Structure-activity relationship study of permethyl ningalin B analogues as P-glycoprotein chemosensitizers

Jin Wen Bin, Iris L K Wong, Xuesen Hu, Zhang Xiao Yu, Li Fu Xing, Tao Jiang, Ming Cheung Chow, Wan Sheng Biao

Research output: Journal article publicationJournal articleAcademic researchpeer-review

29 Citations (Scopus)


A novel series of permethyl ningalin B analogues were synthesized and evaluated for their P-glycoprotein (P-gp)-modulating activities in a P-gp-overexpressing breast cancer cell line (LCC6MDR). Compounds 35 and 37, which possess one methoxy group and one benzyloxy group at aryl ring C, displayed the most potent P-gp-modulating activity. A 1 μM concentration of 35 and 37 resensitized LCC6MDR cells toward paclitaxel by 42.7-fold, with respective EC50 values of 93.5 and 110.0 nM. Their mechanism of P-gp modulation is associated with an increase in intracellular drug accumulation. Their advantages also include low cytotoxicity (IC50 for L929 fibroblast >100 μM) and high therapeutic indexes (>909 after normalization with their EC50 values). 35 is not a substrate of P-gp. They are potentially dual-selective modulators for both P-gp and breast cancer resistance protein transporters. The present study demonstrates that these new compounds can be employed as effective and safe modulators of P-gp-mediated drug resistance in cancer cells.
Original languageEnglish
Pages (from-to)9057-9070
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number22
Publication statusPublished - 27 Nov 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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