title: Synthesis, activity, and pharmacophore development for isatin-beta-thiosemicarbazones with selective activity toward multidrug-resistant cells.
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.
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
authors.forename: Noeris K
authors.initials: NK
authors.lastname: Salam
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hellawell
authors.forename: Henry M
authors.initials: HM
authors.lastname: Fales
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Kensler
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ludwig
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakács
authors.forename: David E
authors.initials: DE
authors.lastname: Hibbs
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D016923:Cell Death / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000494:pharmacology; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D007211:Indoles; C511311:NSC73306; C013578:isatin beta-thiosemicarbazone; D007510:Isatin