A5018919952- Asymmetric Synthesis and Catalysis
- Cyclopropane Reaction Mechanisms
- Organic Chemistry Cycloaddition Reactions
- Synthesis and Catalytic Reactions
- Oxidative Organic Chemistry Reactions
- Synthetic Organic Chemistry Methods
- Catalytic C–H Functionalization Methods
- DNA Repair Mechanisms
- Catalytic Cross-Coupling Reactions
- Synthesis and Reactions of Organic Compounds
- Crystallization and Solubility Studies
- PARP inhibition in cancer therapy
- X-ray Diffraction in Crystallography
- Sesquiterpenes and Asteraceae Studies
- Liver physiology and pathology
- Quinazolinone synthesis and applications
- Chemical Thermodynamics and Molecular Structure
- Ubiquitin and proteasome pathways
- Thermodynamic properties of mixtures
- Phenothiazines and Benzothiazines Synthesis and Activities
- Enzyme Structure and Function
- Synthesis and Biological Activity
- Cancer therapeutics and mechanisms
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- CRISPR and Genetic Engineering
University of Arkansas for Medical Sciences
2019-2024
United Utilities (United Kingdom)
2018
University of Arkansas at Little Rock
2012-2017
Washington University in St. Louis
2011-2015
Alvin J. Siteman Cancer Center
2014-2015
Pfizer (United States)
2010-2012
Inova Health System
2007
Vifor Pharma (United States)
2003
University of Sheffield
1999-2001
Swansea University
1997-2000
Abstract Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that expression is upregulated in many cancers. We employed chemical library screening identify optimize methylxanthine derivatives as selective bioavailable Multiple crystal structures reveal how...
Abstract Polymerase theta (Polθ) acts in DNA replication and repair, its inhibition is synthetic lethal BRCA1 BRCA2-deficient tumor cells. Novobiocin (NVB) a first-in-class inhibitor of the Polθ ATPase activity, it currently being tested clinical trials as an anti-cancer drug. Here, we investigated molecular mechanism NVB-mediated inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational cellular assays, found NVB non-competitive ATP...
To study the mechanism(s) controlling expression of tumor-associated aldehyde dehydrogenase (tumor ALDH), which appears during rat hepatocarcinogenesis, cDNAs encoding this isozyme were cloned and identified with an antibody probe. Poly(A)-containing RNA from HTC hepatoma cells, have been shown to possess high levels tumor ALDH, was used as template synthesize double-stranded cDNA. The cDNA methylated protect internal sites. Two different synthetic DNA linkers added sequentially insure...
Hepatocyte growth factor activators (HGFA), matriptase, and hepsin are S1 family trypsin-like serine proteases. These proteases proteolytically cleave the single-chain zymogen precursors, pro-HGF (hepatocyte factor), pro-MSP (macrophage stimulating protein) into active heterodimeric forms. HGF MSP activating ligands for oncogenic receptor tyrosine kinases (RTKs), c-MET RON, respectively. We have discovered first substrate-based ketothiazole inhibitors of HGFA, matriptase hepsin. The...
DNA double-strand break (DSB) repair is initiated by MRE11 nuclease for both homology-directed (HDR) and alternative end joining (Alt-EJ). Here, we found that GRB2, crucial to timely proliferative RAS/MAPK pathway activation, unexpectedly forms a biophysically validated GRB2-MRE11 (GM) complex efficient HDR initiation. GRB2-SH2 domain targets the GM phosphorylated H2AX at DSBs. GRB2 K109 ubiquitination E3 ubiquitin ligase RBBP6 releases promoting HDR. depletion results in prolonged defects....
Abstract Drug discovery relies on efficient identification of small-molecule leads and their interactions with macromolecular targets. However, understanding how chemotypes impact mechanistically important conformational states often remains secondary among high-throughput methods. Here, we present a pipeline integrating time-resolved, small-angle X-ray scattering (TR-HT-SAXS) classic fragment screening applied to allosteric the mitochondrial import oxidoreductase apoptosis-inducing factor...
Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors the Tissue Factor/Factor VIIa (TF/VIIa) complex. The crystal structure tripeptide-alpha-ketothiazole complexed with TF/VIIa was utilized in docking experiment identify core as starting scaffold. could orient substituents correct spatial arrangement probe S1, S2, S3 pockets enzyme. A multistep PASP designed prepare substituted pyrazinones...
The sesquiterpene lactones dehydroleucodine (1) and leucodine (2) were isolated from Gynoxys verrucosa, a species used in traditional medicine southern Ecuador. activity of these compounds was determined against eight acute myeloid leukemia (AML) cell lines compared with their normal peripheral blood mononuclear cells. Compound 1 showed cytotoxic the tested lines, LD50 values between 5.0 18.9 μM. 2 inactive all demonstrating that exocyclic methylene lactone ring is required for activity....
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIntramolecular [4+3] Cycloadditions. Studies of Relative Asymmetric InductionMichael Harmata, Chandra B. Gamlath, Charles L. Barnes, and Darin E. JonesCite this: J. Org. Chem. 1995, 60, 16, 5077–5092Publication Date (Print):August 1, 1995Publication History Published online1 May 2002Published inissue 1 August 1995https://pubs.acs.org/doi/10.1021/jo00121a028https://doi.org/10.1021/jo00121a028research-articleACS PublicationsRequest reuse...
A range of C2-symmetric, chiral CuII·bisoxazoline complexes were tested as catalysts for the asymmetric Diels−Alder cycloaddition between cyclopentadiene and a α-sulfenylacrylates. The optimum acrylate was ethyl α-phenylthioacrylate catalyst bisoxazoline derived from phenylalanine which, upon complexation with Cu(SbF6)2, gave cycloadducts in 92% yield, 88% de >95% ee endo product. α-phenylthio ester moiety easily converted into carbonyl group furnishing (1S,4S)-norbornenone high...