Chalcogenopyrylium compounds as modulators of the ATP-binding cassette transporters P-glycoprotein (P-gp/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1).
Chalcogenopyrylium compounds as modulators of the ATP-binding cassette transporters P-glycoprotein (P-gp/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1).
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DOI：
10.1021/jm3004398
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发表时间：
2012-05
影响因子：
7.3
通讯作者：
Sean P. Ebert;Bryan R Wetzel;Robert L. Myette;G. Conseil;S. Cole;G. Sawada;T. Loo;M. Bartlett;D. Clarke;M. Detty
中科院分区：
文献类型：
--
作者：
Sean P. Ebert;Bryan R Wetzel;Robert L. Myette;G. Conseil;S. Cole;G. Sawada;T. Loo;M. Bartlett;D. Clarke;M. Detty
检查了27种在吡喃鎓核心的杂原子和2-、4-和6-位的取代基上不同的硫属吡喃鎓衍生物对人MRP 1介导的氚化雌二醇葡糖苷酸摄取到由内而外的膜囊泡中的影响，它们对纯化的人P-糖蛋白（P-gp）-His的ATP酶活性的亲和力和刺激其活性的能力（10），以及它们在多药耐药细胞中促进钙黄绿素AM和长春碱摄取的能力。注意到它们对MRP 1和P-gp活性影响的差异，并检查了具有系统取代基变化的第二组thiopyrylium化合物，以进一步细化这些差异。在2-和6-位具有叔丁基取代基的衍生物对两种转运蛋白的抑制活性最低。在4位具有硫代酰胺官能团的衍生物比具有酰胺官能团的衍生物对MRP 1更有活性。相反，在4位具有酰胺官能团的衍生物在P-gp中比具有硫代酰胺官能团的衍生物更有活性。
Twenty-seven chalcogenopyrylium derivatives varying in the heteroatom of the pyrylium core and substituents at the 2-, 4-, and 6-positions were examined for their effect on human MRP1-mediated uptake of tritiated estradiol glucuronide into inside-out membrane vesicles, their affinity for and ability to stimulate the ATPase activity of purified human P-glycoprotein (P-gp)-His(10), and their ability to promote uptake of calcein AM and vinblastine in multidrug-resistant cells. Differences in their effects on MRP1 and P-gp activity were noted, and a second set of thiopyrylium compounds with systematic substituent changes was examined to refine these differences further. Derivatives with tert-butyl substituents in the 2- and 6-positions had the lowest inhibitory activity toward both transporters. Derivatives with thioamide functionality in the 4-position were more active against MRP1 than derivatives with amide functionality. Conversely, derivatives with amide functionality in the 4-position were more active in P-gp than derivatives with thioamide functionality.