Investigation of chalcones as selective inhibitors of the breast cancer resistance protein: critical role of methoxylation in both inhibition potency and cytotoxicity.
Investigation of chalcones as selective inhibitors of the breast cancer resistance protein: critical role of methoxylation in both inhibition potency and cytotoxicity.
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DOI：
10.1021/jm2016528
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发表时间：
2012-04-12
影响因子：
7.3
通讯作者：
Boumendjel, Ahcene
中科院分区：
文献类型：
--
作者：
Valdameri, Glaucio;Gauthier, Charlotte;Terreux, Raphael;Kachadourian, Remy;Day, Brian J.;Winnischofer, Sheila M. B.;Rocha, Maria E. M.;Frachet, Veronique;Ronot, Xavier;Di Pietro, Attilio;Boumendjel, Ahcene
ABCG2在抗癌药物外排及相关肿瘤多药耐药中起重要作用。通过对已知ABCG2底物米托蒽醌（mitoxantrone）转运的抑制作用，研究了44种查尔酮及其类似物（1,3-二烷基丙烯酮）中具有低细胞毒性的高效选择性ABCG2抑制剂。6种化合物对ABCG2具有完全抑制作用，IC50值小于0.5µM，具有高选择性。甲氧基取代基的数量和位置似乎对抑制和细胞毒性都至关重要。结果表明，含1个n -甲基-1-吲哚基（化合物38）或1个6′-羟基-2′，4′-二甲氧基-1-苯基（化合物27）（a环）和2、6个甲氧基（b环）的最佳化合物具有较强的抑制作用和较低的毒性。甲氧基取代对第3位和第5位有抑制作用，但对第4位有抑制作用。最后，b环上3,4,5位的甲氧基明显增加细胞毒性，因此应避免使用。
ABCG2 plays a major role in anticancer-drug efflux and related tumor multidrug resistance. Potent and selective ABCG2 inhibitors with low cytotoxicity were investigated among a series of 44 chalcones and analogues (1,3-diarylpropenones), by evaluating their inhibitory effect on the transport of mitoxantrone, a known ABCG2 substrate. Six compounds producing complete inhibition with IC50 values below 0.5 µM and high selectivity for ABCG2 were identified. The number and position of methoxy substituents appeared to be critical for both inhibition and cytotoxicity. The best compounds, with potent inhibition and low toxicity, contained an N-methyl-1-indolyl (compound 38) or a 6′-hydroxyl-2′,4′-dimethoxy-1-phenyl (compound 27) moiety (A-ring) and two methoxy groups at positions 2 and 6 of the 3-phenyl moiety (B-ring). Methoxy substitution contributed to inhibition at positions 3 and 5, but had a negative effect at position 4. Finally, methoxy groups at positions 3, 4, and 5 of the B-ring markedly increased cytotoxicity and, therefore, should be avoided.
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影响因子：
3.5
作者：
Boumendjel, Ahcene;Macalou, Sira;Di Pietro, Attilio
通讯作者：
Di Pietro, Attilio
DOI：
10.1073/pnas.95.26.15665
发表时间：
1998-12-22
影响因子：
11.1
作者：
Doyle, LA;Yang, WD;Ross, DD
通讯作者：
Ross, DD
影响因子：
3.5
作者：
Juvale, Kapil;Pape, Veronika F. S.;Wiese, Michael
通讯作者：
Wiese, Michael
影响因子：
3.5
作者：
Liu, Xiao-Ling;Tee, Hui-Wearn;Go, Mei-Lin
通讯作者：
Go, Mei-Lin
影响因子：
3.8
作者：
Boumendjel, Ahcene;McLeer-Florin, Anne;Boutonnat, Jean
通讯作者：
Boutonnat, Jean