A5057477527- Carbohydrate Chemistry and Synthesis
- Glycosylation and Glycoproteins Research
- Proteoglycans and glycosaminoglycans research
- Chemical Synthesis and Analysis
- DNA and Nucleic Acid Chemistry
- Heparin-Induced Thrombocytopenia and Thrombosis
- Fluorine in Organic Chemistry
- Organophosphorus compounds synthesis
- Synthetic Organic Chemistry Methods
- RNA and protein synthesis mechanisms
- Blood Coagulation and Thrombosis Mechanisms
- Legume Nitrogen Fixing Symbiosis
- Peptidase Inhibition and Analysis
- Advanced biosensing and bioanalysis techniques
- Protease and Inhibitor Mechanisms
- Enzyme Catalysis and Immobilization
- Synthesis of Organic Compounds
- Polyamine Metabolism and Applications
- Enzyme Production and Characterization
- Cannabis and Cannabinoid Research
- Platelet Disorders and Treatments
- Biochemical and Molecular Research
- Synthesis and Characterization of Heterocyclic Compounds
- Synthesis and Reactions of Organic Compounds
- Origins and Evolution of Life
Leiden University
1998-2024
Oncode Institute
2020-2024
Eindhoven University of Technology
1990-2014
MSD (Netherlands)
2012
Sanofi (Turkey)
2004
Sanofi (France)
1993-2002
Mercer University
2002
Beth Israel Deaconess Medical Center
2002
VA Boston Healthcare System
2002
SNV Netherlands Development Organisation
1993-1999
Abstract Heparin, a sulfated glycosaminoglycan, is well known for its anticoagulant effect mediated by the serine protease inhibitor antithrombin III (AT III). Heparin has been used clinically more than half century prophylaxis and treatment of venous thrombosis thromboembolism. Up until 1980s it was assumed that biological activity heparin mainly caused polyanionic character. However, this paradigm contradicted when discovered part polysaccharides contains well‐defined pentasaccharide...
Two enantiomeric glycosyl donors 1 and 2 were coupled to the acceptor 3 under same conditions. The first case leads a disaccharide with an α/β ratio of 2/1, second 1/8.4. This other experiments show that stereochemical outcome glycosylation can be strongly influenced by unfavorable interactions (the formation matched mismatched pairs) between donor acceptor.
Abstract The synthesis of a protected pentasaccharide 27b corresponding to the antithrombin III binding region heparin is presented. This was prepared from two disaccharides (12c and 23) monosaccharide (1). glucuronic acid containing disaccharide 12c easily available monomers 6 7. Oxidation uronic performed in stage. L-Idose derivative 16, via new route, coupled with 1,6-anhydro 17, oxidized transformed into 23. Coupling 23 tetrasaccharide 24a has been investigated. Better yields were...
Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate reactivity and resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as latent electrophile into small molecule cathepsin K (CatK). Alkyne-based do not show thiol potently inhibit CatK protease activity by formation irreversible bond with catalytic cysteine residue, confirmed crystal structure...
Abstract Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need identify antibiotics that operate via novel mechanisms. Here we report a class of allosteric inhibitors DNA gyrase with antibacterial activity against fluoroquinolone-resistant clinical isolates Escherichia coli . Screening small-molecule library revealed an initial isoquinoline sulfonamide hit, which was optimized medicinal chemistry efforts afford more potent LEI-800. Target identification...
A novel flexible assembly strategy is described for the modular synthesis of heparin and heparan sulfates. The reported uses monomeric building bocks to construct oligosaccharide chain attain a maximum degree flexibility. In assembly, 1-hydroxyl glucosazido- 1-thio uronic acid donors are combined in sequential glycosylation protocol using sulfonium triflate activator systems. key acids were obtained an efficient manner from diacetone glucose employing chemo- regioselective oxidation...
The interpretation of high-dimensional structure–activity data sets in drug discovery to predict ligand–protein interaction landscapes is a challenging task. Here we present Drug Discovery Maps (DDM), machine learning model that maps the activity profile compounds across an entire protein family, as illustrated here for kinase family. DDM based on t-distributed stochastic neighbor embedding (t-SNE) algorithm generate visualization molecular and biological similarity. chemical target space...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTConstructing a molecular model of the interaction between antithrombin III and potent heparin analogPeter D. J. Grootenhuis Constant A. Van BoeckelCite this: Am. Chem. Soc. 1991, 113, 7, 2743–2747Publication Date (Print):March 1, 1991Publication History Published online1 May 2002Published inissue 1 March 1991https://pubs.acs.org/doi/10.1021/ja00007a058https://doi.org/10.1021/ja00007a058research-articleACS PublicationsRequest reuse...
Pregnancy in pill form? The identification of low molecular weight (LMW) agonists for receptors normally triggered by high (HMW) endogenous ligands is a great challenge medicinal chemists. Thienopyrimidines and thienopyridines general structures 1 2, respectively, are the first orally active LMW G-protein-coupled luteinizing hormone receptor, which responsible ovulation induction. display micromolar to nanomolar potencies vivo induction could be demonstrated mice after oral administration....
Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible inhibitor, using high throughput screening medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, not mouse brain. attenuated liver...
Abstract High‐field NMR spectroscopy of synthetic heparin‐like di‐ and trisaccharides has afforded a complete set inter‐proton‐coupling data on α‐L‐idopyranosyluronic acid, which have been used for conformational analysis. These lead to the conclusion that α‐L‐iduronic acid may display considerable freedom including 1 C 4 , 2 S 0 (e.g. compound ) conformers. The 2‐ O ‐sulphate substituent at iduronic tends stabilize conformation ( e.g. compounds ). In addition carbohydrate substituents...
This work details the evaluation of a number N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral glucosylceramidase inhibitors. Building our previous work, we synthesized series D-gluco and L-ido-configured iminosugars N-modified with variety hydrophobic functional groups. We found that featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors synthase than aliphatic counterparts. In next optimization round, explored...