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Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors.

Abstract
In the present study, a total of 9 novel permethyl ningalin B analogs have been synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Among these derivatives, compound 12 with dimethoxy groups at rings A and B and tri-substitution at ring C with ortho-methoxyethylmorpholine, meta-bromo and para-benzyloxy groups displays the most potent P-gp modulating activity with EC50 of 423 nM to reverse paclitaxel resistance. It is non-toxic towards L929 fibroblast with IC50 greater than 100 μM and with selective index greater than 236. Its mechanism to reverse P-gp mediated drug resistance is by virtue of inhibiting transport activity of P-gp, restoring intracellular drug accumulation and eventually chemosensitizing the cancer cells to anticancer drug again. Moreover, compound 12 showed better solubility (405 ng/mL) than hit compound 1 in phosphate buffer (pH 4.0). In summary, our study demonstrates that permethyl ningalin B derivative 12 is non-toxic and efficient P-gp inhibitor that is a potential candidate to be used clinically to reverse P-gp mediated cancer drug resistance.
AuthorsZhen Wang, Iris L K Wong, Fu Xing Li, Chao Yang, Zhen Liu, Tao Jiang, Ting Fu Jiang, Larry M C Chow, Sheng Biao Wan
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 17 Pg. 5566-73 (Sep 01 2015) ISSN: 1464-3391 [Electronic] England
PMID26233798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP-Binding Cassette Transporters
  • Heterocyclic Compounds, 3-Ring
  • ningalin B
Topics
  • ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors, metabolism)
  • ATP-Binding Cassette Transporters (metabolism)
  • Cell Line, Tumor
  • Drug Resistance, Multiple
  • Heterocyclic Compounds, 3-Ring (metabolism)
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship

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