A5027409892- Chemical Synthesis and Analysis
- Carbohydrate Chemistry and Synthesis
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Glycosylation and Glycoproteins Research
- Synthetic Organic Chemistry Methods
- Click Chemistry and Applications
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Synthesis and Catalytic Reactions
- Advanced biosensing and bioanalysis techniques
- Synthesis and Biological Evaluation
- Monoclonal and Polyclonal Antibodies Research
- Cyclopropane Reaction Mechanisms
- Crystallography and molecular interactions
- Microbial Natural Products and Biosynthesis
- Asymmetric Synthesis and Catalysis
- Asymmetric Hydrogenation and Catalysis
- Nicotinic Acetylcholine Receptors Study
- Catalytic C–H Functionalization Methods
- Radical Photochemical Reactions
- RNA modifications and cancer
- Innovative Microfluidic and Catalytic Techniques Innovation
- Sulfur-Based Synthesis Techniques
- biodegradable polymer synthesis and properties
GlaxoSmithKline (United States)
2021-2023
Broad Institute
2008-2013
Harvard University
2010
Massachusetts General Hospital
2010
Infinity Pharmaceuticals (United States)
2009
University of California, Berkeley
1998-2003
IIT@MIT
2002-2003
Howard Hughes Medical Institute
2001-2002
Massachusetts Institute of Technology
2002
Lawrence Berkeley National Laboratory
1999-2002
Most small-molecule probes and drugs alter cell circuitry by interacting with 1 or more proteins. A complete understanding of the proteins their associated protein complexes, whether compounds are discovered cell-based phenotypic target-based screens, is extremely rare. Such a capability expected to be highly illuminating—providing strong clues mechanisms used small-molecules achieve recognized actions suggesting potential unrecognized actions. We describe powerful method combining...
An aldol-based build/couple/pair (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, series asymmetric syn- anti-aldol reactions were performed produce four stereoisomers Boc-protected γ-amino acid. addition, both O-PMB-protected alaninol generated provide chiral amine coupling partner. couple step, eight stereoisomeric amides synthesized by acid building blocks. The subsequently reduced corresponding secondary...
The synthesis and diversification of a densely functionalized azetidine ring system to gain access wide variety fused, bridged, spirocyclic systems is described. in vitro physicochemical pharmacokinetic properties representative library members are measured order evaluate the use these scaffolds for generation lead-like molecules be used targeting central nervous system. solid-phase 1976-membered azetidines also
DNA-encoded library (DEL) technology facilitates the rapid identification of therapeutic candidates in pharmaceutical settings. Herein, development photoredox-mediated hydrocarbofunctionalization protocols olefins is described.
Structural and functional mimetics of naturally occurring glycopeptides are attractive synthetic targets owing to their potential as biological tools therapeutic agents. The syntheses C- S-glycopeptides, glycopeptoids, oxime- (figure) thioether-linked have now been realized, many these currently undergoing evaluation.
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTAminooxy-, Hydrazide-, and Thiosemicarbazide-Functionalized Saccharides: Versatile Reagents for Glycoconjugate SynthesisElena C. Rodriguez, Lisa A. Marcaurelle, Carolyn R. BertozziView Author Information Department of Chemistry, University California, Berkeley, California 94720 Cite this: J. Org. Chem. 1998, 63, 21, 7134–7135Publication Date (Web):October 1, 1998Publication History Received13 July 1998Published online1 October inissue 1...
A regioselective intramolecular Huisgen cycloaddition was performed on various azido alkyne substrates giving rise to macrocyclic triazole rings. Using catalyst control, a common intermediate has been converted two structurally unique macrocycles with either 1,5- or 1,4-triazole resulting in an n + 1 ring size. This is the first example of ruthenium-catalyzed cycloaddition.
DNA-encoded library technology has emerged as an efficient interrogation platform for the identification of therapeutic candidates in pharmaceutical settings. Herein, a direct photochemical C–H arylation functionalized heteroarenes is reported.
The synthesis of a 93-residue chemokine, lymphotactin, containing eight sites O-linked glycosylation, was achieved using the technique native chemical ligation. A single GalNAc residue incorporated at each glycosylation site standard Fmoc-chemistry to achieve first total mucin-type glycoprotein. Using this approach quantities homogeneous material were obtained for structural and functional analysis.
A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines was produced using a combination solution- and solid-phase synthesis techniques. tetrahydroquinoline (THQ) scaffold prepared via an asymmetric Povarov reaction cooperative catalysis to generate three contiguous stereogenic centers. matrix 4 stereoisomers the THQ enable development stereo/structure–activity relationships (SSAR) upon biological testing. sparse design strategy employed select members be synthesized with goal...
Here, we describe the discovery of a novel antimalarial agent using phenotypic screening Plasmodium falciparum asexual blood-stage parasites. Screening compound collection created diversity-oriented synthesis (DOS) led to initial hit. Structure–activity relationships guided compounds having improved potency and water solubility, yielding subnanomolar inhibitor parasite growth. Optimized 27 has an excellent off-target activity profile in erythrocyte lysis HepG2 assays is stable human plasma....
The synthesis of oxime-linked mucin mimics was accomplished via the incorporation multiple ketone residues into a peptide followed by reaction with aminooxy sugars corresponding to tumor-related TN and sialyl (STN) antigens.
The synthesis of a stereochemically diverse library medium-sized rings accessible via 'build/couple/pair' strategy is described. Key aspects the include S(N)Ar cycloetherification linear amine template to afford eight stereoisomeric 8-membered lactams and subsequent solid-phase diversification these scaffolds yield 6488-membered library. Screening this compound collection in cell-based assay for suppression cytokine-induced beta-cell apoptosis resulted identification small-molecule...
We have implemented an aldol-based "build/couple/pair" (B/C/P) strategy for the synthesis of stereochemically diverse 8-membered lactam and sultam scaffolds via SNAr cycloetherification. Each scaffold contains two handles, amine aryl bromide, solid-phase diversification N-capping Pd-mediated cross coupling. A sparse matrix design that achieves dual objective controlling physicochemical properties selecting library members was implemented. The production 8000-membered libraries is discussed...
A build/couple/pair (B/C/P) strategy was employed to generate a library of 7936 stereochemically diverse 12-membered macrolactams. All 8 stereoisomers common linear amine precursor were elaborated form the corresponding two regioisomeric macrocyclic scaffolds via head-to-tail cyclization. Subsequently, these 16 further diversified capping functionalities on SynPhase Lanterns. Reagents used for solid-phase diversification selected using sparse matrix design with aim maximizing coverage...
DNA-encoded library (DEL) technology is a powerful platform for hit identification in academia and the pharmaceutical industry. When conducting off-DNA resynthesis confirmation after affinity selection, PCR/sequencing, data analysis, one typically assumes "one-to-one" relationship between DNA tag chemical structure of attached small-molecule it encodes. Because synthesis often yields mixture, this approximation increases risk overlooking positive discoveries valuable information. To address...
Developing new on-DNA reactions is paramount to the development of encoded libraries in pursuit novel pharmaceutical lead compounds. Lactam-containing molecules have been shown be effective a wide range therapeutic areas and therefore represent promising target for further investigation by DNA-encoded library screening. In this motif, we report method introduction lactam-containing structures onto DNA headpiece through Ugi four-center three-component reaction (4C-3CR). This successful three...
A critical branch point in mucin-type oligosaccharides is the β1 → 3 glycosidic linkage to core α-N-acetylgalactosamine (GalNAc) residue. We report here a strategy for synthesis of O-linked glycopeptide analogues that replaces this with thioether amenable construction by chemoselective ligation. The key building block was 2-azido-3-thiogalactose-Thr analogue incorporated into peptide fluorenylmethoxycarbonyl (Fmoc)-based solid-phase synthesis. Higher order were readily generated alkylation...
The tumor-associated carbohydrate antigens Globo-H, SSEA-3, and Gb3 were synthesized in a linear fashion using glycosyl phosphate monosaccharide building blocks. All of the blocks prepared from readily available common precursors. difficult alpha-(1-->4-cis)-galactosidic linkage was installed galactosyl donor with high selectivity. Introduction beta-galactosamine unit required screening variety amine protecting groups to ensure good reactivity group compatibility. An...
Complexity and the presence of stereogenic centers have been correlated with success as compounds transition from discovery through clinic. Here we describe synthesis a library pyran-containing macrocycles high degree structural complexity up to five centers. A key feature design strategy was use modular synthetic route three fragments that can be readily interchanged or “shuffled” produce subtly different variants distinct molecular shapes. total 352 were synthesized ranging in size 14-...