Synthesis, activity, and pharmacophore development for isatin-beta-thiosemicarbazones with selective activity toward multidrug-resistant cells.
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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
Drug Target Property Measurement pH Temperature (°C) Staurosporine Cyclin-dependent kinase 2 IC 50 (nM) 0.36 N/A N/A Details Staurosporine Glycogen synthase kinase-3 beta IC 50 (nM) 5.2 N/A N/A Details Staurosporine Serine/threonine-protein kinase pim-1 IC 50 (nM) 2.7 N/A N/A Details Staurosporine Tyrosine-protein kinase Lck IC 50 (nM) 4 N/A N/A Details