Discrimination between Olfactory Receptor Agonists and Non‐agonists

A joint approach combining free‐energy calculations and calcium‐imaging assays on the broadly tuned human 1G1 olfactory receptor is reported. The free energy of binding of ten odorants was computed by means of molecular‐dynamics simulations. This state function allows separating the experimentally determined eight agonists from the two non‐agonists. This study constitutes a proof‐of‐principle for the computational deorphanization of olfactory receptors.     

Total Syntheses of 11-Acetoxy-4-deoxyasbestinin D, 4-Deoxyasbestinin C,Asbestinin-10, -20, -21 and -23

Six members of the asbestinin family of marine diterpene natural products have been synthesized in an efficient and stereoselective manner from a single oxa-bridged intermediate. Five of these natural products have not been synthesized previously and the structures of four of them have been confirmed as those proposed originally or following revisions to the original structures. The fifth natural product—asbestinin-21—has been shown to be a diastereomer of the compound that had been proposed previously.     

Discovery of Chemicals to Either Clear or Indicate Amyloid Aggregates by Targeting Memory‐Impairing Anti‐Parallel Aβ Dimers

Amyloid‐β (Aβ) oligomers are implicated in Alzheimer disease (AD). However, their unstable nature and heterogeneous state disrupts elucidation of their explicit role in AD progression, impeding the development of tools targeting soluble Aβ oligomers. Herein parallel and anti‐parallel variants of Aβ(1–40) dimers were designed and synthesized, and their pathogenic properties in AD models characterized. Anti‐parallel dimers induced cognitive impairments with increased amyloidogenesis and cytotoxicity, and this dimer was then used in a screening platform. Through screening, two FDA‐approved drugs, Oxytetracycline and Sunitinib, were identified to dissociate Aβ oligomers and plaques to monomers in 5XFAD transgenic mice. In addition, fluorescent Astrophloxine was shown to detect aggregated Aβ in brain tissue and cerebrospinal fluid samples of AD mice. This screening platform provides a stable and homogeneous environment for observing Aβ interactions with dimer‐specific molecules.     

Carbon–chalcogen bond formation initiated by [Al(NONDipp)(E)]− anions containing Al–E{16} (E{16} = S,Se) multiple bonds

Multiply-bonded main group metal compounds are of interest as a new class of reactive species able to activate and functionalize a wide range of substrates. The aluminium sulfido compound K[Al(NON^Dipp)(S)] (NON^Dipp = [O(SiMe₂NDipp)₂]²⁻, Dipp = 2,6-ⁱPr₂C₆H₃), completing the series of [Al(NON^Dipp)(E)]⁻ anions containing Al–E{16} multiple bonds (E{16} = O, S, Se, Te), was accessed via desulfurisation of K[Al(NON^Dipp)(S₄)] using triphenylphosphane. The crystal structure showed a tetrameric aggregate joined by multiple K⋯S and K⋯π(arene) interactions that were disrupted by the addition of 2.2.2-cryptand to form the separated ion pair, [K(2.2.2-crypt)][Al(NON^Dipp)(S)]. Analysis of the anion using density functional theory (DFT) confirmed multiple-bond character in the Al–S group. The reaction of the sulfido and selenido anions K[Al(NON^Dipp)(E)] (E = S, Se) with CO₂ afforded K[Al(NON^Dipp)(κ²E,O-EC{O}O)] containing the thio- and seleno-carbonate groups respectively, consistent with a [2 + 2]-cycloaddition reaction and C–E bond formation. An analogous cycloaddition reaction took place with benzophenone affording compounds containing the diphenylsulfido- and diphenylselenido-methanolate ligands, [κ²E,O-EC{O}Ph₂]²⁻. In contrast, when K[Al(NON^Dipp)(E)] (E = S, Se) was reacted with benzaldehyde, two equivalents of substrate were incorporated into the product accompanied by formation of a second C–E bond and complete cleavage of the Al–E{16} bonds. The products contained the hitherto unknown κ²O,O-thio- and κ²O,O-seleno-bis(phenylmethanolate) ligands, which were exclusively isolated as the cis-stereoisomers. The mechanisms of these cycloaddition reactions were investigated using DFT methods.

Reaction of Al–E (E = S, Se) multiple bonds with C O functionalities generates new C–E bonds.     

Metal‐Free Synthesis of Functional 1‐Substituted‐1,2,3‐Triazoles from Ethenesulfonyl Fluoride and Organic Azides

The boom in growth of 1,4‐disubstituted triazole products, in particular, since the early 2000’s, can be largely attributed to the birth of click chemistry and the discovery of the Cu^I‐catalyzed azide–alkyne cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit important, 1‐substituted‐1,2,3‐triazoles has been surprisingly more challenging. Reported here is a straightforward and scalable click‐inspired protocol for the synthesis of 1‐substituted‐1,2,3‐triazoles from organic azides and the bench stable acetylene surrogate ethenesulfonyl fluoride (ESF). The new transformation tolerates a wide selection of substrates and proceeds smoothly under metal‐free conditions to give the products in excellent yield. Under controlled acidic conditions, the 1‐substituted‐1,2,3‐triazole products undergo a Michael addition reaction with a second equivalent of ESF to give the unprecedented 1‐substituted triazolium sulfonyl fluoride salts.     

Design of Oligourea-Based Foldamers with Antibacterial and Antifungal Activities

There is an urgent need to develop new therapeutic strategies to fight the emergence of multidrug resistant bacteria. Many antimicrobial peptides (AMPs) have been identified and characterized, but clinical translation has been limited partly due to their structural instability and degradability in physiological environments. The use of unnatural backbones leading to foldamers can generate peptidomimetics with improved properties and conformational stability. We recently reported the successful design of urea-based eukaryotic cell-penetrating foldamers (CPFs). Since cell-penetrating peptides and AMPs generally share many common features, we prepared new sequences derived from CPFs by varying the distribution of histidine- and arginine-type residues at the surface of the oligourea helix, and evaluated their activity on both Gram-positive and Gram-negative bacteria as well as on fungi. In addition, we prepared and tested new amphiphilic block cofoldamers consisting of an oligourea and a peptide segment whereby polar and charged residues are located in the peptide segment and more hydrophobic residues in the oligourea segment. Several foldamer sequences were found to display potent antibacterial activities even in the presence of 50% serum. Importantly, we show that these urea-based foldamers also possess promising antifungal properties.     

Theoretical and empirical approaches to understanding the effect of phosphonate groups on the thermal degradation for two chemically modified PMMA

The influence of phosphonated groups on thermal degradation and flammability has been investigated in the case of two chemically modified PMMA. Thermogravimetric analysis as well as pyrolysis combustion flow calorimetry have been used to define the efficiency of phosphorus in both condensed and vapor phases. A theoretical study was also performed to determine the contribution of phosphonated groups to the effective heat of combustion, residue content and heat release capacity. Empirical and theoretical approaches agreed to highlight that PMMA modified with monophosphonated comonomer is more efficient in both condensed and vapor phases in terms of flammability and char formation. These results were attributed to the ability of phosphonate groups to interact with ester groups and also to the weakness of the P–C–N bonds. Moreover, this study proposes a method for designing the chemical environment of phosphonate group in polymers to achieve better flame retardancy.     

Ligand trans-effect: using an old concept as a novel approach to bis(dipolar) NLO-phores

In plane parallel arrangement and enhancement of NLO-activity are observed upon coordination of heteroditopic dipoles containing a phosphole ring on square-planar d8-palladium centre.