Synthesis, Activity, and Pharmacophore Development for Isatin-β-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-β-thiosemicarbazones from our initial study have been validated, and a range of analogs 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 cytotoxicty 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.

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…that in contrast to the export of toxic substrates, P-gp can directly sensitize MDR cells [15,21,40,43]. Interestingly, the structurally diverse MDR-selective compounds share the ability to chelate metal ions.…”

“…Interestingly, the structurally diverse MDR-selective compounds share the ability to chelate metal ions. In particular, there is a strong link between the thiosemicarbazone backbone and MDR selective toxicity, as exemplified by several isatin-β-thiosemicarbazones including NSC73306 (1a, Figure 1, upper left panel), NSC658339, NSC716765, NSC716766, NSC716768, NSC716771 and NSC716772 (for structures, see Table S1) [15,21,40,43,44]. In addition to these TSCs the pharmacogenomic approach also identified a benzothiazole (NSC693630, Figure 1, upper middle panel) as a candidate MDRselective agent [15].…”

“…The current understanding of the structure activity relationship of MDR selective isatin-β-TSCs suggests a beneficial effect of an aromatic moiety at N4 [21,39]. Similarly, introduction of a phenyl substituent to the N4 position has been shown to increase the toxicity of dipyridylketone TSCs to a comparable extent as terminal dimethylation [23,47].…”

“…Similarly, introduction of a phenyl substituent to the N4 position has been shown to increase the toxicity of dipyridylketone TSCs to a comparable extent as terminal dimethylation [23,47]. In contrast to Dp44mT and NSC73306, the toxicity of the terminally unsubstituted NNS thiosemicarbazone Triapine is attenuated by P-gp [20,21,48].…”

“…In addition to the reported TSC compounds 1a [15,21,40,43,44], the N4 para tolyl derivative M A N U S C R I P T…”