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

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.
AuthorsXiaoke Gu, Yanfei Jiang, Yingying Qu, Jing Chen, Dingding Feng, Chenglin Li, Xiaoxing Yin
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 145 Pg. 379-388 (Feb 10 2018) ISSN: 1768-3254 [Electronic] France
PMID29335204 (Publication Type: Journal Article)
CopyrightCopyright © 2018 Elsevier Masson SAS. All rights reserved.
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Azepines
  • Biphenyl Compounds
  • bifendate
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Azepines (chemistry, pharmacology)
  • Biphenyl Compounds (chemical synthesis, chemistry, pharmacology)
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple (drug effects)
  • Drug Resistance, Neoplasm (drug effects)
  • Drug Screening Assays, Antitumor
  • Humans
  • K562 Cells
  • Molecular Structure
  • Neoplasms (drug therapy, metabolism, pathology)
  • Structure-Activity Relationship

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