药效团
化学
伊萨丁
细胞毒性
数量结构-活动关系
部分
P-糖蛋白
立体化学
流出
氨基脲
结构-活动关系
组合化学
多重耐药
选择性
生物活性
体外
生物化学
有机化学
抗生素
催化作用
作者
Matthew D. Hall,Noeris K. Salam,Jennifer Hellawell,Henry M. Fales,Caroline B. Kensler,Joseph A. Ludwig,Gergely Szakács,David E. Hibbs,Michael M. Gottesman
摘要
We have recently identified a new class of compounds that selectively kill cells that express P-glycoprotein (P-gp, MDR1), the ATPase efflux pump that confers multidrug resistance on cancer cells. Several isatin-β-thiosemicarbazones from our initial study have been validated and a range of analogues synthesized and tested. A number demonstrated improved MDR1-selective activity over the lead, NSC73306 (1). Pharmacophores for cytotoxicity and MDR1 selectivity were generated to delineate the structural features required for activity. The MDR1-selective pharmacophore highlights the importance of aromatic/hydrophobic features at the N4 position of the thiosemicarbazone and the reliance on the isatin moiety as key bioisosteric contributors. Additionally, a quantitative structure−activity relationship (QSAR) model that yielded a cross-validated correlation coefficient of 0.85 effectively predicts the cytotoxicity of untested thiosemicarbazones. Together, the models serve as effective approaches for predicting structures with MDR1-selective activity and aid in directing the search for the mechanism of action of 1.
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