653572-66-8Relevant academic research and scientific papers
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.
Structure-activity relationship study of permethyl ningalin B analogues as P-glycoprotein chemosensitizers
Bin, Jin Wen,Wong, Iris L. K.,Hu, Xuesen,Yu, Zhang Xiao,Xing, Li Fu,Jiang, Tao,Chow, Larry M. C.,Biao, Wan Sheng
, p. 9057 - 9070 (2014/01/06)
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.
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.
Catechol-Substituted L-Chicoric acid analogues as HIV integrase inhibitors
Lee, Jae Yeol,Yoon, Kwon Joong,Lee, Yong Sup
, p. 4331 - 4334 (2007/10/03)
HIV integrase catalyzes the integration of HIV DNA copy into the host cell DNA, which is essential for the production of progeny viruses. L-Chicoric acid and dicaffeoylquinic acids, isolated from plants, are well known potent inhibitors of HIV integrase. The common structural features of these inhibitors are caffeic acid derivatives connected to tartaric acid or quinic acid through ester bonds. In the present study, we have synthesized and tested the inhibitory activities of a new type of HIV IN inhibitors, which has catechol groups in place of caffeoyl groups in the structure of L-chicoric acid. Upon substitution of catechol groups at succinic acid, pyrrole-dicarboxylic acid, maleimide or maleic anhydride, the inhibitory activities (IC50=3.8- 23.6 μM) were retained or remarkably increased when compared to parent compound L-chicoric acid (IC50=13.7 μM).
