MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition

The nucleotide-binding-domain (NBD)-and leucine-rich repeat (LRR)-containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome drives pathological inflammation in a suite of autoimmune, metabolic, malignant, and neurodegenerative diseases. Additionally, NLRP3 gain-of-function point mutations cause systemic periodic fever syndromes that are collectively known as cryopyrin-associated periodic syndrome (CAPS). There is significant interest in the discovery and development of diarylsulfonylurea Cytokine Release Inhibitory Drugs (CRIDs) such as MCC950/CRID3, a potent and selective inhibitor of the NLRP3 inflammasome pathway, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight into the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome pathway. Here, we show that the NAIP, CIITA, HET-E, and TP1 (NACHT) domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labeling (PAL) of the NACHT domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance with this finding, MCC950/CRID3 failed to inhibit NLRP3-driven inflammatory pathology in two mouse models of CAPS. Moreover, it abolished circulating levels of interleukin (IL)-1 beta and IL-18 in lipopolysaccharide (LPS)-challenged wild-type mice but not in Nlrp3(L351P) knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wild-type NLRP3 as the molecular target of MCC950/CRID3 and show that CAPS-related NLRP3 mutants escape efficient MCC950/CRID3 inhibition. Collectively, this work suggests that MCC950/CRID3-based therapies may effectively treat inflammation driven by wild-type NLRP3 but not CAPS-associated mutants

Synthesis and biology of cyclic imine toxins, an emerging class of potent, globally distributed marine toxins.

International audienceFrom a small group of exotic compounds isolated only two decades ago, Cyclic Imine (CI) toxins have become a major class of marine toxins with global distribution. Their distinct chemical structure, biological mechanism of action, and intricate chemistry ensures that CI toxins will continue to be the subject of fascinating fundamental studies in the broad fields of chemistry, chemical biology, and toxicology. The worldwide occurrence of potent CI toxins in marine environments, their accumulation in shellfish, and chemical stability are important considerations in assessing risk factors for human health. This review article aims to provide an account of chemistry, biology, and toxicology of CI toxins from their discovery to the present day

A General Strategy for the Construction of Functionalized Azaindolines via Domino Palladium-Catalyzed Heck Cyclization/Suzuki Coupling

The preparation of substituted azaindolines utilizing a domino palladium-catalyzed Heck cyclization/Suzuki coupling is described. The approach is amenable for the construction of all four azaindoline isomers. A range of functional groups such as esters, amides, ketones, sulfones, amines, and nitriles are all tolerated under the reaction conditions

Studies toward the Synthesis of Spirolide C: Exploration into the Formation of the 23-Membered All-Carbon Macrocyclic Framework

The synthesis of two complex subunits en route to spirolide C is described. A key alkyllithium addition to an aldehyde joins the fragments, which are advanced in order to investigate a ring-closing metathesis to form the 23-membered all-carbon macrocyclic framework

Studies toward the Synthesis of Spirolide C: Exploration into the Formation of the 23-Membered All-Carbon Macrocyclic Framework

The synthesis of two complex subunits en route to spirolide C is described. A key alkyllithium addition to an aldehyde joins the fragments, which are advanced in order to investigate a ring-closing metathesis to form the 23-membered all-carbon macrocyclic framework

Stability of Cyclic Imine Toxins: Interconversion of Pinnatoxin Amino Ketone and Pinnatoxin A in Aqueous Media

Pinnatoxins belong to the cyclic imine (CI) group of marine toxins with a unique toxicological profile. The need for structural integrity of the aliphatic 7-membered cyclic imine for the potent bioactivity of pinnatoxins has been experimentally demonstrated. In this study, we probe interconversion of the natural cyclic imine and its open form, pinnatoxin A amino ketone (PnTX AK), under physiologically relevant aqueous conditions. Our studies demonstrate the high stability of PnTX A. The unusual stability of the imine ring in PnTX A has implications for its oral toxicity and detoxification. These studies, as well the access to PnTX amino ketone, were enabled by the total synthesis of (+)-pinnatoxin A completed previously in our laboratory

Amphiphilic π‑Allyliridium <i>C</i>,<i>O</i>‑Benzoates Enable Regio- and Enantioselective Amination of Branched Allylic Acetates Bearing Linear Alkyl Groups

The first examples of amphiphilic reactivity in the context of enantio­selective catalysis are described. Commercially available π-allyliridium <i>C</i>,<i>O</i>-benzoates, which are stable to air, water and SiO₂ chromatography, and are well-known to catalyze allyl acetate-mediated carbonyl allylation, are now shown to catalyze highly chemo-, regio- and enantio­selective substitutions of branched allylic acetates bearing linear alkyl groups with primary amines

Total Synthesis of (−)-Lasonolide A

The lasonolides are novel polyketides that have displayed remarkable biological activity in vitro against a variety of cancer cell lines. Herein we describe our first-generation approach to the formal synthesis of lasonolide A. The key findings from these studies ultimately allowed us to go on and complete a total synthesis of lasonolide A. The convergent approach unites two highly complex fragments utilizing a Ru-catalyzed alkene–alkyne coupling. This type of coupling typically generates branched products; however, through a detailed investigation, we are now able to demonstrate that subtle structural changes to the substrates can alter the selectivity to favor the formation of the linear product. The synthesis of the fragments features a number of atom-economical transformations which are highlighted by the discovery of an engineered enzyme to perform a dynamic kinetic reduction of a β-ketoester to establish the absolute stereochemistry of the southern tetrahydropyran ring with high levels of enantio­selectivity