2014-01- Synthetic Variants of Mycolactone Bind and Activate Wiskott-Aldrich Syndrome Proteins
Chany, A.-C.; Veyron-Churlet, R.; Tresse, C.; Mayau, V.; Casarotto, V.; Le Chevalier, F.; Guenin-Macé, L.; Demangel, C.; Blanchard, N. J. Med. Chem.2014, 57, 7382–7395.
Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of skin lesions called Buruli ulcers. Mycolactone-mediated activation of neural (N) Wiskott–Aldrich syndrome proteins (WASP) induces defects in cell adhesion underpinning cytotoxicity and disease pathogenesis. We describe the chemical synthesis of 23 novel mycolactone analogues that differ in structure and modular assembly of the lactone core with its northern and southern polyketide side chains. The lactone core linked to southern chain was the minimal structure binding N-WASP and hematopoietic homolog WASP, where the number and configuration of hydroxyl groups on the acyl side chain impacted the degree of binding. A fluorescent derivative of this compound showed time-dependent accumulation in target cells. Furthermore, a simplified version of mycolactone mimicked the natural toxin for activation of WASP in vitro and induced comparable alterations of epithelial cell adhesion. Therefore, it constitutes a structural and functional surrogate of mycolactone for WASP/N-WASP-dependent effects.
In the last year, a new strategy for the synthesis of organonitriles, whether aliphatic or aromatic, has emerged based on the direct carbon–carbon double or triple bond cleavage of alkenyl or alkynyl precursors. This Highlight mainly focuses on the efforts made, often nearly simultaneously, by three research teams that shaped the implementation of this new paradigm, which should be of great value for the synthetic community facing the ever-growing demand for new organonitriles, especially in medicinal chemistry.
This is not breaking news: copper acetylides, readily available polymeric rock-stable solids, have been known for more than a century to be unreactive species and piteous nucleophiles. This lack of reactivity actually makes them ideal alkyne transfer reagents that can be easily activated under mild oxidizing conditions. When treated with molecular oxygen in the presence of simple chelating nitrogen ligands such as TMEDA, phenanthroline or imidazole derivatives, they are smoothly oxidized to highly electrophilic species that formally behave like acetylenic carbocations and can therefore be used for the mild and practical alkynylation of a wide range of nitrogen, phosphorus and carbon nucleophiles.
Two practical and complementary methods are reported for the synthesis of trifluoromethylated alkynes. The first one, a mix-and-stir process, is based on the oxidative trifluoromethylation of readily available and bench-stable copper acetylides while the second one, which displays a broad substrate scope and has several advantages over existing procedures, is based on the oxidative copper-catalyzed direct trifluoromethylation of terminal alkynes. Both reactions provide user-friendly processes for the synthesis of trifluoromethylated acetylenes which can be easily obtained from readily available starting materials.
The synthesis and physical characterization of a new class of N-heterocycle–boryl radicals is presented, based on five membered ring ligands with a N(sp2) complexation site. These pyrazole–boranes and pyrazaboles exhibit a low bond dissociation energy (BDE; BH) and accordingly excellent hydrogen transfer properties. Most importantly, a high modulation of the BDE(BH) by the fine tuning of the N-heterocyclic ligand was obtained in this series and could be correlated with the spin density on the boron atom of the corresponding radical. The reactivity of the latter for small molecule chemistry has been studied through the determination of several reaction rate constants corresponding to addition to alkenes and alkynes, addition to O2, oxidation by iodonium salts and halogen abstraction from alkyl halides. Two selected applications of N-heterocycle–boryl radicals are also proposed herein, for radical polymerization and for radical dehalogenation reactions.
Buruli ulcer is a tropical skin disease due to a mycobacteria called Mycobacterium ulcerans. The fi rst clinical description of this infection can be traced back to 1948 but it’s only in 1999 that the sole pathogenic agent of this disease was discovered and named mycolactone A/B. This article traces the main discoveries associated with this disease and shows the importance of natural products total syntheses for the understanding of the in vivo and in vitro mechanisms of action.
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H) and accordingly excellent hydrogen transfer properties. Most importantly, a high modulation of the BDE(B
