A5015952556- Synthetic Organic Chemistry Methods
- interferon and immune responses
- Immune Response and Inflammation
- Oxidative Organic Chemistry Reactions
- Cytokine Signaling Pathways and Interactions
- Inflammatory Bowel Disease
- Marine Sponges and Natural Products
- Monoclonal and Polyclonal Antibodies Research
- Cyclopropane Reaction Mechanisms
- Catalytic Cross-Coupling Reactions
- X-ray Diffraction in Crystallography
- Protein Degradation and Inhibitors
- Cell death mechanisms and regulation
- Inflammation biomarkers and pathways
- Ubiquitin and proteasome pathways
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Multiple Myeloma Research and Treatments
- Crystallization and Solubility Studies
- Clostridium difficile and Clostridium perfringens research
- Flavonoids in Medical Research
- Boron and Carbon Nanomaterials Research
- Boron Compounds in Chemistry
- Viral Infections and Outbreaks Research
- Receptor Mechanisms and Signaling
- Marine Toxins and Detection Methods
GlaxoSmithKline (United States)
2011-2021
South College
2011-2021
University of North Carolina at Chapel Hill
2008-2009
University of California, Irvine
2009
Irvine University
2009
Conway School of Landscape Design
1998-2007
Hendrix College
1998-2007
Abstract Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through recruitment E3 ligase complexes to non-native protein substrates. The catalytic mechanism action PROTACs represents an exciting new modality in drug discovery offers several potential advantages over traditional small-molecule inhibitors, including deliver pharmacodynamic (PD) efficacy which extends...
RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation pattern recognition receptors NOD1 NOD2, leading to production inflammatory cytokines. Recently, several inhibitors have been disclosed that contributed fundamental understanding role in this pathway. However, because they lack either broad selectivity or strong affinity for RIP2, these tools only limited utility assess complex environments. We present, herein, discovery...
Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important of the innate immune system. Herein, we describe optimization a series RIPK2 PROTACs which recruit members inhibitor apoptosis (IAP) family E3 ligases. Our PROTAC strategy focused on reducing lipophilicity early lead resulted in identification analogues with improved solubility and increased human rat microsomal stability. We identified range IAP binders that were successfully incorporated into potent attractive...
RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors or its signaling partners on that are suitable for advancement into clinic have yet be described. Herein, we report our discovery and profile prodrug clinical compound, inhibitor 3, currently phase 1 studies. Compound 3 potently binds with good specificity excellent activity blocking...
NOD2 is an intracellular pattern recognition receptor that assembles with receptor-interacting protein (RIP)-2 kinase in response to the presence of bacterial muramyl dipeptide (MDP) host cell cytoplasm, thereby inducing signals leading production pro-inflammatory cytokines. The dysregulation signaling has been associated various inflammatory disorders suggesting small-molecule inhibitors this complex may have therapeutic utility. To identify pathway, we utilized a cell-based screening...
Brevetoxin A is a decacyclic ladder toxin that possesses 5-, 6-, 7-, 8-, and 9-membered oxacycles, as well 22 tetrahedral stereocenters. Herein, we describe unified approach to the B, E, G, J rings based upon ring-closing metathesis strategy from corresponding dienes. The enolate technologies developed in our laboratory allowed access precursor acyclic dienes for G medium-ring ethers. strategies syntheses of these four monocycles ultimately provided multigram quantities each rings,...
A total synthesis of brevetoxin is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner-Wittig olefination. The resulting octacycle was progressed to substrates that explored for reductive etherification, the success which led penultimate tetraol intermediate. converted natural product through an expeditious selective oxidative process followed by methylenation.
RIP2 kinase was recently identified as a therapeutic target for variety of autoimmune diseases. We have reported previously selective 4-aminoquinoline-based inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling cellular models, rodent vivo human ex disease models. While this tool compound valuable validating the biological pathway, it suffered from activity at hERG ion channel poor PK/PD profile thereby limiting progression analog. Herein, we detail our...
Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors receptor interacting protein 2 (RIP2). Fragment based screening design principles led to identification inhibitor series, X-ray crystallography was used inform key structural changes. Through substitutions about N1 C5 N positions on pyrazole ring significant selectivity potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a potent RIP2 will allow for more detailed...
NOD1 is an intracellular pattern recognition receptor that recognizes diaminopimelic acid (DAP), a peptidoglycan component in gram negative bacteria. Upon ligand binding, assembles with receptor-interacting protein (RIP)-2 kinase and initiates signaling cascade leading to the production of pro-inflammatory cytokines. Increased has been associated variety inflammatory disorders suggesting small-molecule inhibitors this complex may have therapeutic utility. We utilized cell-based screening...
(-)-Isopulegol derivatives undergo a ring contraction under silylene-mediated conditions to provide cyclopentane products. Silylene transfer other homoallylic ethers did not the Allylic silane products were elaborated determine stereochemical course of reaction. A mechanism for transformation is proposed.
Molecular clusters of BBr3 were subjected to electron ionization and mass analysis in a reflectron time-of-flight spectrometer. Five series cluster ions observed, with formulas corresponding each the possible fragment being solvated by neutral molecules. Geometry optimizations on observed using density functional theory (B3LYP/6-31G*) predict that smaller than BBr3+ undergo reactions molecules form covalently bound adduct species function as core within clusters. Once all boron atoms are...
Boron trifluoride clusters are formed in a supersonic expansion and ionized by electron impact. The resulting ion distribution is analyzed time-of-flight mass spectrometry. only consistently observed, extended series of peaks EI BF3 BnF3n-1+. Ab initio modeling these ions informs our speculation regarding their internal structure ion−molecule chemistry involved formation. Formation B2F5δ+ computationally predicted to occur all the cluster we observe (n = 2−8) except B3F8+. BF4δ- units evident B8F23+.
Abstract RIP2 is a Ser/Thr protein kinase, which undergoes autophosphorylation and activates NF-κB MAPKs following stimulation of the upstream NOD1/NOD2 receptors resulting in proinflammatory cytokine production. Previous studies using transient overexpression systems have suggested that kinase activity mediates NOD1/2-dependent signaling by regulating cellular levels. To interrogate whether this also case for endogenous we used novel, potent highly-selective small-molecule inhibitors to...
A convenient synthesis of an isotopically-labelled version (13C,2H3) the long-acting β2-adrenergic agonist, salmeterol, is described, starting from methyl salicylate, 1,6-dibromohexane and 4-phenyl-1-butanol. This compound was designed as analytical internal standard for mass spectrometric determination salmeterol in pharmacokinetic studies. Copyright © 2000 John Wiley & Sons, Ltd.
Abstract NOD1 and NOD2 are cytoplasmic PRRs, which bind peptides derived from bacterial peptidoglycans. Signaling via these receptors involves recruitment activation of RIP2 kinase, results in NF-κB- MAPK-dependent pro-inflammatory cytokine production. To enable a chemical biology approach to evaluate the role inflammation we screened an in-house compound collection. Optimization aminoquinoline template led discovery GSK’214 related analogs. potently reversibly inhibited human, rat mouse...
Abstract Loss of intestinal epithelial barrier integrity in inflammatory bowel disease (IBD) leads to aberrant interaction between commensal bacteria and mucosal immune cells. This triggers inflammation via activation pattern recognition receptor (PRR) signaling pathways. Which PRR complexes are critical mediating pathogenesis remains be elucidated. Our recent studies have shown that selective potent inhibitors RIP2 kinase, the partner NOD1 NOD2, can dramatically reduce murine TNBS-induced...