Rational design and synthesis of 6-aryl-6H-benzo[c]chromenes as non-steroidal progesterone receptor antagonists for use against cancers.

Autor: Qin J; Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Water Pollution Control and Resource Reuse, School of Environmental Science and Engineering, Shandong University, Qingdao, Shandong 266237, China., Qu S; School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Zhu K; College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, China., Cheng Y; Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Pan G; Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Jing W; Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China., Liu X; School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China., Sun X; Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: sunxia@sdu.edu.cn., Liu L; School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China. Electronic address: leiliu@sdu.edu.cn.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2021 Feb 15; Vol. 32, pp. 116003. Date of Electronic Publication: 2021 Jan 09.
DOI: 10.1016/j.bmc.2021.116003
Abstrakt: Progesterone receptor (PR) antagonists have been found to be effective for treating certain human cancers. However, the steroidal structure of PR antagonists could bind to other hormone receptors, thus leading to serious side effects. On the other hand, non-steroidal PR antagonists have rarely been evaluated for their anti-cancer efficacy. Therefore, identifying novel non-steroidal PR antagonists possessing potent anti-cancer efficacy would be an attractive project to pursue. In this study, we presented a new metal-free oxidative CH arylation method to rapidly synthesize a series of 6-aryl-6H-benzo[c]chromene derivatives. Multiple cancer cell lines were used for their anti-cancer activity screening. An extensive analysis of structure-activity relationships (SAR) of the derivatives revealed that compounds 32 and 34 markedly inhibited the proliferation of MCF-7 cells with IC 50 values of 6.32 ± 0.52 μM and 5.71 ± 0.49 μM, respectively. Further investigation indicated that derivatives 32 and 34 could elevate the expression of p21 and decrease the expressions of CDK4 and cyclin D1, leading to cell cycle arrest at G0/G1 phase. In addition, derivatives 32 and 34 could induce apoptosis of MCF-7 cells in both dose- and time-dependent manners by activation of p53 pathway, i.e., activation of Cleaved Caspase-3, p53 and P-p53 as well as elevation of the Bax/Bcl-2 ratio. Docking of derivatives 32 and 34 into a PR homology model exhibited potent PR antagonistic activity indicating the 6-aryl-6H-benzo[c]chromene derivatives are promising PR antagonists. We envisioned that derivatives 32 and 34 might be potential anti-cancer drug candidates as novel therapeutic treatment for breast cancer.
(Copyright © 2021. Published by Elsevier Ltd.)
Databáze: MEDLINE
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