[2.2]Paracyclophane-based coumarins: effective organo-photocatalysts for light-induced desulfonylation processes.

Herein, we demonstrate for the first time that coumarins derived from [2.2]paracyclophane (pCp) can act as effective organo-photocatalysts and promote the reductive cleavage of sulfonamides under light-irradiation. In the presence of these original compounds, photodesulfonylation reactions occur under mild conditions at low catalyst loadings in the presence of Hantzsch ester.

The HIV-1 maturation inhibitor, EP39, interferes with the dynamic helix-coil equilibrium of the CA-SP1 junction of Gag.

During the maturation of HIV-1 particle, the Gag polyprotein is cleaved into several proteins by the HIV-1 protease. These proteins rearrange to form infectious virus particles. In this study, the solution structure and dynamics of a monomeric mutated domain encompassing the C-terminal of capsid, the spacer peptide SP1 and the nucleocapsid from Gag was characterized by Nuclear Magnetic Resonance in the presence of maturation inhibitor EP39, a more hydro-soluble derivative of BVM.

Diastereoselective Ring Homologation of Bicyclic Hydrazines: Access to -1,3-Diaminocyclohexitols.

A sequence of oxidative cleavage/double nitroaldol condensation followed by a few simple synthetic transformations can lead to polyhydroxylated di- and triaminocyclohexanes from a readily available bicyclic hydrazine. This new synthetic route provides a simple and general access to densely substituted privileged scaffolds or fragments with a perfect control of their relative configuration.

Highly Enantioselective Asymmetric Transfer Hydrogenation: A Practical and Scalable Method To Efficiently Access Planar Chiral [2.2]Paracyclophanes.

We report herein a general, practical method based on asymmetric transfer hydrogenation (ATH) to control the planar chirality of a range of substituted [2.2]paracyclophanes (pCps). Our strategy enabled us to perform both the kinetic resolution (KR) of racemic compounds and the desymmetrization of centrosymmetric meso derivatives on synthetically useful scales.

Insight into the mechanism of action of EP-39, a bevirimat derivative that inhibits HIV-1 maturation.

Maturation of human immunodeficiency virus type 1 (HIV-1) particles is a key step for viral infectivity. This process can be blocked using maturation inhibitors (MIs) that affect the cleavage of the capsid-spacer peptide 1 (CA-SP1) junction. Here, we investigated the mechanisms underlying the activity of EP-39, a bevirimat (BVM) derivative with better hydrosolubility.

3D Coumarin Systems Based on [2.2]Paracyclophane: Synthesis, Spectroscopic Characterization, and Chiroptical Properties.

In this article, we report the preparation of a series of [2.2]paracyclophane-fused coumarin systems through a simple and general procedure involving a transition-metal-catalyzed cyclization of aryl alkynoates as the key step. We also highlight the influence of the [2.

Use of a redox probe for an electrochemical RNA-ligand binding assay in microliter droplets.

In this work, we report an affordable, sensitive, fast and user-friendly electroanalytical method for monitoring the binding between unlabeled RNA and small compounds in microliter-size droplets using a redox-probe and disposable miniaturized screen-printed electrochemical cells.

Rhodium(II)-Alkynyl Carbenoids Insertion into Si-H bonds: An Entry to Propargylic Geminal Bis(silanes).

α-Alkynyl-α'-trimethylsilylhydrazones are used as novel Rh(II)-carbenoids precursors. These new carbenoids have shown very good reactivity in Si-H insertion reactions, leading to original propargylic geminal-bis(silanes) in a two-step sequential process.

The reaction of dimethylalkynylaluminum reagents with trimethylsilyldiazomethane: original reactivity leading to new α-silylated alkynyl hydrazones.

Trimethylsilyl (TMS) diazomethane does not react as a homologating reagent but as a C-electrophilic species with dimethylalkynylaluminum reagents. This unprecedented reactivity enables a simple access to unusual α-silylated alkynyl hydrazones.

Modular access to N-substituted cis-3,5-diaminopiperidines.

A sequence of oxidative cleavage/reductive amination/hydrogenolysis enables the preparation of N-substituted cis-3,5-diaminopiperidines from a readily available bicyclic hydrazine. This new synthetic route provides a simple and general access to RNA-friendly fragments with a good chemical diversity.

Carbene-mediated functionalization of the anomeric C-H bond of carbohydrates: scope and limitations.

Herein we investigate the scope and limitations of a new synthetic approach towards α- and β-ketopyranosides relying on the functionalization of the anomeric C-H bond of carbohydrates by insertion of a metal carbene. A key bromoacetate grafted at the 2-position is the cornerstone of a stereoselective glycosylation/diazotransfer/quaternarization sequence that makes possible the construction of a quaternary center with complete control of the stereochemistry. This sequence shows a good tolerance toward protecting groups commonly used in carbohydrate chemistry and gives rise to quaternary disaccharides with good efficiency.

Synthesis and biological evaluation of a new derivative of bevirimat that targets the Gag CA-SP1 cleavage site.

Bevirimat (2), the first-in-class HIV-1 maturation inhibitor, shows a low efficacy due essentially to the natural polymorphism of its target, the CA-SP1 junction. Moreover, its low hydrosolubility makes it difficult to study its interaction with the CA-SP1 junction. We have synthesized new derivatives of bevirimat by adding different hydrophilic substituents at the C-28 position to improve their hydrosolubility and perform the structural study of a complex by NMR.

Characterization of a novel type of HIV-1 particle assembly inhibitor using a quantitative luciferase-Vpr packaging-based assay.

The HIV-1 auxiliary protein Vpr and Vpr-fusion proteins can be copackaged with Gag precursor (Pr55Gag) into virions or membrane-enveloped virus-like particles (VLP). Taking advantage of this property, we developed a simple and sensitive method to evaluate potential inhibitors of HIV-1 assembly in a living cell system. Two proteins were coexpressed in recombinant baculovirus-infected Sf9 cells, Pr55Gag, which formed the VLP backbone, and luciferase fused to the N-terminus of Vpr (LucVpr).

Rh(II) carbene-promoted activation of the anomeric C-H bond of carbohydrates: a stereospecific entry toward α- and β-ketopyranosides.

In this communication we report a new strategy toward ketopyranosides based on a carbene-mediated activation of the anomeric C-H bond of carbohydrates. By forming a new carbon-carbon bond after a glycosylation step, this approach enables the preparation of both α- and β-ketopyranosides from advanced precursors.

Diastereoselective alkynylation of N-p-tolylsulfinylimines with aluminum acetylides.

The addition of alkynyl dimethyl aluminum compounds onto N-p-tolylsulfinylimines was investigated. The reaction was proved to be totally regioselective, leading to propargylamines with high diastereoselectivity (up to 99% de). Addition of aluminum derivatives gave a reversal of diastereoselectivity compared to the addition reaction of lithium acetylide.

Asymmetric alpha-alkynylation of piperidine via N-sulfinyliminium salts.

Piperidine was stereoselectively alpha-alkynylated in a four-step sequence made up of transformation to a chiral nonracemic N-sulfinylpiperidine, anodic oxidation to N-sulfinyliminium ion equivalent, alkynylation through addition of a mixed organoaluminum derivative, and final acidic deprotection of the sulfoxide. Overall yields are around 50%, and the diastereoselectivity of the nucleophilc addition was between 92 and 99% de, allowing isolation of the final product with 99% enantiomeric purity.

Partial protection against Botulinum B neurotoxin-induced blocking of exocytosis by a potent inhibitor of its metallopeptidase activity.

Clostridium botulinum neurotoxins (BoNTs) cause botulism, which is characterized by a flaccid paralysis, through inhibition of acetylcholine release by peripheral cholinergic nerve terminals. This is due to the zinc metallopeptidase activity of the neurotoxin, cleaving one component (synaptobrevin for BoNT/B) of the exocytosis machinery. Yet, there are no specific agents able to control the peptidase-related effects of BoNT/B.

Small tripeptide surrogates with low nanomolar affinity as potent inhibitors of the botulinum neurotoxin B metallo-proteolytic activity.

Botulinum neurotoxin type B is a high-weight (150 kDa) protein produced by the anaerobic bacillus Clostridium botulinum. This metallo-protease neurotoxin cleaves synaptobrevin, a protein, which is crucial to neurotransmission, resulting in the muscle paralysis, which characterizes botulism. Inhibition of the metallo-peptidase activity is a possible approach to obtain specific therapeutics to treat botulism.

Development of potent inhibitors of botulinum neurotoxin type B.

Botulinum neurotoxins are the most potent toxins known to date. They are zinc-metalloproteases able to cleave selectively an essential component of neurotransmitter exocytosis, causing the syndrome of botulism characterized by a flaccid paralysis. There is a great interest in designing antagonists of the action of these toxins.

Thio-derived disulfides as potent inhibitors of botulinum neurotoxin type B: implications for zinc interaction.

Botulinum neurotoxin type B causes the inhibition of acetylcholine release at the neuromuscular junction resulting in a flaccid paralysis designated botulism. This occurs through the cleavage of synaptobrevin, an intracellular critical component of neurotransmitter exocytosis, by the zinc-metallopeptidase activity of the smallest subunit of the toxin. Blocking the proteolytic activity may present an attractive approach to treat botulism as to date there is no efficient specific drug therapy available.

Pain-suppressive effects on various nociceptive stimuli (thermal, chemical, electrical and inflammatory) of the first orally active enkephalin-metabolizing enzyme inhibitor RB 120.

RB 101 (N-((R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxopr opyl)-L-phenylalanine benzyl ester) is a full inhibitor of the enkephalin-catabolizing enzymes, which induces strong naloxone-reversible antinociceptive responses after i.v. or i.