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

被引：155

作者：

Hall, Matthew D. ^{[1
]}

Salam, Noeris K. ^{[2
]}

Hellawell, Jennifer L. ^{[1
]}

Fales, Henry M. ^{[3
]}

Kensler, Caroline B. ^{[3
]}

Ludwig, Joseph A. ^{[4
]}

Szakacs, Gergely ^{[5
]}

Hibbs, David E. ^{[2
]}

Gottesman, Michael M. ^{[1
]}

机构：

[1] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA

[2] Univ Sydney, Fac Pharm, Pharmaceut Chem Div, Grp Biomol Struct & Informat, Sydney, NSW 2006, Australia

[3] NHLBI, Lab Appl Mass Spectrometry, NIH, Bethesda, MD 20892 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA

[5] Hungarian Acad Sci, Inst Enzymol, H-1113 Budapest, Hungary

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 10期

基金：

美国国家卫生研究院; 澳大利亚研究理事会;

关键词：

PRIMARY CYTOTOXICITY EVALUATION; RIBONUCLEOTIDE REDUCTASE; 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE; IRON CHELATORS; PHASE-I; CANCER; INHIBITOR; DISCOVERY; TRANSPORTERS; DERIVATIVES;

D O I：

10.1021/jm800861c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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-beta-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.

引用

页码：3191 / 3204

页数：14

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