Synthesis and biological evaluation of novel 1,4-benzodiazepin-3-one derivatives as potential antitumor agents against prostate cancer
| Autor: | Simon Vézina-Dawod, Stéphane Gobeil, Nicolas Gerber, Louis-David Guay, Eric Biron, Martin Perreault |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents 01 natural sciences Biochemistry High-performance liquid chromatography Benzodiazepines Structure-Activity Relationship 03 medical and health sciences Prostate cancer DU145 In vivo Drug Discovery LNCaP Tumor Cells Cultured medicine Humans Molecular Biology Cell Proliferation 030304 developmental biology 0303 health sciences Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Diastereomer Prostatic Neoplasms medicine.disease Combinatorial chemistry 0104 chemical sciences 3. Good health Liver Cell culture Microsome Molecular Medicine Drug Screening Assays Antitumor |
| Zdroj: | Bioorganic & Medicinal Chemistry. 45:116314 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2021.116314 |
| Popis: | A novel tumor suppressing agent was discovered against PC-3 prostate cancer cells from the screening of a 1,4-benzodiazepin-3-one library. In this study, 96 highly diversified 2,4,5-trisubstituted 1,4-benzodiazepin-3-one derivatives were prepared by a two-step approach using sequential Ugi multicomponent reaction and simultaneous deprotection and cyclization to afford pure compounds bearing a wide variety of substituents. The most promising compound showed a potent and selective antiproliferative activity against prostate cancer cell line PC-3 (GI50 = 10.2 µM), but had no effect on LNCAP, LAPC4 and DU145 cell lines. The compound was initially prepared as a mixture of two diastereomers and after their separation by HPLC, similar antiproliferative activities against PC-3 cells were observed for both diastereomers (2S,5S: GI50 = 10.8 µM and 2S,5R: GI50 = 7.0 µM). Additionally, both diastereomers showed comparable stability profiles after incubation with human liver microsomes. Finally, in vivo evaluation of the hit compound with the chick chorioallantoic membrane xenograft assay revealed a good toxicity profile and significant antitumor activity after intravenous injection. |
| Databáze: | OpenAIRE |
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