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J Med Chem. 2013 Nov 27;56(22):9057-70. doi: 10.1021/jm400930e. Epub 2013 Nov 14.

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

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  • 1Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China , Qingdao, 266003 Shandong, China.


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.

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