Design and syntheses of permethyl ningalin B analogues: Potent multidrug resistance (MDR) reversal agents of cancer cells

Pu Yong Zhang, Iris L.K. Wong, Clare S.W. Yan, Xiao Yu Zhang, Tao Jiang, Ming Cheung Chow, Sheng Biao Wan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

47 Citations (Scopus)


A series of novel N-arylalkyl-3,4-diaryl-substituted pyrrole-2,5-diones were synthesized. They exhibited promising P-gp modulating activity in a P-gp overexpressing breast cancer cell line (LCC6MDR). Compound 6 (with three methoxy groups at D-ring) displayed the highest P-gp modulating activity. 6 at 1 μM can sensitize LCC6MDR cells toward paclitaxel by 18.2-fold. Interestingly, a synergy on modulating P-gp was noted when 6 and 25 were used together (fractional inhibitory concentration index FICI = 0.42). Combination of 6 (0.5 μM) and 25 (0.5 μM) resulted in a 66-fold sensitization of LCC6MDR cells toward paclitaxel. They also reversed P-gp mediated doxorubicin (DOX) and vincristine resistance. Kinetic characterization suggests that permethyl ningalin B analogues likely act as a noncompetitive inhibitor of P-gp-mediated DOX transport (Ki= 5.4-5.8 μM). The present study demonstrates that synthetic analogues of permethyl ningalin B can be employed as effective and safe modulators of P-gp-mediated drug resistance in cancer cells.
Original languageEnglish
Pages (from-to)5108-5120
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number14
Publication statusPublished - 22 Jul 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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