ABSTRACT
The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition mechanism enabling the design of stable analogues.
ABSTRACT
The polyethylene glycol (PEG) moiety has become increasingly important in medicinal chemistry. Herein, we describe the PEG functionalization of amines via hydrogen borrowing reductive amination. This was accomplished using the [Ru(p-cymene)Cl2]2 catalyst and phosphorus-containing ligand dppf or DPE to yield a variety of PEGylated primary and secondary amine products. Furthermore, we illustrate the utility of this method with the synthesis of quetiapine (Seroquel) in 62% isolated yield.
ABSTRACT
C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.
Subject(s)
Amines/chemical synthesis , Electrochemical Techniques , Amination , Amines/chemistry , Catalysis , Density Functional Theory , Kinetics , Molecular StructureABSTRACT
Along with amide bond formation, Suzuki cross-coupling, and reductive amination, the Buchwald-Hartwig-Ullmann-type amination of aryl halides stands as one of the most employed reactions in modern medicinal chemistry. The work herein demonstrates the potential of utilizing electrochemistry to provide a complementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions. Of note is the scalability, functional-group tolerance, rapid rate, and the ability to employ a variety of aryl donors (Ar-Cl, Ar-Br, Ar-I, Ar-OTf), amine types (primary and secondary), and even alternative X-H donors (alcohols and amides).
Subject(s)
Amines/chemistry , Nickel/chemistry , Alcohols/chemistry , Amination , Benzyl Compounds/chemistry , Catalysis , Electrochemical Techniques , ElectrodesABSTRACT
A practical electrochemical oxidation of unactivated C-H bonds is presented. This reaction utilizes a simple redox mediator, quinuclidine, with inexpensive carbon and nickel electrodes to selectively functionalize "deep-seated" methylene and methine moieties. The process exhibits a broad scope and good functional group compatibility. The scalability, as illustrated by a 50 g scale oxidation of sclareolide, bodes well for immediate and widespread adoption.
Subject(s)
Carbon/chemistry , Hydrogen/chemistry , Electrochemical Techniques , Molecular Structure , Oxidation-ReductionABSTRACT
An unprecedented cheap, mild and easy methodology for an intramolecular Minisci reaction based on a hydrogen atom transfer (HAT) initiated hydrofunctionalization of olefins was developed. The method is suitable for the construction of unusual dihydropyrano-pyridine and 1,2,3,4-tetrahydronaphthiridine structures and, unlike most similar reactions, does not require exclusion of air from the reaction medium.
ABSTRACT
Interleukin-17A (IL-17A) is a principal driver of multiple inflammatory and immune disorders. Antibodies that neutralize IL-17A or its receptor (IL-17RA) deliver efficacy in autoimmune diseases, but no small-molecule IL-17A antagonists have yet progressed into clinical trials. Investigation of a series of linear peptide ligands to IL-17A and characterization of their binding site has enabled the design of novel macrocyclic ligands that are themselves potent IL-17A antagonists.
Subject(s)
Interleukin-17/antagonists & inhibitors , Interleukin-17/chemistry , Peptides, Cyclic/pharmacology , Small Molecule Libraries/pharmacology , Algorithms , Binding Sites , Cells, Cultured , Drug Design , Humans , Keratinocytes/cytology , Keratinocytes/drug effects , Keratinocytes/metabolism , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Molecular Dynamics Simulation , Peptides, Cyclic/chemistry , Protein Binding , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
Lysophospholipase-like 1 (LYPLAL1) is an uncharacterized metabolic serine hydrolase. Human genome-wide association studies link variants of the gene encoding this enzyme to fat distribution, waist-to-hip ratio, and nonalcoholic fatty liver disease. We describe the discovery of potent and selective covalent small-molecule inhibitors of LYPLAL1 and their use to investigate its role in hepatic metabolism. In hepatocytes, selective inhibition of LYPLAL1 increased glucose production supporting the inference that LYPLAL1 is a significant actor in hepatic metabolism. The results provide an example of how a selective chemical tool can contribute to evaluating a hypothetical target for therapeutic intervention, even in the absence of complete biochemical characterization.
Subject(s)
Hydrolases/metabolism , Lysophospholipase/antagonists & inhibitors , Serine/metabolism , Animals , Crystallization , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Humans , Lysophospholipase/chemistryABSTRACT
Reported here are procedures for a one-pot oxidation and rearrangement of propargylamines to synthesize enaminones, with supporting mechanistic studies. Also reported are the extended one-pot syntheses of pyrazoles, including celecoxib and various heterocyclic compounds.
Subject(s)
Pargyline/analogs & derivatives , Propylamines/chemistry , Pyrazoles/chemical synthesis , Sulfonamides/chemical synthesis , Catalysis , Celecoxib , Combinatorial Chemistry Techniques , Molecular Structure , Oxidation-Reduction , Pargyline/chemistry , Pyrazoles/chemistry , Sulfonamides/chemistryABSTRACT
Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
Subject(s)
Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Monobactams/pharmacology , Pyridones/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Escherichia coli/drug effects , Inhibitory Concentration 50 , Klebsiella pneumoniae/drug effects , Male , Microbial Sensitivity Tests , Molecular Structure , Monobactams/chemistry , Monobactams/pharmacokinetics , Pseudomonas aeruginosa/drug effects , Pyridones/chemistry , Pyridones/pharmacokinetics , Rats , Rats, WistarABSTRACT
We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.
Subject(s)
Cross Infection/drug therapy , Drug Discovery , Drug Resistance, Multiple/drug effects , Gram-Negative Bacteria/drug effects , Polymyxins/chemistry , Polymyxins/pharmacology , beta-Alanine/analogs & derivatives , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Dogs , Female , Gram-Negative Bacteria/physiology , Humans , Male , Microbial Sensitivity Tests , Polymyxins/pharmacokinetics , Polymyxins/toxicity , Rats , beta-Alanine/chemistryABSTRACT
Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.
Subject(s)
Drug Resistance, Multiple, Bacterial/drug effects , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , Monobactams/pharmacology , Animals , Binding Sites/drug effects , Blood Proteins/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Gram-Negative Bacterial Infections/microbiology , Humans , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Monobactams/chemical synthesis , Monobactams/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Dual inhibitors of bacterial gyrB and parE based on a 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridine template exhibited MICs (microg/mL) of 0.06-64 (Sau), 0.25-64 (MRSA), 0.06-64 (Spy), 0.06-64 (Spn), and 0.03-64 (FQR Spn). Selected examples were efficacious in mouse sepsis and lung infection models at <50mg/kg (PO dosing).
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , DNA Gyrase/metabolism , DNA Topoisomerase IV/metabolism , Pyridines/pharmacology , Pyridines/therapeutic use , Animals , Anti-Bacterial Agents/chemistry , Gram-Positive Bacteria/drug effects , Imidazoles/chemistry , Imidazoles/pharmacology , Imidazoles/therapeutic use , Lung/drug effects , Lung/microbiology , Mice , Microbial Sensitivity Tests , Pyridines/chemistry , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Rats , Sepsis/drug therapy , Structure-Activity RelationshipABSTRACT
A simple one-pot method for the synthesis of diversely functionalized pyrazoles from aryl nucleophiles, di-tert-butylazodicarboxlate, and 1,3-dicarbonyl or equivalent compounds is presented.
Subject(s)
Hydrocarbons, Halogenated/chemistry , Pyrazoles/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , Pyrazoles/chemistryABSTRACT
An asymmetric synthesis of the cytotoxic natural product, (-)-FR182877 (1), has been achieved. Chirality for the entire structure was established using two (4R)-4-benzyl-2-oxazolidinone-mediated boron aldol reactions. A 19-membered macrocarbocycle was synthesized by the coupling of two fragments using a regioselective Suzuki coupling (17 + 23 --> 26; 84%) and macrocyclization of a beta-keto ester (30 --> 31; 77%). Oxidation of 31 triggered a sequence of stereoselective transannular Diels-Alder reactions (32 -->34; 63%) forming four new rings and seven new stereocenters in the pivotal construction event. This pentacyclic intermediate was subsequently transformed to (-)-FR182877. Semiempirical calculations of the transannular Diels-Alder cycloaddition cascade were carried out to determine the origins of asymmetric induction.
