A5044115787- Click Chemistry and Applications
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Fluorine in Organic Chemistry
- Synthesis and Catalytic Reactions
- Receptor Mechanisms and Signaling
- Ubiquitin and proteasome pathways
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Sulfur-Based Synthesis Techniques
- Neuroscience and Neuropharmacology Research
- Drug Transport and Resistance Mechanisms
- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Cancer therapeutics and mechanisms
- Phosphodiesterase function and regulation
- Radical Photochemical Reactions
- Synthesis and biological activity
- Cellular transport and secretion
- Synthesis and Characterization of Heterocyclic Compounds
- Protein Degradation and Inhibitors
- Synthesis and Biological Evaluation
- Synthesis of heterocyclic compounds
Pfizer (United States)
2015-2024
Connecticut Sea Grant
2021
Stony Brook University
2008-2019
Foton Motors (China)
2013-2016
Worldwide Clinical Trials (United States)
2016
Pfizer (United Kingdom)
2014
Medicina
2013
University of Delaware
2010
Molecular editing such as insertion, deletion, and single atom exchange in highly functionalized compounds is an aspirational goal for all chemists. Here, we disclose a photoredox protocol the replacement of fluorine with hydrogen electron-deficient trifluoromethylarenes including complex drug molecules. A robustness screening experiment shows that this reductive defluorination tolerates range functional groups heterocycles commonly found bioactive Preliminary studies allude to catalytic...
Chemical modulation of proteins enables a mechanistic understanding biology and represents the foundation most therapeutics. However, despite decades research, 80% human proteome lacks functional ligands. proteomics has advanced fragment-based ligand discovery toward cellular systems, but throughput limitations have stymied scalable identification fragment-protein interactions. We report proteome-wide maps protein-binding propensity for 407 structurally diverse small-molecule fragments....
Bioorthogonal reactions, including the strain-promoted azide-alkyne cycloaddition (SPAAC) and inverse electron demand Diels-Alder (iEDDA) have become increasingly popular for live-cell imaging applications. However, stability reactivity of reagents has never been systematically explored in context a living cell. Here we report universal, organelle-targetable system based on HaloTag protein technology directly comparing bioorthogonal reagent reactivity, specificity, using clickable ligands...
The design, synthesis, and application of [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis sulfur(VI) fluorides, is described. utility AISF demonstrated in diverse array aryl fluorosulfates sulfamoyl fluorides under mild conditions. Additionally, single-step preparation was developed that installed bis(fluorosulfonyl)imide group on acetanilide utilizing an oxidative C–H functionalization protocol.
A method to activate sulfamoyl fluorides, fluorosulfates, and sulfonyl fluorides with calcium triflimide DABCO for SuFEx amines is described. The reaction was applied a diverse set of sulfamides, sulfamates, sulfonamides at room temperature under mild conditions. Additionally, we highlight this transformation parallel medicinal chemistry generate broad array nitrogen-based S(VI) compounds.
γ-Secretase is an intramembrane aspartyl protease that cleaves the amyloid precursor protein to produce neurotoxic β-amyloid peptides (i.e. Aβ42) have been implicated in pathogenesis of Alzheimer disease. Small molecule γ-secretase modulators (GSMs) emerged as potential disease-modifying treatments for disease because they reduce formation Aβ42 while not blocking processing substrates. We developed clickable GSM photoaffinity probes with goal identifying target various classes GSMs and...
A method using calcium triflimide [Ca(NTf2)2] as a Lewis acid to activate sulfonyl fluorides toward nucleophilic addition with amines is described. The reaction converts wide array of sterically and electronically diverse into the corresponding sulfonamides in good yield.
Described is the spatiotemporally controlled labeling and patterning of biomolecules in live cells through catalytic activation bioorthogonal chemistry with light, referred to as "CABL". Here, an unreactive dihydrotetrazine (DHTz) photocatalytically oxidized intracellular environment by ambient O2 produce a tetrazine that immediately reacts trans-cyclooctene (TCO) dienophile. 6-(2-Pyridyl)dihydrotetrazine-3-carboxamides were developed stable, cell permeable DHTz reagents upon oxidation most...
Electrophilic small molecules that can reversibly modify proteins are of growing interest in drug discovery. However, the ability to study reversible covalent probes live cells be limited by their reactivity after cell lysis and proteomic workflows, leading scrambling signal loss. We describe how thiomethyltetrazines function as warheads for cysteine modification, this dynamic labeling behavior "switched off" via bioorthogonal chemistry inside cells. Simultaneously, tetrazine serves a...
Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) contributes to endosomal and lysosomal function. LIMP-2 deficiency is associated with neurological abnormalities kidney failure and, as an acid glucocerebrosidase receptor, impacts Gaucher Parkinson's diseases. Here we report a crystal structure of luminal domain dimer bound cholesterol phosphatidylcholine. Binding these lipids alters from functioning glucocerebrosidase-binding monomer toward dimeric state that preferentially binds...
Inhibition of β-secretase BACE1 is considered one the most promising approaches for treating Alzheimer's disease. Several structurally distinct inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but target mediating this has not identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as principal off-target human cells. We find that several blocked CatD activity cells with much greater potency than displayed...
Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of endocannabinoid 2-arachidonoylglycerol (2-AG) in CNS. MAGL catalyzes conversion 2-AG to arachidonic acid (AA), a precursor proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient inhibitors, identified through parallel medicinal chemistry approach that highlighted improved efficiency azetidine and piperidine-derived carbamates. The discovery optimization 3-substituted carbamate...
Described is a general method for the installation of minimal 6-methyltetrazin-3-yl group via first example Ag-mediated Liebeskind–Srogl cross-coupling. The attachment bioorthogonal tetrazines on complex molecules typically relies linkers that can negatively impact physiochemical properties conjugates. Cross-coupling with arylboronic acids and new reagent, 3-((p-biphenyl-4-ylmethyl)thio)-6-methyltetrazine (b-Tz), proceeds under mild, PdCl2(dppf)-catalyzed conditions to introduce minimal,...
Abstract Since tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches synthesize unsymmetrical and 3‐monosubstituted tetrazines. Described here general, one‐pot method converting (3‐methyloxetan‐3‐yl)methyl carboxylic esters into 3‐thiomethyltetrazines. These versatile intermediates were applied synthesis through Pd‐catalyzed cross‐coupling in first catalytic thioether reduction access monosubstituted This enables development tetrazine...
The synthesis of the novel squalene synthase inhibitor, bisabosqual A, was completed in 14 steps (longest linear sequence) from commercially available starting materials. doubly convergent route employs a tandem 5-exo, 6-exo radical cyclization as key step. This reaction assembles fully functionalized tetracyclic core and introduces three stereogenic centers. Other effective transformations are regioselective deoxygenation an advanced enone intermediate chemo- diastereoselective addition...
Herein, we report the radiosynthesis of <sup>18</sup>F-difluoromethylarenes <italic>via</italic> assembly three components, a boron reagent, ethyl bromofluoroacetate, and cyclotron-produced non-carrier added [<sup>18</sup>F]fluoride.
A photochemical synthesis of AgNO3 complexes trans-cycloheptene (TCH) and trans-1-sila-4-cycloheptene (Si-TCH) derivatives is described. low temperature flow photoreactor was designed to enable the carbocyclic TCH due their thermal sensitivity in absence metal coordination. Unlike free carbocycles, TCH·AgNO3 can be handled at rt stored for weeks freezer (-18 °C). Si-TCH·AgNO3 are especially robust, bench stable days rt, months freezer. X-ray crystallography used characterize a complex first...