653572-66-8Relevant articles and documents
Extending the structure?activity relationship study of marine natural ningalin B analogues as P-glycoprotein inhibitors
Yang, Chao,Wong, Iris L.K.,Peng, Kai,Liu, Zhen,Wang, Peng,Jiang, Tingfu,Jiang, Tao,Chow, Larry M.C.,Wan, Sheng Biao
, p. 795 - 806 (2016/10/25)
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 EC50of 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.
Design and syntheses of permethyl ningalin B analogues: Potent multidrug resistance (MDR) reversal agents of cancer cells
Zhang, Pu Yong,Wong, Iris L. K.,Yan, Clare S. W.,Zhang, Xiao Yu,Jiang, Tao,Chow, Larry M. C.,Wan, Sheng Biao
experimental part, p. 5108 - 5120 (2010/09/16)
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.
