A5046197698- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Toxin Mechanisms and Immunotoxins
- Synthetic Organic Chemistry Methods
- Antibiotic Resistance in Bacteria
- Chemical Synthesis and Analysis
- Nutrition, Genetics, and Disease
- Pharmaceutical and Antibiotic Environmental Impacts
- Cancer therapeutics and mechanisms
- Cyclopropane Reaction Mechanisms
- Synthesis and Biological Evaluation
- Asymmetric Synthesis and Catalysis
- Phenothiazines and Benzothiazines Synthesis and Activities
- Synthesis and Catalytic Reactions
- Nicotinic Acetylcholine Receptors Study
- Transgenic Plants and Applications
- Click Chemistry and Applications
- Receptor Mechanisms and Signaling
- Microbial Metabolic Engineering and Bioproduction
- Advanced Synthetic Organic Chemistry
- Synthesis and Reactions of Organic Compounds
- Synthesis and biological activity
- Pneumocystis jirovecii pneumonia detection and treatment
- Cancer-related gene regulation
- Ion channel regulation and function
Eloxx Pharmaceuticals (United States)
2022-2023
Tetraphase Pharmaceuticals (United States)
2011-2017
University of Michigan
1997-1999
Ann Arbor Center for Independent Living
1999
This and the accompanying report (DOI: 10.1021/jm201467r ) describe design, synthesis, evaluation of a new generation tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through recently developed total synthesis approach. These fluorocyclines possess potent activities against multidrug resistant (MDR) Gram-positive Gram-negative pathogens. One fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline...
Utilizing a fully synthetic route to tetracycline analogues, the C-9 side-chain of fluorocyclines was optimized for both antibacterial activity and oral efficacy. Compounds were identified that overcome efflux (tet(K), tet(A)) ribosomal protection (tet(M)) tetracycline-resistance mechanisms are active against Gram-positive Gram-negative organisms. A murine systemic infection model used as an efficacy screen rapidly identify compounds with bioavailability. Two exhibit bioavailability in rat...
Process research and development of the first fully synthetic broad spectrum 7-fluorotetracycline in clinical is described. The process utilizes two key intermediates a convergent approach. transformation Michael–Dieckmann reaction between suitable substituted aromatic moiety cyclohexenone derivative. Subsequent deprotection acylation provide desired active pharmaceutical ingredient good overall yield.
Employing a highly efficient total synthesis approach, we synthesized and evaluated for antibacterial activity diverse novel pentacycline analogs with systematic variations at C7, C8, C9, C10. Certain substitution groups, as well patterns various positions, were found to be preferred increased activity. A number of displayed potent in vitro vivo, especially against Gram-positive organisms. Several have also shown promising oral bioavailability rats cynomolgus monkey.
The cholinergic anti-inflammatory pathway can downregulate inflammation via the release of acetylcholine (ACh) by vagus nerve. This neurotransmitter binds to α7 subunit nicotinic receptors (α7nAChR), expressed on macrophages and other immune cells. We tested pharmacological functional profile two novel compounds, PMP-311 PMP-072 investigated their role in modulating collagen-induced arthritis (CIA) mice.Both compounds were characterized with binding, electrophysiological, pharmacokinetic...
A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) ribosomal protection (tet(M)) tetracycline resistance mechanisms are active against Gram-positive Gram-negative organisms. Two compounds exhibit comparable efficacy to marketed tetracyclines in vivo models bacterial infection.
Herein we report the design, synthesis, and structure-activity relationships for a new class of α7 nicotinic acetylcholine receptor (nAChR) modulators based on 2-((pyridin-3-yloxy)methyl)piperazine scaffold. The oxazolo[4,5-b]pyridine, (R)-18, 4-methoxyphenylurea, (R)-47, were identified as potent selective nAChR with favorable in vitro safety profiles good oral bioavailability mouse. Both compounds shown to significantly inhibit cellular infiltration murine model allergic lung inflammation....
A series of novel hexacyclic tetracycline analogues ("hexacyclines") was designed, synthesized, and evaluated for antibacterial activity against a wide range clinically important bacteria isolates, including multidrug-resistant, Gram-negative pathogens. Valuable structure–activity relationships were identified, several hexacyclines displayed potent, broad spectrum activity, promising anti-Pseudomonas aeruginosa in vitro vivo.
Treatment of a (2-azaallyl)stannane with HF·pyridine generated nonstabilized N-unsubstituted azomethine ylide, which was found to undergo an efficient and stereoselective dipolar cycloaddition phenyl vinyl sulfone produce trans-2,5-dialkylpyrrolidine that further transformed into the dendrobatid alkaloid indolizidine 239CD.
The C-8 position of the tetracyclines has been largely underexplored because limitations in traditional semisynthetic techniques. Employing a total synthetic approach allowed for modifications at C-7 and positions, enabling generation structure–activity relationships overcoming two most common tetracycline bacterial-resistance mechanisms: ribosomal protection (tet(M)) efflux (tet(A)). Ultimately, several compounds were identified with balanced activity against both Gram-positive...
Ribosomes in cancer cells accumulate numerous patient-specific structural and functional modifications that facilitate tumor progression by modifying protein translation. We have taken a unique synthetic chemistry approach to generate novel macrolides, Ribosome modulating agents (RMA), are proposed act distal catalytic sites exploit ribosome heterogeneity. The RMA ZKN-157 shows two levels of selectivity: (i) selective translation inhibition subset proteins enriched for components the...
<div>Abstract<p>Ribosomes in cancer cells accumulate numerous patient-specific structural and functional modifications that facilitate tumor progression by modifying protein translation. We have taken a unique synthetic chemistry approach to generate novel macrolides, Ribosome Modulating Agents (RMAs), are proposed act distal catalytic sites exploit ribosome heterogeneity. The RMA ZKN-157 shows two levels of selectivity: 1) selective translation inhibition subset proteins...
<p>Supplementary methods</p>
<p>FACS analysis demonstrating ZKN-157 selectively induces cell cycle arrest and apoptosis</p>
<div><p>Ribosomes in cancer cells accumulate numerous patient-specific structural and functional modifications that facilitate tumor progression by modifying protein translation. We have taken a unique synthetic chemistry approach to generate novel macrolides, Ribosome modulating agents (RMA), are proposed act distal catalytic sites exploit ribosome heterogeneity. The RMA ZKN-157 shows two levels of selectivity: (i) selective translation inhibition subset proteins enriched for...
<p>ZKN-157- chemical characterization</p>
<p>Supplementary methods</p>
<p>Results for pSILAC Mass Spec study demonstrating ZKN-157 inhibits translation of a subset proteins</p>
<p>ZKN-157- chemical characterization</p>