found to efficiently trigger the C-C bond cleavage reaction under biocompatible conditions. In drug activation assays in cells, the protected analogue of ß-lapachone was activated by nontoxic amounts of nanoparticles, which restored drug toxicity. The palladium-mediated ortho-quinone prodrug activation was further demonstrated in zebrafish tumor xenografts, which resulted in a significant anti-tumoral effect. This work expands the transition-metal-mediated bioorthogonal decaging toolbox to include cleavage of C-C bonds and payloads that were previously not accessible by conventional strategies.

Catalytic Antioxidant Activity of Bis-Aniline-Derived Diselenides as GPx Mimics.

Herein, we describe a simple and efficient route to access aniline-derived diselenides and evaluate their antioxidant/GPx-mimetic properties. The diselenides were obtained in good yields via ipso-substitution/reduction from the readily available 2-nitroaromatic halides (Cl, Br, I). These diselenides present GPx-mimetic properties, showing better antioxidant activity than the standard GPx-mimetic compounds, ebselen and diphenyl diselenide. DFT analysis demonstrated that the electronic properties of the substituents determine the charge delocalization and the partial charge on selenium, which correlate with the catalytic performances. The amino group concurs in the stabilization of the selenolate intermediate through a hydrogen bond with the selenium.

Mechanistic insights into transition metal-mediated bioorthogonal uncaging reactions.

Cleavage of C-O and C-N bonds mediated by transition metals is a promising bioorthogonal approach to rescue the activity of caged molecules, such as proteins and cytotoxic drugs, under biological conditions. However, the precise mechanism of such uncaging reactions remains elusive. This review provides mechanistic insights into metal-mediated bond-cleavage reactions, with the goals of understanding the main factors that influence the reaction and aiding the rational development of new caging groups/catalysts for chemical biology and drug-delivery applications.

Core-shell PdCu bimetallic colloidal nanoparticles in Sonogashira cross-coupling reaction: mechanistic insights into the catalyst mode of action.

Core-shell PdCu nanoparticles with different metal proportions were synthesized using a one-pot methodology and characterized by STEM, HRTEM, XANES and EXAFS analysis. The bimetallic nanoparticles were applied as catalysts in the Sonogashira cross-coupling reaction to investigate the mode of action of the PdCu in the reaction. The copper content directly influenced the generation of the cross-coupling product, shaping the performance of the catalyst. A quasi-homogeneous reaction pathway was evidenced by kinetics and poisoning experiments as well as XAS, HRTEM and HRMS analysis. These findings help to elucidate the mode of action of the PdCu nanocatalysts in the, as yet, unrevealed Sonogashira mechanism and the potential development of new nanocatalysts.

Palladium Catalyst with Task-Specific Ionic Liquid Ligands: Intracellular Reactions and Mitochondrial Imaging with Benzothiadiazole Derivatives.

A water-soluble and charge-tagged palladium complex (PdMAI) was found to function inside breast cancer live cells of the MCF-7 lineage as an efficient catalyst for cross-coupling reaction. PdMAI, bearing two ionophilic task-specific ionic liquids as ligands, efficiently catalyzed both in cellulo Suzuki and Buchwald-Hartwig amination reactions. For the first time, therefore, the Buchwald-Hartwig amination is described to occur inside the highly complex cellular environment. The 2,1,3-benzothiadiazole (BTD) core was used as the base for the syntheses, and two π-extended fluorescent derivatives (BTD-2APy) and (BTD-1AN), which were found to emit in the green and red channels, had impressive mitochondrial affinity. These chromophores allowed for selective mitochondrial imaging and tracking.

Theoretical and Experimental Investigation of Acidity of the Glutamate Receptor Antagonist 6,7-Dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding.

The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pKa values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV-vis spectroscopy. The experimental pKa of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by 1H NMR analysis. Five computational methods were applied for estimating the theoretical pKa values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pKa associated with DNQX. Molecular dynamics studies have demonstrated that DNQXA1' binds more effectively to the pocket of the GluA2 than neutral DNQX, and this fact is coherent to the interactions between amidic oxygens and Arg845 being the main interactions of this host-guest system. Moreover, interaction of GluA2 with endogenous glutamate is stronger than that with DNQXA1, which is in agreement with literature. To the best of our knowledge, we report herein an unprecedented approach involving acidity of the antagonist DNQX, as well as the possible implications in binding to GluA2.

Kinetic investigation into the chemoselective hydrogenation of α,ß-unsaturated carbonyl compounds catalyzed by Ni(0) nanoparticles.

A series of Ni(0) nanocatalysts was prepared from a Ni(COD)2 complex in the presence of different stabilizers (hexadecylamine, polyvinylpyrrolidone (PVP), PVP/triphenylphosphine, octanoic acid and stearic acid) for their evaluation in the selective hydrogenation reaction of α,ß-unsaturated carbonyl compounds by H2 under mild reaction conditions, i.e., low H2 pressure, temperature and catalyst loading. All nanocatalysts were active in reducing only the C[double bond, length as m-dash]C bond and this chemoselectivity was attributed to the reduced nature of the Ni-NPs surface. Moreover, the hydrogenation reaction rate appeared to be sensitive to ligand type, with the carboxylic acid-stabilized systems showing the best performances. A full kinetic investigation into the t-chalcone chemoselective reduction of the C[double bond, length as m-dash]C bond, with the best catalyst (Ni-octanoic acid) revealed that the rate-determining step is the hydrogenation of the adsorbed substrate on the NPs surface, following a Horiuti-Polanyi type of mechanism. Regarding sustainable chemistry concerns, the best catalyst could be reused up to 10 times without significant loss of activity.

Synthesis of silver glyconanoparticles from new sugar-based amphiphiles and their catalytic application.

Oligosaccharide-based amphiphiles were readily prepared by click chemistry from ω-azido-hexanoic or dodecanoic acids with propargyl-functionalized maltoheptaose or xyloglucanoligosaccharides. These amphiphilic compounds were used as capping/stabilizer agents in order to obtain highly stable catalytic silver glyconanoparticles (Ag-GNPs) through the in situ reduction of silver nitrate with NaBH4. With a view to long-term storage, the stabilization was optimized using a multivariate approach, and the nanoparticles were characterized by UV-vis, TEM, SAXS, and DLS. In order to explore the functionality of the Ag-GNPs in catalysis, a full kinetic analysis of the reduction of p-nitrophenol by NaBH4 in water and in water/ethanol mixtures was performed under semi-heterogeneous and quasi-homogeneous conditions. A pseudomonomolecular surface reaction was performed, and the kinetic data obtained were treated according to the Langmuir model. The Ag-GNPs were very active, and both substrates adsorbed onto the surface of the nanoparticles. For comparison purposes, the reaction was also performed in the presence of silver-sodium dodecanoate nanoparticles, which showed catalytic activity similar to that of the glyconanoparticles, supporting the choice of the carboxyl group as the stabilizing agent, although it provided much lower temporal stability. Finally, by combining kinetic and water/ethanol surface tension data it was possible to observe the effect of the addition of the less polar solvent (ethanol) to the reaction medium.

Second-coordination-sphere effects increase the catalytic efficiency of an extended model for Fe(III)M(II) purple acid phosphatases.

Herein we describe the synthesis of a new heterodinuclear Fe(III)Cu(II) model complex for the active site of purple acid phosphatases and its binding to a polyamine chain, a model for the amino acid residues around the active site. The properties of these systems and their catalytic activity in the hydrolysis of bis(2,4-dinitrophenyl)phosphate are compared, and conclusions regarding the effects of the second coordination sphere are drawn. The positive effect of the polymeric chain on DNA hydrolysis is also described and discussed.

Properties of aqueous solutions of hydrophobically modified polyethylene imines in the absence and presence of sodium dodecylsulfate.

Four modified hyperbranched polyethylene imines (PEIs) were synthesized by means of the alkylation of PEI. SAXS, viscosity, surface tension, and pyrene fluorescence emission were then used as techniques to examine the conformation and aggregation of the modified PEIs in aqueous solution, in the absence and presence of sodium dodecylsulfate (SDS). Analysis of the SAXS data showed that the radius of gyration decreases with an increase in the alkyl chain length of the polymer, while the viscosity data indicated a decrease in the intrinsic viscosity under the same conditions. The nonmodified PEI was not surface active, while the hydrophobically modified samples showed pronounced surface activity and the presence of hydrophobic domains. On addition of SDS, the onset of the formation of polymer-surfactant complexes was determined, indicating a decrease in the critical aggregate concentration with an increase in the alkyl chain length of the polymer backbone.

Development of catalytically active silver colloid nanoparticles stabilized by dextran.

Colloidal silver nanoparticles (Ag-NPs) with a mean diameter of 6.1 nm and a narrow size distribution were prepared by reduction of the correspondent metal salt with injection of NaBH(4), in the presence of dextran, and characterized by UV-vis, TEM, and DLS. The concentration of all reactants involved in the formation of the nanoparticles was optimized with the use of a new multivariate method, which revealed a significant reduction in the number of experiments when compared with the vast majority of univariate methods described in the literature. The Ag-NPs-dextran composite was able to efficiently catalyze the p-nitrophenol reduction in water by NaBH(4) with a rate constant normalized to the surface area of the nanoparticles per unit volume (k(1)) of 1.41 s(-1) m(-2) L, which is higher than values ever reported for Ag-NPs catalytic systems.

Formation of catalytic silver nanoparticles supported on branched polyethyleneimine derivatives.

A new and straightforward method for screening highly catalytically active silver nanoparticle-polymer composites derived from branched polyethyleneimine (PEI) is reported. The one-step systematic derivatization of the PEI scaffold with alkyl (butyl or octyl) and ethanolic groups led to a structural diversity correlated to the stabilization of silver nanoparticles and catalysis. Analysis of PEI derivative libraries identified a silver nanoparticle-polymer composite that was able to efficiently catalyze the p-nitrophenol reduction by NaBH(4) in water with a rate constant normalized to the surface area of the nanoparticles per unit volume (k(1)) of 0.57 s(-1) m(-2) L. Carried out in the presence of excess NaBH(4), the catalytic reaction was observed to follow pseudo-first-order kinetics and the apparent rate constant was linearly dependent on the total surface area of the silver nanoparticles (Ag-NPs), indicating that catalysis takes place on the surface of the nanoparticles. All reaction kinetics presented induction periods, which were dependent on the concentration of substrates, the total surface of the nanoparticles, and the polymer composition. All data indicated that this induction time is related to the resistance to substrate diffusion through the polymer support. Hydrophobic effects are also assumed to play an important role in the catalysis, through an increase in the local substrate concentration.

Synthesis and characterization of Pt0 nanoparticles in imidazolium ionic liquids.

The controlled decomposition of Pt2(dba)3 (dba = dibenzylideneacetone) dispersed in 1-n-butyl-3-methylimidazolium tetrafluoroborate (BMI.BF4) and hexafluorophosphate (BMI.PF6) ionic liquids in the presence of cyclohexene by molecular hydrogen produces Pt0 nanoparticles. The formation of these nanoparticles follows the two-step [A --> B, A + B --> 2B (k1, k2)] autocatalytic mechanism. The catalytic activity in the hydrogenation of cyclohexene is influenced by the nature of the anion rather than the mean-diameter of the nanoparticles. Thus, higher catalytic activity was obtained with Pt0 dispersed in BMI.BF4 containing the less coordinating anion although these nanoparticles possess a larger mean diameter (3.4 nm) than those obtained in BMI.PF6 (2.3 nm). Similar mean diameter values were estimated from in situ XRD and SAXS. XPS analyses clearly show the interactions of the ionic liquid with the metal surface demonstrating the formation of an ionic liquid protective layer surrounding the platinum nanoparticles. SAXS analysis indicated the formation of a semi-organized ionic liquid layer surrounding the metal particles with an extended molecular length of around 2.8 nm in BMI.BF4 and 3.3 nm in BMI.PF6.

Reaction of bis(2,4-dinitrophenyl) phosphate with hydrazine and hydrogen peroxide. Comparison of O- and N- phosphorylation.

Nonionic hydrazine reacts with anionic bis(2,4-dinitrophenyl) phosphate (BDNPP), giving 2,4-dinitrophenyl hydrazine and dianionic 2,4-dinitrophenyl phosphate by an S(N)2(Ar) reaction, and at the phosphoryl center, giving 2,4-dinitrophenoxide ion and a transient phosphorylated hydrazine that rearranges intramolecularly to N-(2,4-dinitrophenyl)-N-phosphonohydrazine. Approximately 58% of the reaction at pD = 10 occurs by N-phosphorylation, as shown by (31)P NMR spectroscopy. Reaction of HO(2)(-) is wholly at phosphorus, and the intermediate peroxophosphate reacts intramolecularly, displacing a second 2,4-dinitrophenoxide ion, or with H(2)O(2), giving 2,4-dinitrophenyl phosphate and O(2). Rate constants of O- and N-phosphorylation in reactions at phosphorus of NH(2)NH(2), HO(2)(-), and NH(2)OH and its methyl derivatives follow Bronsted relationships with similar slopes, but plots differ for oxygen and nitrogen nucleophiles. The reaction with NH(2)NH(2) has been probed by using both NMR spectroscopy and electrospray ionization mass and tandem mass spectrometry, with the novel interception of key reaction intermediates in the course of reaction.

Mechanisms of nucleophilic substitution reactions of methylated hydroxylamines with bis(2,4-dinitrophenyl)phosphate. Mass spectrometric identification of key intermediates.

Mono- and dimethylation of hydroxylamine on nitrogen does not significantly affect rates of initial attack of NHMeOH and NMe(2)OH on bis(2,4-dinitrophenyl)phosphate (BDNPP), which is largely by oxygen phosphorylation. O-Methylation, however, blocks this reaction and NH(2)OMe then slowly reacts with BDNPP via N-attack at phosphorus and at the aryl group. With NHMeOH, the initial product of O-attack at phosphorus reacts further, either by reaction with a second NHMeOH or by a spontaneous shift of NHMe to the aryl group via a transient cyclic intermediate. There is a minor N-attack of NHMeOH on BDNPP in an S(N)2(Ar) reaction. Reactions occurring via N-attack are blocked by N-dimethylation, and reaction of NMe(2)OH with BDNPP occurs via O-attack, generating a long-lived product. Reaction mechanisms have been probed, and intermediates identified, by using both NMR and MS spectroscopy, with the novel interception of key reaction intermediates in the course of reaction by electrospray ionization mass and tandem mass spectrometry.

Reactions of bis(2,4-dinitrophenyl) phosphate with hydroxylamine.

For dephosphorylation of bis(2,4-dinitrophenyl) phosphate (BDNPP) by hydroxylamine in water, pH region 4-12, the observed first-order rate constant, k(obs), initially increases as a function of pH, but is pH-independent between pH 7.2 and pH 10. The initial BDNPP cleavage by nonionic NH(2)OH (<0.2 M) involves attack by the OH group and follows first-order kinetics, but the overall initial reaction of BDNPP liberates ca. 1.7 mol of 2,4-dinitrophenoxide ion (DNP). This initial reaction generates a short-lived O-phosphorylated hydroxylamine, 2, followed by three possible reactions: (1) reaction of 2 with hydroxylamine, generating 2,4-dinitrophenyl phosphate (DNPP, 3), which subsequently forms DNP; (2) intramolecular displacement of the second DNP group and rapid decomposition of the cyclic intermediate to form phosphonohydroxylamine and eventually inorganic phosphate; (3) a novel rearrangement with intramolecular aromatic nucleophilic substitution involving a cyclic intermediate and migration of the 2,4-dinitrophenyl group from O to N. Values of k(obs) increase modestly with pH > 10, the reaction is biphasic, and the yield of DNP increases. An increase in [NH(2)OH] also increases the yield of DNP, due largely to accelerated hydrolysis of DNPP.