jm400930e_si_001.pdf (9.28 MB)
Structure–Activity Relationship Study of Permethyl Ningalin B Analogues as P‑Glycoprotein Chemosensitizers
journal contribution
posted on 2013-11-27, 00:00 authored by Jin Wen Bin, Iris L. K. Wong, Xuesen Hu, Zhang Xiao Yu, Li Fu Xing, Tao Jiang, Larry M. C. Chow, Wan Sheng BiaoA 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.