Anne-Caroline Chany

A Diverted Total Synthesis of Mycolactone Analogues: An Insight into Buruli Ulcer Toxins

Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structure-activity relationship based on cytopathic assays on L929 fibroblasts. The lowest concentration inducing a cytopathic effect was determined for selected analogues, allowing a clear picture to emerge by comparison with the natural toxins.

New Boryl Radicals Derived from N‐Heteroaryl Boranes: Generation and Reactivity

Recently, boryl radicals have been the subject of revived interest. These structures were generated by hydrogen-abstraction reactions from the corresponding boranes (i.e., from amine or phosphine boranes). However, the classical issue remains their high B--H bond-dissociation energy (BDE), thereby preventing a very efficient hydrogen-abstraction process. In the present paper, new N-heteroaryl boranes that exhibiting low B--H BDE are presented; excellent hydrogen-transfer properties have been found. Both the generation and the reactivity of the associated boryl radicals have been investigated through their direct observation in laser flash photolysis. The boryl radical interactions with double bonds, oxygen, oxidizing agent, and alkyl halides have been studied. Some selected applications of N-heteroaryl boryl radicals as new polymerization-initiating structures are proposed to evidence their high intrinsic reactivity.

Shaping mycolactone for therapeutic use against inflammatory disorders

A synthetic mycobacterial macrolide mycolactone decreases skin inflammation and inflammatory pain. Modifying microbial immunosuppressants Microbes have evolved an arsenal of methods to avoid host response, including decreasing inflammation. Now, Guenin-Macé et al. repurpose a compound with ulcerative, analgesic, and anti-inflammatory effects produced by Mycobacterium ulcerans—mycolactone—as an anti-inflammatory drug. They found a synthetic subunit of mycolactone that retained its immunosuppressive and analgesic activities but was less toxic in terms of ulcerative activity. This subunit suppressed chronic skin inflammation and inflammatory pain in an animal model with minimal side effects, and could serve as a new anti-inflammatory agent if these results hold true in humans. Inflammation adversely affects the health of millions of people worldwide, and there is an unmet medical need for better anti-inflammatory drugs. We evaluated the therapeutic interest of mycolactone, a polyketide-derived macrolide produced by Mycobacterium ulcerans. Bacterial production of mycolactone in human skin causes a combination of ulcerative, analgesic, and anti-inflammatory effects. Whereas ulcer formation is mediated by the proapoptotic activity of mycolactone on skin cells via hyperactivation of Wiskott-Aldrich syndrome proteins, analgesia results from neuronal hyperpolarization via signaling through angiotensin II type 2 receptors. Mycolactone also blunts the capacity of immune cells to produce inflammatory mediators by an independent mechanism of protein synthesis blockade. In an attempt to isolate the structural determinants of mycolactone’s immunosuppressive activity, we screened a library of synthetic subunits of mycolactone for inhibition of cytokine production by activated T cells. The minimal structure retaining immunosuppressive activity was a truncated version of mycolactone, missing one of the two core-branched polyketide chains. This compound inhibited the inflammatory cytokine responses of human primary cells at noncytotoxic doses and bound to angiotensin II type 2 receptors comparably to mycolactone in vitro. Notably, it was considerably less toxic than mycolactone in human primary dermal fibroblasts modeling ulcerative activity. In mouse models of human diseases, it conferred systemic protection against chronic skin inflammation and inflammatory pain, with no apparent side effects. In addition to establishing the anti-inflammatory potency of mycolactone in vivo, our study therefore highlights the translational potential of mycolactone core-derived structures as prospective immunosuppressants.

Synthetic variants of mycolactone bind and activate Wiskott-Aldrich syndrome proteins.

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.

On the Synthesis, Characterization and Reactivity of N-Heteroaryl–Boryl Radicals, a New Radical Class Based on Five-Membered Ring Ligands

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(sp(2) ) complexation site. These pyrazole-boranes and pyrazaboles exhibit a low bond dissociation energy (BDE; Buf8ffH) and accordingly excellent hydrogen transfer properties. Most importantly, a high modulation of the BDE(Buf8ffH) 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.

Total Syntheses of Mycolactone A/B and its Analogues for the Exploration of the Biology of Buruli Ulcer

Buruli ulcer, classified as a neglected tropical disease by the World Health Organization, is caused by a mycobacterium which secretes a macrolidic exotoxin called mycolactone A/B. In this article, several synthetic strategies for the preparation of this toxin are discussed, highlighting the importance of total synthesis for the exploration of biological mechanism underpinning relevant human diseases.

Chapter 4 – A Walk Across Africa with Captain Grant: Exploring Mycobacterium ulcerans Infection with Mycolactone Analogs

In this chapter are summarized a personal account of 9 years of research in the field of human Mycobacterium ulcerans infection, from both a chemical perspective and in close collaboration with biologists of the Institut Pasteur in Paris. This dramatic necrotizing skin disease affects mainly the African continent and is caused by an exotoxin called mycolactone A/B that is secreted by M. ulcerans. Thanks to modular synthetic strategies, we have forged a unique collection of mycolactone A/B analogs, including fluorescent ones that have been essential in the exploration of the biology of the disease. Fascinating discoveries were made during this odyssey, not only from both a chemical and biological standpoint but also from a more human perspective.