Synthesis, Activity, and Pharmacophore Development for Isatin-β-thiosemicarbazones with Selective Activity toward Multidrug-Resistant Cells

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• 作者：Matthew D. Hall ; Noeris K. Salam ; Jennifer L. Hellawell ; Henry M. Fales ; Caroline B. Kensler ; Joseph A. Ludwig ; Gergely Szakcs ; David E. Hibbs ; Michael M. Gottesman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 28, 2009
• 年：2009
• 卷：52
• 期：10
• 页码：3191-3204
• 全文大小：447K
• 年卷期：v.52,no.10(May 28, 2009)
• ISSN：1520-4804

文摘

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.