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Title: Extending the structure-activity relationship study of marine natural ningalin B analogues as P-glycoprotein inhibitors
Authors: Yang, C
Wong, ILK
Peng, K
Liu, Z
Wang, P
Jiang, TF
Jiang, T
Chow, LMC
Wan, SB
Keywords: Ningalin B
Multidrug resistance (MDR)
P-glycoprotein (P-gp)
P-gp chemosensitizer
ATP-Binding cassette (ABC) transporter
Issue Date: 2017
Publisher: Elsevier Masson
Source: European journal of medicinal chemistry, 5 Jan. 2017, v. 125, p. 795-806 How to cite?
Journal: European journal of medicinal chemistry 
Abstract: In the present study, a total of 25 novel ningalin B analogues were synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Preliminary structure activity study shows that A ring and its two methoxy groups are important pharmacophores for P-gp inhibiting activity. Among all derivatives, 23 is the most potent P-gp modulator with EC50 of 120-165 nM in reversing paclitaxel, DOX, vinblastine and vincristine resistance. It is relatively safe to use with selective index at least greater than 606 compared to verapamil. Mechanistic study demonstrates that compound 23 reverses P-gp mediated drug resistance by inhibiting transport activity of P-gp, thereby restoring intracellular drug accumulation. In summary, our study demonstrates that ningalin B analogue 23 is a non-cytotoxic and effective P-gp chemosensitizer that can be used in the future for reversing P-gp mediated clinical cancer drug resistance.
EISSN: 0223-5234
DOI: 10.1016/j.ejmech.2016.09.070
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