Synthesis and biological evaluation of bifendate derivatives bearing 6,7-dihydro-dibenzo[c,e]azepine scaffold as potential P-glycoprotein and tumor metastasis inhibitors

Synthesis and biological evaluation of bifendate derivatives bearing... As a continuation of previous research, fifteen bifendate derivatives bearing 6,7-dihydro-dibenzo [c,e]azepine scaffold were synthesized and evaluated as P-gp-medicated multidrug resistance (MDR) reversal agents. Biological evaluation indicated that compounds 6k and 9c more potently reversed P-gp-mediated MDR than bifendate and verapamil (VRP) by blocking P-gp mediated drug efflux function and not by decreasing P-gp expression in K562/A02 MDR cells. Interestingly, wound-healing and chamber migration assay showed that 6k and 9c could significantly attenuate the migration of MDA-MB-231 cells. Notably, 6k and 9c could markedly suppress the invasive activity of MDA-MB-231 cells, thus displayed potential anti-metastasis activity. Preliminary mechanism studies indicated that the anti-metastasis activity of 6k and 9c was associated with their inhibitory effect on the activity and expression of MMP-2 and MMP-9. These results, together with the MDR reversal results indicated that compounds 6k and 9c might be promising leads for developing novel anti-cancer agents with P-gp and tumor metastasis inhibitory activities. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Medicinal Chemistry Elsevier

Synthesis and biological evaluation of bifendate derivatives bearing 6,7-dihydro-dibenzo[c,e]azepine scaffold as potential P-glycoprotein and tumor metastasis inhibitors

Synthesis and biological evaluation of bifendate derivatives bearing 6,7-dihydro-dibenzo[c,e]azepine scaffold as potential P-glycoprotein and tumor metastasis inhibitors

European Journal of Medicinal Chemistry 145 (2018) 379e388 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Research paper Synthesis and biological evaluation of bifendate derivatives bearing 6,7-dihydro-dibenzo[c,e]azepine scaffold as potential P-glycoprotein and tumor metastasis inhibitors 1 1 ** Xiaoke Gu , Yanfei Jiang , Yingying Qu, Jing Chen, Dingding Feng, Chenglin Li , Xiaoxing Yin Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China art i cle i nfo abstract Article history: As a continuation of previous research, fifteen bifendate derivatives bearing 6,7-dihydro-dibenzo [c,e] Received 23 October 2017 azepine scaffold were synthesized and evaluated as P-gp-medicated multidrug resistance (MDR) reversal Received in revised form agents. Biological evaluation indicated that compounds 6k and 9c more potently reversed P-gp-mediated 28 December 2017 MDR than bifendate and verapamil (VRP) by blocking P-gp mediated drug efflux function and not by Accepted 5 January 2018 decreasing P-gp expression in K562/A02 MDR cells. Interestingly, wound-healing and chamber migration Available online 9 January 2018 assay showed that 6k and 9c could significantly attenuate the migration of MDA-MB-231 cells. Notably, 6k and 9c could markedly suppress the invasive activity of MDA-MB-231 cells, thus displayed potential Keywords: anti-metastasis activity. Preliminary mechanism studies indicated that the anti-metastasis activity of 6k Bifendate and 9c was associated with their inhibitory effect on the activity and expression of MMP-2 and MMP-9. Dibenzo[c,e]azepine These results, together with the MDR reversal results indicated that compounds 6k and 9c might be P-gp inhibitor Multidrug resistance promising leads for developing novel...
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Publisher
Elsevier
Copyright
Copyright © 2018 Elsevier Masson SAS
ISSN
0223-5234
eISSN
1768-3254
D.O.I.
10.1016/j.ejmech.2018.01.019
Publisher site
See Article on Publisher Site

Abstract

As a continuation of previous research, fifteen bifendate derivatives bearing 6,7-dihydro-dibenzo [c,e]azepine scaffold were synthesized and evaluated as P-gp-medicated multidrug resistance (MDR) reversal agents. Biological evaluation indicated that compounds 6k and 9c more potently reversed P-gp-mediated MDR than bifendate and verapamil (VRP) by blocking P-gp mediated drug efflux function and not by decreasing P-gp expression in K562/A02 MDR cells. Interestingly, wound-healing and chamber migration assay showed that 6k and 9c could significantly attenuate the migration of MDA-MB-231 cells. Notably, 6k and 9c could markedly suppress the invasive activity of MDA-MB-231 cells, thus displayed potential anti-metastasis activity. Preliminary mechanism studies indicated that the anti-metastasis activity of 6k and 9c was associated with their inhibitory effect on the activity and expression of MMP-2 and MMP-9. These results, together with the MDR reversal results indicated that compounds 6k and 9c might be promising leads for developing novel anti-cancer agents with P-gp and tumor metastasis inhibitory activities.

Journal

European Journal of Medicinal ChemistryElsevier

Published: Feb 10, 2018

References

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