Naphthalenyl derivatives for hitting P-gp/MRP1/BCRP transporters
Naphthalenyl derivatives for hitting P-gp/MRP1/BCRP transporters
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DOI：
10.1016/j.bmc.2012.12.021
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发表时间：
2013-03-01
影响因子：
3.5
通讯作者：
Perrone, Roberto
中科院分区：
文献类型：
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作者：
Colabufo, Nicola A.;Contino, Marialessandra;Perrone, Roberto
带有恶唑、噻唑或呋喃基异核的取代萘基衍生物已作为先前报道的芳基恶唑和噻唑衍生物的生物等排体进行研究，以研究对 P-gp/BCRP/和 MRP1 转运蛋白活性的阻碍作用。此外，还确定了萘基在调节这些化合物的 P-gp 内在活性中的作用。结果表明，所有萘基衍生物都表现出与我们先前在 SAR 研究中表征的先导化合物相当的 P-gp 活性，但对 BCRP 和 MRP1 泵的活性较低。就内在活性而言，用萘基部分取代芳基导致P-gp抑制剂、杂核碱基上的明确或模糊底物以及萘基片段上的取代基。事实上，恶唑衍生物是：抑制剂（R = H、F、OH）、明确底物（R = OCH3）或模糊底物（R = Br）；噻唑衍生物为：明确底物（R = OCH3、Br）或模糊底物（R = H、F）。最后，呋喃基衍生物是不明确的底物。 (C) 2013 Elsevier Ltd. 保留所有权利。
Substituted naphthalenyl derivatives bearing oxazole, or thiazole or furyl heteronuclei have been carried out as bioisosters of aryl-oxazoles and -thiazoles derivatives previously reported in order to investigate the role of the hindrance on the activity towards P-gp/BCRP/and MRP1 transporters. In addition, the role of naphthalenyl group to modulate P-gp intrinsic activity of these compounds was ascertained.The results demonstrated that all naphthalenyl derivatives displayed comparable P-gp activity with respect to lead compounds previously characterized in our SAR studies but were less active towards BCRP and MRP1 pumps. In terms of intrinsic activity, the replacement of aryl with naphthalenyl moiety led to P-gp inhibitors, unambiguous or ambiguous substrates on the base of the heteronucleus and the substituent on the naphthalenyl fragment. Indeed, oxazole derivatives were: inhibitors (R = H, F, OH), unambiguous substrates (R = OCH3), or ambiguous substrate (R = Br); thiazole derivatives were: unambiguous substrates (R = OCH3, Br), or ambiguous substrates (R = H, F). Finally furyl derivatives were ambiguous substrates. (C) 2013 Elsevier Ltd. All rights reserved.