PubMed · 15550406
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Anne M Holbrook. 2004-11-20. Treating insomnia.. https://doi.org/10.1136/bmj.329.7476.1198
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In this work, the results of studying the possibilities of surface ionization mass spectrometry (SI/MS) and atmosphere pressure thermodesorption surface ionization (APTDSI) spectroscopy for high-sensitivity and selective detection and identification of psychotropic preparations of benzodiazepine derivatives--medazepam, diazepam and chlordiazepoxide--are presented. It has been established that the SI mass spectra of benzodiazepines have a small number of lines and are significantly different from those obtained by electron ionization (EI) and that the molecules of benzodiazepines can be ionized by surface ionization with high efficiency (> or = 100 times and more than by EI) and the current density increases from diazepam to medazepam. It has been found that the APTDSI spectra of benzodiazepine derivatives have two characteristic maxima connected with energy of sublimation and desorption. The ionization efficiency is several C/g (Coulomb per gram), the linear range of the concentration dependence is 3-4 orders of a magnitude. The results obtained by the SI/MS and APTDSI methods have been compared with those obtained by the conventional TLC and GC/MS with electron ionization.
[reaction: see text] A novel methodology was developed for the efficient synthesis of 4-chloro-pyrimido[4,5-b][1,4]benzodiazepines. The key is the intramolecular Friedel-Crafts cyclization of 5-amino-4-(N-substituted)anilino-6-chloropyrimidine with either a carboxylic acid or its derivatives to construct the 4-chloro-pyrimido[4,5-b][1,4]benzodiazepine core. Subsequent nucleophilic substitution allows the introduction of one more diversity point in the target molecules. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.
HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their alpha-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.