16 research outputs found
Electrochemical Aminoxyl-Mediated α-Cyanation of Secondary Piperidines for Pharmaceutical Building Block Diversification
Secondary
piperidines are ideal pharmaceutical building blocks
owing to the prevalence of piperidines in commercial drugs. Here,
we report an electrochemical method for cyanation of the heterocycle
adjacent to nitrogen without requiring protection or substitution
of the NâH bond. The reaction utilizes ABNO (9-azabicyclononane N-oxyl) as a catalytic mediator. Electrochemical oxidation
of ABNO generates the corresponding oxoammonium species, which promotes
dehydrogenation of the 2° piperidine to the cyclic imine, followed
by addition of cyanide. The low-potential, mediated electrolysis process
is compatible with a wide range of heterocyclic and oxidatively sensitive
substituents on the piperidine ring and enables synthesis of unnatural
amino acids
Current status and future prospects for enabling chemistry technology in the drug discovery process [version 1; referees: 2 approved]
This review covers recent advances in the implementation of enabling chemistry technologies into the drug discovery process. Areas covered include parallel synthesis chemistry, high-throughput experimentation, automated synthesis and purification methods, flow chemistry methodology including photochemistry, electrochemistry, and the handling of âdangerousâ reagents. Also featured are advances in the âcomputer-assisted drug designâ area and the expanding application of novel mass spectrometry-based techniques to a wide range of drug discovery activities
A rearrangement of 3-hydroxyazetidines into 2-oxazolines
A novel rearrangement sequence of 3-hydroxyazetidines via a Ritter initiated cascade provides highly substituted 2-oxazolines in high yields. The reaction conditions and substrate scope of the transformation have been studied demonstrating the generality of the process. The derived products can also be functionalized in order to undergo further intramolecular cyclisation leading to a new class of macrocycle. The final cyclisation step was shown to be a transformation amenable to continuous flow processing allowing for a dramatic reduction in the reaction time and simple scale-up
A high-capacity scintillation proximity assay for the discovery and evaluation of ZAP-70 tandem SH2 domain antagonists
A scintillation proximity assay (SPA) is described, which quantitates the ability of compounds to inhibit the binding interaction of a select phosphopeptide with the tandem SH2 domains of the ZAP-70 protein tyrosine kinase. The method is based on the ability of a truncated ZAP-70 tandem SH2 domain-derived peptide to bind an 125I-labeled, diphosphorylated peptide corresponding to the human T-cell receptor ζ-1 immunoglobulin receptor family tyrosine-based activation motif (ITAM). ZAP-70 tandem SH2 domain peptide was biotinylated and bound to streptavidin-coated SPA beads. 125I-labeled ζ-1 ITAM ([125I]-ζ-1 ITAM) bound to immobilized ZAP-70 tandem SH2 domain peptide in a saturable, time- and peptide concentration-dependent fashion. Unlabeled diphosphorylated ζ-1 ITAM competed binding with an ICso value equal to approximately 10-15 nM. Binding of ζ-1 ITAM to the ZAP-70 tandem SH2 domain was dependent on the cooperative interaction of the dual phosphotyrosine residues. Unlabeled monotyrosyl-phosphorylated peptides failed to compete with [125I]-ζ-1 ITAM binding to ZAP-70 SH2 domain. Also, labeled monotyrosyl-phosphorylated peptides failed to associate with the ZAP-70 SH2 domain in direct binding studies. Association and dissociation binding kinetics were determined to be extremely rapid at room temperature, reaching equilibrium within 5 min. The Kd for [125I]-ζ-1 ITAM binding to ZAP-70 tandem SH2 domain peptide was determined by Scatchard analysis to be 1.5-2 nM. The SPA assay was adapted for automated, high-capacity screening, which allowed evaluation of 23,040 small molecular weight compounds per day. The assay is useful for both drug discovery and as a research tool for the study of binding interactions between signal-transducing molecules critical for T-cell activation
High-Temperature Boc Deprotection in Flow and Its Application in Multistep Reaction Sequences
A simplified Boc deprotection using
a high-temperature flow reactor
is described. The system afforded the qualitative yield of a wide
variety of deprotected substrates within minutes using acetonitrile
as the solvent and without the use of acidic conditions or additional
workups. Highly efficient, multistep reaction sequences in flow are
also demonstrated wherein no extraction or isolation was required
between steps
HighâThroughput Reaction Screening with Nanomoles of Solid Reagents Coated on Glass Beads
Synthesis of Fused Pyrimidinone and Quinolone Derivatives in an Automated High-Temperature and High-Pressure Flow Reactor
Fused pyrimidinone and quinolone
derivatives that are of potential
interest to pharmaceutical research were synthesized within minutes
in up to 96% yield in an automated Phoenix high-temperature and high-pressure
continuous flow reactor. Heterocyclic scaffolds that are either hard
to synthesize or require multisteps are readily accessible using a
common set of reaction conditions. The use of low-boiling solvents
along with the high conversions of these reactions allowed for facile
workup and isolation. The methods reported herein are highly amenable
for fast and efficient heterocycle synthesis as well as compound scale-ups