Synthesis, activity, and pharmacophore development for isatin-beta-thiosemicarbazones with selective activity toward multidrug-resistant cells.

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Citation

Hall MD, Salam NK, Hellawell JL, Fales HM, Kensler CB, Ludwig JA, Szakacs G, Hibbs DE, Gottesman MM

Synthesis, activity, and pharmacophore development for isatin-beta-thiosemicarbazones with selective activity toward multidrug-resistant cells.

J Med Chem. 2009 May 28;52(10):3191-204. doi: 10.1021/jm800861c.

PubMed ID
19397322 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
StaurosporineCyclin-dependent kinase 2IC 50 (nM)0.36N/AN/ADetails
StaurosporineGlycogen synthase kinase-3 betaIC 50 (nM)5.2N/AN/ADetails
StaurosporineSerine/threonine-protein kinase pim-1IC 50 (nM)2.7N/AN/ADetails
StaurosporineTyrosine-protein kinase LckIC 50 (nM)4N/AN/ADetails