An Aldehyde Responsive,Cleavable Linker for Glucose Responsive Insulins

A glucose responsive insulin (GRI) that responds to changes in blood glucose concentrations has remained an elusive goal. Here we describe the development of glucose cleavable linkers based on hydrazone and thiazolidine structures. We developed linkers with low levels of spontaneous hydrolysis but increased level of hydrolysis with rising concentrations of glucose, which demonstrated their glucose responsiveness in vitro. Lipidated hydrazones and thiazolidines were conjugated to the LysB29 side-chain of HI by pH-controlled acylations providing GRIs with glucose responsiveness confirmed in vitro for thiazolidines. Clamp studies showed increased glucose infusion at hyperglycemic conditions for one GRI indicative of a true glucose response. The glucose responsive cleavable linker in these GRIs allow changes in glucose levels to drive the release of active insulin from a circulating depot. We have demonstrated an unprecedented, chemically responsive linker concept for biopharmaceuticals.     

DFT Study of the Molybdenum‐Catalyzed Deoxydehydration of Vicinal Diols

The mechanism of the molybdenum‐catalyzed deoxydehydration (DODH) of vicinal diols has been investigated using density functional theory. The proposed catalytic cycle involves condensation of the diol with an Mo^VI oxo complex, oxidative cleavage of the diol resulting in an Mo^IV complex, and extrusion of the alkene. We have compared the proposed pathway with several alternatives, and the results have been corroborated by comparison with the molybdenum‐catalyzed sulfoxide reduction recently published by Sanz et al. and with experimental observations for the DODH itself. Improved understanding of the mechanism should expedite future optimization of molybdenum‐catalyzed biomass transformations.     

Reduction of the Δ13-15-Keto Grouping of Prostaglandin Intermediates

In an attempt to gain further information on a stereo-structural model for activity of prostaglandins,² we undertook the synthesis of a number of new analogues.³ In particular, 17,17-dimethyl-F₂α was chosen as a good test of the “hairpin” conformation because the two 17-methyl groups would prevent side chain alignment in the particular sense of the “hairpin” model.⁴     

Insight into Oxide‐Bridged Heterobimetallic Al/Zr Olefin Polymerization Catalysts

Reaction of (TBBP)AlMe ? THF with [Cp*₂Zr(Me)OH] gave [(TBBP)Al(THF)?O?Zr(Me)Cp*₂] (TBBP=3,3’,5,5’‐tetra‐tBu‐2,2'‐biphenolato). Reaction of [DIPPnacnacAl(Me)?O?Zr(Me)Cp₂] with [PhMe₂NH]⁺[B(C₆F₅)₄]^? gave a cationic Al/Zr complex that could be structurally characterized as its THF adduct [(DIPPnacnac)Al(Me)?O?Zr(THF)Cp₂]⁺[B(C₆F₅)₄]^? (DIPPnacnac=HC[(Me)C=N(2,6‐iPr₂?C₆H₃)]₂). The first complex polymerizes ethene in the presence of an alkylaluminum scavenger but in the absence of methylalumoxane (MAO). The adduct cation is inactive under these conditions. Theoretical calculations show very high energy barriers (ΔG=40–47 kcal mol^?1) for ethene insertion with a bridged AlOZr catalyst. This is due to an unfavorable six‐membered‐ring transition state, in which the methyl group bridges the metal and ethene with an obtuse metal‐Me‐C angle that prevents synchronized bond‐breaking and making. A more‐likely pathway is dissociation of the Al‐O‐Zr complex into an aluminate and the active polymerization catalyst [Cp*₂ZrMe]⁺.     

Synthesis of 3,4-Dihydro-2H-Pyrroles from Ketones,Aldehydes, and Nitro Alkanes via Hydrogenative Cyclization

Syntheses of N-heterocyclic compounds that permit a flexible introduction of various substitution patterns by using inexpensive and diversely available starting materials are highly desirable. Easy to handle and reusable catalysts based on earth-abundant metals are especially attractive for these syntheses. We report here on the synthesis of 3,4-dihydro-2H-pyrroles via the hydrogenation and cyclization of nitro ketones. The latter are easily accessible from three components: a ketone, an aldehyde and a nitroalkane. Our reaction has a broad scope and 23 of the 33 products synthesized are compounds which have not yet been reported. The key to the general hydrogenation/cyclization reaction is a highly active, selective and reusable nickel catalyst, which was identified from a library of 24 earth-abundant metal catalysts.     

Quantitative Derivation of the Gross‐Pitaevskii Equation

Starting from first‐principle many‐body quantum dynamics, we show that the dynamics of Bose‐Einstein condensates can be approximated by the time‐dependent nonlinear Gross‐Pitaevskii equation, giving a bound on the rate of the convergence. Initial data are constructed on the bosonic Fock space applying an appropriate Bogoliubov transformation on a coherent state with expected number of particles N. The Bogoliubov transformation plays a crucial role; it produces the correct microscopic correlations among the particles. Our analysis shows that, on the level of the one‐particle reduced density, the form of the initial data is preserved by the many‐body evolution, up to a small error that vanishes as N^?1/2 in the limit of large N.© 2015 Wiley Periodicals, Inc.     

LC-MS/MS Analysis and Comparison of Oxidative Damages on Peptides Induced by Pathogen Reduction Technologies for Platelets

Pathogen reduction technologies (PRT) are photochemical processes that use a combination of photosensitizers and UV-light to inactivate pathogens in platelet concentrates (PCs), a blood-derived product used to prevent hemorrhage. However, different studies have questioned the impact of PRT on platelet function and transfusion efficacy, and several proteomic analyses revealed possible oxidative damages to proteins. The present work focused on the oxidative damages produced by the two main PRT on peptides. Model peptides containing residues prone to oxidation (tyrosine, histidine, tryptophane, and cysteine) were irradiated with a combination of amotosalen/UVA (Intercept process) or riboflavin/UVB (Mirasol-like process). Modifications were identified and quantified by liquid chromatography coupled to tandem mass spectrometry. Cysteine-containing peptides formed disulfide bridges (R-SS-R, ?2 Da; favored following amotosalen/UVA), sulfenic and sulfonic acids (R-SOH, +16 Da, R-SO₃H, +48 Da, favored following riboflavin/UVB) upon treatment and the other amino acids exhibited different oxidations revealed by mass shifts from +4 to +34 Da involving different mechanisms; no photoadducts were detected. These amino acids were not equally affected by the PRT and the combination riboflavin/UVB generated more oxidation than amotosalen/UVA. This work identifies the different types and sites of peptide oxidations under the photochemical treatments and demonstrates that the two PRT may behave differently. The potential impact on proteins and platelet functions may thus be PRT-dependent.

Atom‐Economic,Regiodivergent, and Stereoselective Coupling of Imidazole Derivatives with Terminal Allenes

New Rh‐ and Pd‐catalyzed regiodivergent and stereoselective intermolecular coupling reactions of imidazole derivatives with mono‐substituted allenes are herein reported. Using a Rh^I/Josiphos system, perfect regioselectivities and high enantiomeric excess were obtained, while a Pd^II/dppf system gave linear products with high regioselectivities and high E/Z selectivities. This method permits the atom economic synthesis of valuable branched and linear allylic imidazole derivatives.