Practical synthesis of potential endothelin receptor antagonists of 1,4-benzodiazepine-2,5-dione derivatives bearing substituents at the C3-, N1- and N4-positions
| Autor: | Tong-Ing Ho, Jim-Min Fang, Bor-Wen Ko, Hui-Ming Yu, Ming-Yi Chen, Yu Chang, Ming-Fu Cheng, Yeun-Min Tsai |
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| Rok vydání: | 2006 |
| Předmět: |
Endothelin Receptor Antagonists
Stereochemistry Nitrogen CHO Cells Alkylation Biochemistry Chloride Coupling reaction Potassium carbonate chemistry.chemical_compound Cricetinae Anthranilic acid medicine Molecule Animals Humans Physical and Theoretical Chemistry Benzodiazepinones Molecular Structure Receptors Endothelin Aryl Organic Chemistry Carbon Spectrometry Fluorescence chemistry Intramolecular force Calcium Peptides medicine.drug |
| Zdroj: | Organicbiomolecular chemistry. 4(3) |
| ISSN: | 1477-0520 |
| Popis: | The expedient synthesis of various 1,4-benzodiazepine-2,5-dione compounds, particularly those having substituents at the C3-, N1- and N4-positions is achieved. The important features in these synthetic strategies include: (i) using the coupling reaction of isatoic anhydride with alpha-amino ester for direct construction of the core structure of 1,4-benzodiazepine-2,5-dione; (ii) using potassium carbonate as the base of choice for selective alkylation at the N1-site, while using lithiated 2-ethylacetanilide as the required base to furnish the N4-alkylation; and (iii) using 2-nitrobenzoyl chloride as a synthetic equivalent of anthranilic acid to facilitate the polyethylene resin-bound liquid-phase combinatorial synthesis. The prepared 1,4-benzodiazepine-2,5-dione compounds are evaluated for endothelin receptor antagonism by a functional assay that measures the inhibitory activity against the change of intramolecular calcium ion concentration induced by endothelin-1. The preliminary results indicate that 1,4-benzodiazepine-2,5-diones bearing two flanked aryl substituents at the N1- and N4-sites show better inhibitory activity than the corresponding unalkylated and N-monoalkylated compounds. A promising candidate, 1-benzyl-7-chloro-3-isopropyl-4-(3-methoxybenzyl)-1,4-benzodiazepine-2,5-dione (17b), exhibits an IC50 value in low nM range. |
| Databáze: | OpenAIRE |
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