Document Report Card

ID: ALA1138507

Journal: J Med Chem

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

Authors: Hall MD, Salam NK, Hellawell JL, Fales HM, Kensler CB, Ludwig JA, Szakács G, Hibbs DE, Gottesman MM.

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.

CiteXplore: 19397322

DOI: 10.1021/jm800861c