A5090347841- Microbial Natural Products and Biosynthesis
- Synthetic Organic Chemistry Methods
- Marine Sponges and Natural Products
- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Analysis
- Synthesis and Catalytic Reactions
- Phytochemical compounds biological activities
- Chemical synthesis and alkaloids
- Catalytic C–H Functionalization Methods
- Synthesis and Biological Evaluation
- Histone Deacetylase Inhibitors Research
- Analytical Chemistry and Chromatography
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Cancer Treatment and Pharmacology
- Chromatography in Natural Products
- Oxidative Organic Chemistry Reactions
- Bioactive Compounds and Antitumor Agents
- Alkaloids: synthesis and pharmacology
- Advanced Synthetic Organic Chemistry
- Peptidase Inhibition and Analysis
- Natural product bioactivities and synthesis
- Phosphodiesterase function and regulation
- Cholinesterase and Neurodegenerative Diseases
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
Merck & Co., Inc., Rahway, NJ, USA (United States)
2018-2024
United States Military Academy
2009-2024
Colorado State University
2007-2011
University of Michigan
2008-2011
Kumamoto University
2011
University of Colorado Denver
2007-2010
University of Colorado Cancer Center
2007-2010
Chiba University
2009
Kanazawa University
2009
Howard Hughes Medical Institute
2009
Stereochemically unique: A new prenylated indole alkaloid, (+)-versicolamide B, has been isolated from cultures of Aspergillus versicolor NRRL 35600. The structure assigned by 2D NMR experiments, and confirmed a biomimetic total synthesis. Versicolamide B is the first member paraherquamide/stephacidin family alkaloids found to possess anti relative stereochemistry at C19. ent-Stephacidin ent-notoamide were also for time. Supporting information this article available on WWW under...
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains domain and GTPase among other regions. Individuals possessing gain of function mutations in the such as most prevalent G2019S mutation have been associated with an increased risk for development Parkinson's disease (PD). Given this genetic validation inhibition LRRK2 activity potential means affecting progression, our team set out to develop inhibitors test hypothesis. A high throughput screen compound...
Abstract Lung fibrosis, or the scarring of lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis worse than most types cancer. We previously discovered that MK-0429 an equipotent pan-inhibitor αv integrins reduces proteinuria kidney fibrosis in preclinical model. In present study, we further demonstrated significantly inhibits progression bleomycin-induced lung injury search newer integrin inhibitors for characterized monoclonal...
Antipodal (−)-versicolamide B and notoamides L−N were isolated from a marine-derived Aspergillus sp. The possible biosynthetic pathway of enantiomeric pairs notoamide versicolamide are proposed. Notoamide L is the first metabolite containing 25 carbons in related prenylated indole alkaloids. M potentially precursor to proposed azadiene species involved putative intramolecular Diels−Alder reaction biogenesis bicyclo[2.2.2]diazaoctane ring system.
Stephacidin and notoamide natural products belong to a group of prenylated indole alkaloids containing core bicyclo[2.2.2]diazaoctane ring system. These bioactive fungal secondary metabolites have range unusual structural stereochemical features but their biosynthesis has remained uncharacterized. Herein, we report the first biosynthetic gene cluster for this class based on whole genome sequencing marine-derived Aspergillus sp. Two central pathway enzymes catalyzing both normal reverse...
Copying nature: A biomimetic total synthesis of stephacidin has been accomplished using an intramolecular Diels–Alder reaction. Stephacidin was then converted into notoamide B in a single step by oxaziridine-mediated oxidation to provide the first (see scheme). Supporting information for this article is available on WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z604378_s.pdf or from author. Please note: The publisher not responsible content functionality any supporting supplied...
The peptide isosteres (10 and 11) of the naturally occurring potent histone deacetylase (HDAC) inhibitors FK228 largazole have been synthesized evaluated side-by-side with FK228, largazole, SAHA for inhibition class I HDACs 1, 2, 3, 6.
A new method for the preparation of indoles from readily available alpha-haloenones and alpha-(trialkylstannyl)enecarbamates is described. Following a Stille coupling, trienecarbamate 2 electronically activated to undergo facile 6pi-electrocyclic ring closure subsequent oxidation afford protected aniline 4. Upon deprotection reductive amination, acid 5 underwent clean cyclization N-acetylindole 6 (Ac2O, NEt3, 130 degrees C). This has been used construct variety substituted that are not...
An approach to the total synthesis of antimicrotubule agent welwistatin is described. Key transformations include (1) a 7-endo intramolecular conjugate addition reaction enone 6 deliver strained bicyclo[4.3.1]decanone 5; (2) 6π electrocyclic ring closure trienecarbamate 16 followed by oxidation afford protected aniline 17; and (3) an cyclization acetic acid derivative 18 give rise indole 19.
The direct conversion of β-hydroxyproline derivatives into 5-hydroxypyrazin-2(1H)-ones under Mitsunobu conditions has been discovered to be a general biomimetic protocol generating IMDA intermediates and applied the concise, total syntheses d,l-stephacidin A d,l-brevianamide B.
Notoamide E was identified to be a short-lived precursor in the biosynthesis of prenylated indole alkaloids mussel-derived Aspergillus sp. In addition, feeding experiment (13)C-labeled notoamide afforded structurally novel metabolites.
The reactivity of a representative set 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross-coupling reactions was evaluated by high-throughput experimentation protocols. high-fidelity scaleup successful parallel enabled the isolation sufficient material for biological testing, thus demonstrating high value these new solid zinc reagents drug-discovery setting and potentially many other applications chemistry. Principal component analysis (PCA)...
A scaleable synthesis of the potent histone deacetylase (HDAC) inhibitor FK228 is described. reliable strategy for preparing key β-hydroxy mercapto heptenoic acid partner was accomplished in nine steps and 13% overall yield. Noyori asymmetric hydrogen-transfer reaction established hydroxyl stereochemistry >99:1 er via reduction a propargylic ketone.
The biomimetic total syntheses of both malbrancheamide and B are reported. synthesis the two monochloro species enabled structure to be unambiguously assigned. each feature an intramolecular Diels-Alder reaction a 5-hydroxypyrazin-2(1H)-one construct bicyclo[2.2.2]diazaoctane core, which has also been proposed as biosynthetic route these compounds.
One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been restore neuronal signaling from basal forebrain cholinergic system via activation of M1 muscarinic receptor. A number nonselective agonists have previously shown positive effects on behaviors AD patients, but were limited due adverse events thought be mediated by M2 M5 subtypes. strategy confer selectivity for is identification allosteric modulators, which would target an site receptor rather than highly...
Stereochemisch einzigartig: Das prenylierte Indolalkaloid (+)-Versicolamid B wurde aus Kulturen von Aspergillus versicolor NRRL 35600 isoliert. Auf der Grundlage 2D-NMR-Experimenten eine Struktur zugewiesen, die durch biomimetische Totalsynthese bestätigt wurde. Versicolamid ist das erste Paraherquamid-/Stephacidin-Alkaloid mit einer anti-Relativkonfiguration an C19. Auch ent-Stephacidin A und ent-Notoamid wurden
The advanced natural product stephacidin A is proposed as a biosynthetic precursor to notoamide B in various Aspergillus species. Doubly (13)C-labeled racemic was synthesized and fed cultures of the terrestrial-derived fungus, versicolor NRRL 35600, marine-derived sp. MF297-2. Analysis metabolites revealed enantiospecific incorporation intact (-)-stephacidin into (+)-notoamide (+)-stephacidin (-)-notoamide (13)C-Labeled sclerotiamide also isolated from both fungal cultures.
The total synthesis of the cytotoxin lepadiformine is described. intermolecular cycloaddition a 2-amidoacrolein with dimethyl acetal 4,6-heptadienal gave cycloadduct that was strategically functionalized for elaboration tricyclic ring system. These steps include diastereoselective addition an organoytterbium reagent to aldehyde, cyclization trans-perhydroquinoline substructure via Mitsunobu reaction, and iodine-promoted amine alkene introduce pyrrolidine ring.
Identification of ligands that selectively activate the M1 muscarinic signaling pathway has been sought for decades to treat a range neurological and cognitive disorders. Herein, we describe optimization efforts focused on addressing key physicochemical safety properties, ultimately leading clinical candidate MK-7622, highly selective positive allosteric modulator receptor entered Phase II studies in patients with Alzheimer's disease.
The pharmaceutical industry is increasingly faced with challenging separations of complex crude reaction mixtures at the microscale that require adoption new platforms for rapid target isolation, impurity determination, and quantitation. In this study, we describe an online one- or two-dimensional liquid chromatography (1D/2D-LC) system heart-cutting multi (triple) detector triggering in either dimension to address need. advantages charged aerosol detection (CAD) are discussed direct...
A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of crystal structure initial lead bound to enabled optimization enzyme potency and antiviral activity. This afforded series potent orally bioavailable inhibitors which MK-8718 identified compound with favorable overall profile.
The reactivity of a representative set 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross-coupling reactions was evaluated by high-throughput experimentation protocols. high-fidelity scaleup successful parallel enabled the isolation sufficient material for biological testing, thus demonstrating high value these new solid zinc reagents drug-discovery setting and potentially many other applications chemistry. Principal component analysis (PCA)...