43 research outputs found
Characterization of BU09059:A novel potent selective κ-receptor antagonist
[Image: see text] Kappa-opioid receptor (κ) antagonists are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing κ-antagonists has been limited by the pharmacodynamic properties of prototypic κ-selective antagonists; that is, they inhibit receptor signaling for weeks after a single administration. To address this issue, novel trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) piperidine derivatives, based on JDTic, were designed using soft-drug principles. The aim was to determine if the phenylpiperidine-based series of κ-antagonists was amenable to incorporation of a potentially metabolically labile group, while retaining good affinity and selectivity for the κ-receptor. Opioid receptor binding affinity and selectivity of three novel compounds (BU09057, BU09058, and BU09059) were tested. BU09059, which most closely resembles JDTic, had nanomolar affinity for the κ-receptor, with 15-fold and 616-fold selectivity over μ- and δ-receptors, respectively. In isolated tissues, BU09059 was a potent and selective κ-antagonist (pA(2) 8.62) compared with BU09057 (pA(2) 6.87) and BU09058 (pA(2) 6.76) which were not κ-selective. In vivo, BU09059 (3 and 10 mg/kg) significantly blocked U50,488-induced antinociception and was as potent as, but shorter acting than, the prototypic selective κ-antagonist norBNI. These data show that a new JDTic analogue, BU09059, retains high affinity and selectivity for the κ-receptor and has a shorter duration of κ-antagonist action in vivo
Total Synthesis of Spiroketal Alkaloids Lycibarbarines A–C
Lycibarbarines A–C are spirocyclic alkaloids with a unique tetracyclic framework, consisting of tetrahydroquinoline and spiro-fused oxazine-sugar spiroketal subunits. The first total syntheses of lycibarbarines A–C are reported, achieved over 10 steps (longest linear sequence) each. Through this work, it was discovered that the spiroketal unit of lycibarbarines A–C exhibits unusually high resistance to acid-mediated isomerisation and epimerisation, likely due to the basic nitrogen atom. As such, the lycibarbarines present an interesting case study of preventing the interconversion of spiroketal isomers, which may prove instructive in efforts to obtain non-thermodynamic spiroketal frameworks
Ene-gamma-lactam synthesis via (3+2) vinyl azide-enolate cycloaddition: Enolate addition to vinyl triazolinone intermediates
Vinyl azides have undergone a recent renaissance as versatile synthetic reagents, however their reactivity as 1,3-dipoles in (3+2) cycloadditions remains underexplored. Here the synthesis of ene-gamma-lactam scaffolds via (3+2) cycloaddition of alpha-substituted vinyl azides with ester enolates is established. Mechanistic investigations, including isolation of reaction intermediates and density functional theory calculations, implicate an unprecedented conjugate-type addition to the exocyclic alkene of an N-vinyl triazolinone intermediate generated in the cycloaddition step. Determination of the reaction scope and application to synthesis of the natural product sargassumlactam is reported
Direct alpha-Amination of Amides and Lactams Enabled by the (3+2) Vinyl Azide-Enolate Cycloaddition Manifold
Direct alpha-amination of carbonyl compounds remains an important yet synthetically challenging transformation. Here we report a solution for direct alpha-amination of amides and lactams, identified through fundamental exploration of (3+2) vinyl azide-enolate cycloaddition chemistry. Initial cycloadducts undergo rearrangement via 1,2-N-migration to afford imine intermediates that are readily converted to the target alpha-amino amides or lactams. The sequence requires no pre-functionalisation, can be performed on a range of substrates, including compound classes unsuccessful using reported methods, and delivers primary or secondary alpha-amines. This work highlights the diversity and synthetic potential of the rapidly expanding (3+2) azide-enolate cycloaddition manifold
Total Synthesis of Virgatolide B
The first total synthesis of the benzannulated spiroketal virgatolide A is presented. Key features include sp<sup>3</sup>–sp<sup>2</sup> Suzuki coupling of an enantiomerically enriched β-trifluoroboratoamide and an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-<i>anti</i>-selective Mukaiyama aldol reaction followed by global deprotection/cyclization with regioselectivity governed by internal hydrogen bonding
Total Synthesis of Chaetoquadrins A–C
The first total synthesis of the monoamine oxidase inhibitors chaetoquadrins A–C has been accomplished. Key steps in the synthesis include an aromatic Claisen rearrangement, asymmetric boron aldol reaction and acid-mediated spiroketalization. Comparison of spectral data for the synthetic spiroketals confirmed the proposed structure for these natural products
Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis
Rising resistance to current clinical antibacterial agents is an imminent threat to global public health and highlights the demand for new lead compounds for drug discovery. One such potential lead compound, the peptide antibiotic teixobactin, was recently isolated from an uncultured bacterial source, and demonstrates remarkably high potency against a wide range of resistant pathogens without apparent development of resistance. A rare amino acid residue component of teixobactin, enduracididine, is only known to occur in a small number of natural products that also possess promising antibiotic activity. This review highlights the presence of enduracididine in natural products, its biosynthesis together with a review of analogues of enduracididine. Reported synthetic approaches to the cyclic guanidine structure of enduracididine are discussed, illustrating the challenges encountered to date in the development of efficient synthetic routes to facilitate drug discovery efforts inspired by the discovery of teixobactin
Determination of the Cannabinoid CB1 Receptor’s Positive Allosteric Modulator Binding Site through Mutagenesis Studies
Positive allosteric modulators (PAMs) of the cannabinoid CB1 receptor (CB1) offer potential therapeutic advantages in the treatment of neuropathic pain and addiction by avoiding the adverse effects associated with orthosteric CB1 activation. Here, molecular modeling and mutagenesis were used to identify residues central to PAM activity at CB1. Six putative allosteric binding sites were identified in silico, including novel sites previously associated with cholesterol binding, and key residues within each site were mutated to alanine. The recently determined ZCZ011 binding site was found to be essential for allosteric agonism, as GAT228, GAT229 and ZCZ011 all increased wild-type G protein dissociation in the absence of an orthosteric ligand; activity that was abolished in mutants F191A3.27 and I169A2.56. PAM activity was demonstrated for ZCZ011 in the presence of the orthosteric ligand CP55940, which was only abolished in I169A2.56. In contrast, the PAM activity of GAT229 was reduced for mutants R220A3.56, L404A8.50, F191A3.27 and I169A2.56. This indicates that allosteric modulation may represent the net effect of binding at multiple sites, and that allosteric agonism is likely to be mediated via the ZCZ011 site. This study underlines the need for detailed understanding of ligand receptor interactions in the search for pure CB1 allosteric modulators
Total Synthesis of (−)-Peniphenone A
The
asymmetric total synthesis of the polyketide benzannulated
spiroketal natural product, (−)-peniphenone A, is reported.
The key reaction in the synthesis involved sp<sup>3</sup>–sp<sup>2</sup> Negishi cross-coupling between a chiral organozinc species
and an aryl bromide to construct the challenging α-chiral β-aryl
carbonyl motif present in the natural product. Access to the spiroketal
possessing the correct stereochemistry was facilitated by an unusual
thermodynamic resolution at C10. The synthesis was achieved in 14
steps (longest linear sequence) from commercially available 2,4-dihydroxybenzaldehyde
in 6% overall yield. Investigations into a parallel approach required
extension of Krische’s enantioselective hydrogen-mediated C–C
coupling to α-substituted alcohols and oxetane ring-opening
with an aryllithium for assembly of the polyketide domain. These studies
provide a useful foundation for further work toward the natural product
family, members of which demonstrate significant activity against <i>M. tuberculosis</i> and offer continuing inspiration for the
development of efficient new chemical methods
Total Synthesis of the Resorcyclic Acid Lactone Spiroketal Citreoviranol
The
first total synthesis of resorcyclic acid lactone spiroketal
citreoviranol (<b>1</b>) is described. The synthesis was completed
in nine steps and via Sonogashira cross-coupling, gold-catalyzed cyclization,
and an unusual base-induced ketalization. The relative and absolute
stereochemistry of citreoviranol was unambiguously confirmed using
2D NMR spectroscopy and X-ray crystallography