Isothermal titration calorimetry of supramolecular polymers

A method to characterize the self-association of supramolecular polymers by isothermal titration calorimetry (ITC) has been designed. Association constants in the range 10(4)-10(6) dm(3) mol(-1) have been successfully determined from the heat exchange occurring when a supramolecular polymer solution is injected into a calorimetric cell containing pure solvent. Very good agreement with literature values has been obtained. Compared to other techniques (such as NMR or Fourier transform infrared spectroscopy), the use of ITC presents several advantages: (i) the enthalpy of association is obtained together with the association constant from the same experiment, (ii) the measurements can be performed in almost any solvent, and (iii) systems with higher association constants can be characterized.     

Redox-Switchable Behavior of Transition-Metal Complexes Supported by Amino-Decorated N-Heterocyclic Carbenes

The coordination chemistry of the N-heterocyclic carbene ligand IMes^(NMe2)2, derived from the well-known IMes ligand by substitution of the carbenic heterocycle with two dimethylamino groups, was investigated with d⁶ [Mn(I), Fe(II)], d⁸ [Rh(I)], and d¹⁰ [Cu(I)] transition-metal centers. The redox behavior of the resulting organometallic complexes was studied through a combined experimental/theoretical study, involving electrochemistry, EPR spectroscopy, and DFT calculations. While the complexes [CuCl(IMes^(NMe2)2)], [RhCl(COD)(IMes^(NMe2)2)], and [FeCp(CO)₂ (IMes^(NMe2)2)](BF₄) exhibit two oxidation waves, the first oxidation wave is fully reversible but only for the first complex the second oxidation wave is reversible. The mono-oxidation event for these complexes occurs on the NHC ligand, with a spin density mainly located on the diaminoethylene NHC-backbone, and has a dramatic effect on the donating properties of the NHC ligand. Conversely, as the Mn(I) center in the complex [MnCp(CO)₂ ((IMes^(NMe2)2)] is easily oxidizable, the latter complex is first oxidized on the metal center to form the corresponding cationic Mn(II) complex, and the NHC ligand is oxidized in a second reversible oxidation wave.     

Straightforward Access to a New Class of Dual DYRK1A/CLK1 Inhibitors Possessing a Simple Dihydroquinoline Core

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer’s disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.     

Characterization of New Specific Copper Chelators as Potential Drugs for the Treatment of Alzheimer’s Disease

The non‐controlled redox‐active metal ions, especially copper, in the brain of patients with Alzheimer disease (AD) should be considered at the origin of the intense oxidative damage in the AD brain. Several bis(8‐aminoquinoline) ligands, such as 1 and PA1637, are able to chelate Cu²⁺ with high affinity, and are specific chelators of copper with respect to iron and zinc. They are able to efficiently extract Cu²⁺ from a metal‐loaded amyloid. In addition, these tetradentate ligands are specific for the chelation of Cu²⁺ compared with Cu⁺. Consequently, the copper ion is easily released from the bis(8‐aminoquinoline) ligand under reductive conditions, and can be trapped again by a protein having some affinity for copper such as human serum albumin (HSA) proteins. In addition, the copper is not efficiently released from [Cu(CQ)₂] in reductive conditions. The catalytic production of H₂O₂ by [Cu²⁺‐Aβ_1?28]/ascorbate is inhibited in vitro by the bis(8‐aminoquinoline) 1 , suggesting that 1 should be able to play a protective role against oxidative damages induced by copper‐loaded amyloids.     

The case of the weak N-X bond: Ab initio, semi-experimental, and experimental equilibrium structures of XNO (X = H, F, Cl, OH) and FNO2

The equilibrium structures of FNO, ClNO, HONO, and FNO2 have been determined using three different, somewhat complementary methods: a completely experimental, a semi-experimental (where the equilibrium rotational constants are derived from the experimental effective ground-state rotational constants and an ab initio cubic force field), and an ab initio, where geometry optimizations are usually performed at the coupled cluster level of nonrelativistic electronic structure theory using small to very large Gaussian basis sets. For the sake of comparison, the equilibrium structures of HNO and N2O have also been redetermined, confirming and extending earlier results. The semi-experimental method gives structural parameters in good agreement with the reliable experimental results for each compound investigated. Because of inadequate treatment of electron correlation, the single-reference CCSD(T) method gives N-X (X[double bond]F, Cl, OH) bonds that are too strong and associate bond lengths that are significantly too short. The discrepancy increases with increase in the size of the basis set. A much more elaborate treatment of electron correlation at the CCSDTQ level solves this problem and results in increased bond lengths, correctly representing the weakness of the N-X bond in these XNO and XNO2 species. The equilibrium structures determined are accurate to better than 0.001 A and 0.1 degrees .     

Aqueous Ring‐Opening Polymerization‐Induced Self‐Assembly (ROPISA) of N‐Carboxyanhydrides

Reported here is the first aqueous ring‐opening polymerization (ROP) of N‐carboxyanhydrides (NCAs) using α‐amino‐poly(ethylene oxide) as a macroinitiator to protect the NCA monomers from hydrolysis through spontaneous in situ self‐assembly (ISA). This ROPISA process affords well‐defined amphiphilic diblock copolymers that simultaneously form original needle‐like nanoparticles.     

Preparative isolation of huperzines A and B from Huperzia serrata by displacement centrifugal partition chromatography

The pH-zone refining centrifugal partition chromatography technique was used to separate the two acetylcholinesterase inhibitors huperzines A and B from a crude alkaloid extract of the club moss Huperzia serrata. Complete co-elution of huperzines A and B was initially observed with the well-known methyl tert-butyl ether-acetonitrile-water (4:1:5, v/v/v) solvent system with triethylamine (8mM) as the displacer and methane sulfonic acid (6mM) as the retainer. An efficient biphasic system was designed on the basis of solvent association that provided selectivity in the elution mode: n-heptane/ethyl acetate/n-propanol/water (5:15:35:45, v/v/v/v). Lowering the bridge solvent content (n-propanol) of this system increased the polarity difference between the two phases thus adapting it to the pH-zone refining mode. Thus, the purification of these compounds was achieved using the biphasic system n-heptane/ethyl acetate/n-propanol/water (10:30:15:45, v/v/v/v) with triethylamine (8mM) as the displacer and methane sulfonic acid (6mM) as the retainer.     

Synthesis of a neamine dimer targeting the dimerization initiation site of HIV-1 RNA

A neamine dimer designed to bind to a specific sequence of HIV-1 RNA has been synthesized. Starting from neomycin B (1), a five-step synthesis efficiently provided a key protected neamine monomer 6 (28%). From the latter, coupling reactions with activated diacids gave dimers. After deprotection, a neamine dimer was obtained as the hexachlorohydrate salt 15 with 13% overall yield over nine steps.     

The Importance of 1,5-Oxygen⋅⋅⋅Chalcogen Interactions in Enantioselective Isochalcogenourea Catalysis

The importance of 1,5-O⋅⋅⋅chalcogen (Ch) interactions in isochalcogenourea catalysis (Ch=O, S, Se) is investigated. Conformational analyses of N-acyl isochalcogenouronium species and comparison with kinetic data demonstrate the significance of 1,5-O⋅⋅⋅Ch interactions in enantioselective catalysis. Importantly, the selenium analogue demonstrates enhanced rate and selectivity profiles across a range of reaction processes including nitronate conjugate addition and formal [4+2] cycloadditions. A gram-scale synthesis of the most active selenium analogue was developed using a previously unreported seleno-Hugerschoff reaction, allowing the challenging kinetic resolutions of tertiary alcohols to be performed at 500 ppm catalyst loading. Density functional theory (DFT) and natural bond orbital (NBO) calculations support the role of orbital delocalization (occurring by intramolecular chalcogen bonding) in determining the conformation, equilibrium population, and reactivity of N-acylated intermediates.