Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/17586
Title: Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors
Authors: Wang, Z
Wong, ILK
Li, FX
Yang, C
Liu, Z
Jiang, T
Jiang, TF
Chow, LMC 
Wan, SB
Keywords: ATP-binding cassette (ABC) transporter
Multidrug resistance (MDR)
P-glycoprotein (P-gp)
P-gp chemosensitizer
Permethyl ningalin B
Issue Date: 2015
Publisher: Elsevier Ltd
Source: Bioorganic and medicinal chemistry, 2015 How to cite?
Journal: Bioorganic and Medicinal Chemistry 
Abstract: 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 EC50 of 423nM to reverse paclitaxel resistance. It is non-toxic towards L929 fibroblast with IC50 greater than 100μM 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 (405ng/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.
URI: http://hdl.handle.net/10397/17586
ISSN: 0968-0896
DOI: 10.1016/j.bmc.2015.07.027
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