A5005746956- Synthetic Organic Chemistry Methods
- Microbial Natural Products and Biosynthesis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Asymmetric Synthesis and Catalysis
- Diabetes Treatment and Management
- Chemical Synthesis and Analysis
- Marine Sponges and Natural Products
- Pancreatic function and diabetes
- Receptor Mechanisms and Signaling
- Chemical synthesis and alkaloids
- Oxidative Organic Chemistry Reactions
- Synthesis and Catalytic Reactions
- Neuropeptides and Animal Physiology
- Catalytic C–H Functionalization Methods
- Carbohydrate Chemistry and Synthesis
- Metabolism, Diabetes, and Cancer
- Antimicrobial Peptides and Activities
- Peroxisome Proliferator-Activated Receptors
- DNA and Nucleic Acid Chemistry
- Cyclopropane Reaction Mechanisms
- Lipid metabolism and biosynthesis
- Molecular spectroscopy and chirality
- Advanced Synthetic Organic Chemistry
- Pharmacogenetics and Drug Metabolism
Pfizer (United States)
2013-2025
RoZetta Institute
2021
UNSW Sydney
2016
Foton Motors (China)
2013
Scripps Research Institute
2006-2010
University of California, San Diego
2006-2009
University of Glasgow
2001-2008
University Hospital of Zurich
1987
University of Warwick
1977
Abstract Die Entwicklung und Umsetzung von Kaskadenreaktionen hat zu beachtlichen neuartigen, eleganten effizienten Synthesestrategien geführt. Als besonders anspruchsvoll erwies sich die Anwendung in der Naturstoffsynthese, doch gerade hier winken verblüffende zugleich aufschlussreiche Ergebnisse als Belohnung. In diesem Aufsatz werden ausgewählte Totalsynthese erläutert, wobei neuere Anwendungen hervorgehoben werden. erörterten Beispiele sollen Leistungsfähigkeit dieser Prozesse beim...
Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe discovery orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based that were optimized promote endogenous signaling with nanomolar potency. Incorporation a carboxylic acid moiety provided considerable...
There are two ways about it: One route to the potent antibiotic (−)-platensimycin used a catalytic asymmetric cycloisomerization and other an auxiliary-controlled alkylation set configuration at key chiral center (see scheme, TMS=trimethylsilyl). This latter synthesis also oxidative dearomatization step construct spirocyclic intermediate en natural product.
Beat the superbugs: The newly discovered antibiotic platensimycin (1) promises to combat current drug-resistant infections. natural product shows potent activity against Gram-positive bacteria and contains a novel molecular architecture. total synthesis of this intriguing that opens way variety otherwise inaccessible analogues has now been achieved (calculated structure shown on right).
Platensimycin is the flagship member of a new and growing class antibiotics with promising antibacterial properties against drug-resistant bacteria. The total syntheses platensimycin its congeners, platensimycins B1 B3, platensic acid, methyl platensinoate, platensimide A, homoplatensimide A ester, are described. convergent strategy developed toward these target molecules involved construction their cage-like core followed by attachment various side chains through amide bond formation. In...
Abstract Indolosesquiterpenoids are a growing class of natural products that exhibit wide range biological activities. Here, we report the total syntheses xiamycin A and oridamycins B, indolosesquiterpenoids isolated from Streptomyces . Two parallel strategies were exploited to forge carbazole core: 6π-electrocyclization/aromatization indole C2–H bond activation/Heck annulation. The construction their trans -decalin motifs relied on two diastereochemically complementary radical cyclization...
Abstract The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. prediction bioavailability drugs relies on physicochemical properties that favor passive permeability oxidative stability, but these may not be useful for peptides. Here we investigate effects heterocyclic constraints, intramolecular hydrogen bonds, side chains the cyclic heptapeptides. NMR‐derived structures, amide H–D exchange rates,...
Adenosine monophosphate-activated protein kinase (AMPK) is a involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for treatment diabetic nephropathy. Identification an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided acid lead compound. Optimization core and aryl appendage improved oral absorption culminated identification indole acid, PF-06409577...
Graphical Abstract The asymmetric total synthesis of the newly discovered and potent antibiotic platencin has been achieved. approach makes use an Diels–Alder reaction, a gold(I)-catalyzed cyclization, homoallyl radical rearrangement to forge polycyclic architecture this intriguing target (see scheme, SEM=2-(trimethylsilyl)ethoxymethyl).
The molecular design, chemical synthesis, and biological evaluation of two distinct series platensimycin analogues with varying degrees complexity are described. first compounds probes the importance benzoic acid subunit molecule, while second explores tetracyclic cage domain. data obtained reveal that, substituted domain is a highly conserved structural motif within active strict functional group requirements, molecule can tolerate considerable modifications without losing action. These...
Adamantly pursuing the bugs: The syntheses of two enantiomers adamantaplatensimycin ((−)-1 and (+)-1), a novel analogue newly discovered antibiotic platensimycin, have been achieved. Potent antibacterial action against methicillin-resistant Staphylococcus aureus vancomycin-resistant Enterococcus faecium has revealed for (−) enantiomer.
The secondary metabolites platensimycin and platencin, isolated from the bacterial strain Streptomyces platensis, represent a novel class of natural products exhibiting unique potent antibacterial activity. Platencin, though structurally similar to platensimycin, has been found operate through slightly different mechanism action involving dual inhibition lipid elongation enzymes FabF FabH. Both exhibit strong, broad-spectrum, gram-positive activity key antibiotic resistant strains, including...
Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression disease. A reduced phosphorylation state adenosine monophosphate-activated protein kinase (AMPK) has been correlated diminished kidney function in both humans and animal models renal Here, we describe identification novel, potent, small molecule activators AMPK selectively activate heterotrimers containing β1 subunit. After confirming human rodent...
Rh built: The title reaction is described and applied to a formal total synthesis of (−)-platensimycin (see scheme; Ts=para-toluenesulfonyl, binap=2,2′-bis(diphenylphosphino)-1,1′-binaphthalene).
Development of peptide-based drugs has been severely limited by lack oral bioavailability with less than a handful peptides being truly orally bioavailable, mainly cyclic N-methyl amino acids and few hydrogen bond donors. Here we report that penta- hexa-leucine peptides, no N-methylation five or six amide NH protons, exhibit some degree (4-17%) approaching the heavily N-methylated drug cyclosporine (22%) under same conditions. These simple demonstrate is achievable for fall outside...
Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that upregulated in patients with non-alcoholic fatty liver disease. Recently, there have been several reports predicted loss of function variants HSD17B13 protect against the progression steatosis to steatohepatitis fibrosis and hepatocellular carcinoma. Here we report crystal structures full length complex its NAD+ cofactor, lipid/detergent molecules small molecule inhibitors from two distinct...
Zwei Wege führen zum Ziel – dem hochwirksamen Antibiotikum (−)-Platensimycin: eine katalytische asymmetrische Cycloisomerisierung oder auxiliargesteuerte Alkylierung zur Festlegung der Konfiguration eines wichtigen Chiralitätszentrums (siehe Schema, TMS=Trimethylsilyl). In zweiten Synthese wird ein spirocyclisches Schlüsselintermediat auf Weg Naturstoff durch oxidative Desaromatisierung erzeugt.
Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role regulation of fatty acid oxidation. Alterations lipid metabolism are believed to contribute insulin resistance; thus inhibition ACC offers promising option for intervention type 2 diabetes mellitus. Herein we disclose series inhibitors based on spirocyclic pyrazololactam core. The lactam has improved chemical metabolic stability relative our previously reported pyrazoloketone...
Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus glucagon-like peptide-1 (GLP-1) to investigate effects structure on agonist activity. Cyclization through linking side chains residues 2 and 5 or 9 produced agonists at nM concentrations in a cAMP assay. 2D NMR CD spectra revealed N-terminal β-turn C-terminal helix that differentially influenced affinity potency. These structures can inform development small molecule GLP-1 receptor treat type diabetes.
Several hydroxysteroid dehydrogenase 17-beta 13 variants have previously been identified as protective against metabolic dysfunction-associated steatohepatitis (MASH) fibrosis, ballooning and inflammation, such this target holds significant therapeutic potential. However, over 5 years later, the function of 17B-HSD13 remains unknown. Structure-aided design enables development potent selective sulfonamide-based inhibitors. In order to probe their inhibitory potency in endogenous expression...
A samarium(II)-mediated 4-exo-trig cyclization in which a remote stereocenter serves to control the facial selectivity of is described. The apparent coordination tert-butyldimethylsilyl ether samarium center appears give rise selectivity. remarkable effect cosolvent, 2,2,2-trifluoroethanol, on this substrate, also discussed. stereoselective synthesis general class γ,δ-unsaturated aldehyde substrate reported, and utility demonstrated an approach fully functionalized core pestalotiopsin A.
Aufwind für den Antibiotikasektor: Das unlängst entdeckte Antibiotikum Platensimycin (1) scheint vielversprechend die Behandlung von Infektionen durch wirkstoffresistente Erreger zu sein. Der Naturstoff mit neuartigem Molekülbau wirkt stark gegen Gram-positive Bakterien. Durch Totalsynthese dieser Verbindung steht nun ein Weg ansonsten nicht zugänglichen Analoga offen (rechts im Bild: berechnete Struktur).