Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors

Zhen Wang, Iris L.K. Wong, Fu Xing Li, Chao Yang, Zhen Liu, Tao Jiang, Ting Fu Jiang, Ming Cheung Chow, Sheng Biao Wan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

11 Citations (Scopus)


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 EC50of 423 nM to reverse paclitaxel resistance. It is non-toxic towards L929 fibroblast with IC50greater 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.
Original languageEnglish
Pages (from-to)5566-5573
Number of pages8
JournalBioorganic and Medicinal Chemistry
Issue number17
Publication statusPublished - 15 May 2015


  • ATP-binding cassette (ABC) transporter
  • Multidrug resistance (MDR)
  • P-glycoprotein (P-gp)
  • P-gp chemosensitizer
  • Permethyl ningalin B

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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