A5004375465- Chemical Synthesis and Analysis
- Asymmetric Synthesis and Catalysis
- Asymmetric Hydrogenation and Catalysis
- Chemical Synthesis and Reactions
- Chemical Reaction Mechanisms
- Chemical Reactions and Isotopes
- Synthesis and Catalytic Reactions
- Analytical Chemistry and Chromatography
- Chemical synthesis and alkaloids
- Synthesis and Biological Evaluation
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Axial and Atropisomeric Chirality Synthesis
- Synthesis and Reactions of Organic Compounds
- Synthetic Organic Chemistry Methods
- Advanced Synthetic Organic Chemistry
- Fluorine in Organic Chemistry
- Inorganic and Organometallic Chemistry
- Catalytic Cross-Coupling Reactions
- Molecular spectroscopy and chirality
- Organic Chemistry Cycloaddition Reactions
- Microwave-Assisted Synthesis and Applications
- Catalytic C–H Functionalization Methods
- Cyclopropane Reaction Mechanisms
- Organic and Inorganic Chemical Reactions
- Cancer Treatment and Pharmacology
United States Military Academy
2009-2024
Janssen (Belgium)
2024
Springhouse
2021-2023
Janssen (United States)
2021-2023
Merck & Co., Inc., Rahway, NJ, USA (United States)
2006-2021
Scripps Research Institute
2000-2007
University of Ferrara
2007
University of South Alabama
2006
A simple, high-yielding synthesis of 2,4,5-trisubstituted imidazoles from 1,2-diketones and aldehydes in the presence NH4OAc is described. Under microwave irradiation, alkyl-, aryl-, heteroaryl-substituted are formed yields ranging 80 to 99%. Short syntheses lepidiline B trifenagrel illustrate utility this approach.
A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach with focus on linker effects. large number analogs-with varying length, polarity, and rigidity-were rapidly prepared characterized in four cell-based assays by streamlining time-consuming steps synthesis purification. The expansive dataset informs structure-activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability,...
The scope of intramolecular Diels−Alder and a novel tandem Diels−Alder/1,3-dipolar cycloaddition cascade 1,3,4-oxadiazoles is disclosed. In the cases examined, cycloadditions construct three new rings with formation four C−C bonds set all six stereocenters about central six-membered ring in single step including contiguous total quaternary centers without trace second diastereomer.
The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel groups, we applied a parallel medicinal chemistry (PMC) strategy quickly synthesize substituted benzamide libraries. We discovered series containing 2-substituted benzamides as group which afforded highly selective and potent HDAC3 inhibitors, exemplified compound 16 with 2-methylthiobenzamide. Compound inhibited IC50 30 nM unprecedented >300-fold over...
DNA-encoded library (DEL) screens have emerged as a powerful hit-finding tool for number of biological targets. In this Innovations article, we review published hit-to-lead optimization studies following DEL screens. Trends in molecular property changes from hit to lead are identified, and specific tactics exemplified case studies. Across the studies, physicochemical structural post-DEL screening similar those which occur during high throughputscreens (HTS). However, unique aspects DEL-the...
Yatakemycin represents the newest and now most potent member of a class naturally occurring antitumor compounds that includes CC-1065 duocarmycins, which derive their biological properties from characteristic DNA alkylation reaction. Herein, first description yatakemycin is detailed, constituting such study "sandwiched" this class. Thus, event, sequence selectivity, relative rate efficiency, reversibility reaction are described.
Herein we report the development of an automated deoxygenative C(sp2)-C(sp3) coupling aryl bromide with alcohols to enable parallel medicinal chemistry. Alcohols are among most diverse and abundant building blocks, but their usage as alkyl precursors has been limited. Although metallaphotoredox is becoming a promising strategy form bond, reaction setup limits its widespread application in library synthesis. To achieve high throughput consistency, workflow involving solid-dosing...
A convergent total synthesis of anhydrolycorinone is detailed, enlisting sequential intramolecular Diels−Alder reactions a suitably substituted 2-amino-1,3,4-oxadiazole defining novel oxadiazole → furan benzene strategy.
Convergent total syntheses of anhydrolycorinone, hippadine, and anhydrolycorinium chloride are detailed, enlisting sequential inverse electron demand Diels-Alder reactions an unsymmetrical N-acyl-6-amino-1,2,4,5-tetrazine.
3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition the enzyme an improved toxicity profile versus marketed nitrocatechol tolcapone entacapone. Optimization series was aided by X-ray cocrystal structures novel complex with COMT cofactors SAM Mg2+. The crystal suggest mechanism for these distinct from previously disclosed inhibitors.
The total synthesis of cytostatin, an antitumor agent belonging to the fostriecin family natural products, is described in full detail. convergent approach relied on a key epoxide-opening reaction join two stereotriad units and single-step late-stage stereoselective installation sensitive (Z,Z,E)-triene through beta-chelation-controlled nucleophilic addition. synthetic route provided rapid access C4-C6 stereoisomers cytostatin lactone, which were prepared used define relative stereochemistry...
Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers unique advantage, since this enzyme is primary mechanism elimination cortical areas. Since membrane bound COMT (MB-COMT) predominant isoform human brain, high throughput screen (HTS) to...
Clinically utilized antipsychotic agents share as a common mechanism the ability to antagonize dopamine D2 receptors and it is widely assumed that this activity contributes their efficacy against positive symptoms of schizophrenia. The currently marketed on negative cognitive disease, however, not optimal. One alternate hypothesis "dopamine hypothesis" schizophrenia derives from observation antagonists NMDA receptor better mimic symptomatology in its entirety than do agonists. Findings line...
Abstract Two positron emission tomography radiotracers for the glycine transporter 1 (GlyT1) are reported here. Each radiotracer is a propylsulfonamide‐containing benzamide and was labeled with either carbon‐11 or fluorine‐18. [ 11 C]CMPyPB synthesized by alkylation of 3‐hydroxypyridine precursor using C]MeI, 18 F]MK‐6577 nucleophilic aromatic substitution reaction 2‐chloropyridine precursor. tracer shows good uptake into rhesus monkey brain expected distribution highest in pons, thalamus,...
We have developed convenient and general MAOS protocols for the synthesis of functionalized 1,2,4-triazines, canthines, imidazoles, quinoxalines, pyrazines, quinoxalinones, 5-aminooxazoles.The methodology described herein makes use readily available building blocks, facilitating generation structurally diverse analog libraries to support nascent medicinal chemistry programs.Other advantages over classical heating conditions include shortened reaction times, increased yields, suppression side...
The design, synthesis, and evaluation of a predictably more potent analogue CC-1065 entailing the substitution replacement single skeleton atom in alkylation subunit are disclosed were conducted on basis design principles that emerged from fundamental parabolic relationship between chemical reactivity cytotoxic potency. Consistent with projections, 7-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one (MeCTI) its isomer...