Zinc(II): Thiosemicarbazone Complexes Are Localized to the Lysosomal Compartment Where They Transmetallate with Copper Ions to Induce Cytotoxicity

Alexandra E Stacy, Duraippandi Palanimuthu, Paul V Bernhardt, Danuta Kalinowski, Patric J Jansson, Des Richardson

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

As the di-2-pyridylketone thiosemicarbazone (DpT) and 2-acetylpyridine thiosemicarbazone (ApT) series show potent antitumor activity in vitro and in vivo, we synthesized their fluorescent zinc(II) complexes to assess their intracellular distribution. The Zn(II) complexes generally showed significantly greater cytotoxicity than the thiosemicarbazones alone in several tumor cell-types. Notably, specific structure-activity relationships demonstrated the importance of the di-2-pyridyl pharmacophore in their activity. Confocal fluorescence imaging and live cell microscopy showed that the Zn(II) complex of our lead compound, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which is scheduled to enter clinical trials, was localized to lysosomes. Under lysosomal conditions, the Zn(II) complexes were shown to transmetallate with copper ions, leading to redox-active copper complexes that induced lysosomal membrane permeabilization (LMP) and cytotoxicity. This is the first study to demonstrate direct lysosomal targeting of our novel Zn(II)-thiosemicarbazone complexes that mediate their activity via transmetalation with copper ions and LMP.
Original languageEnglish
Pages (from-to)4965-4984
Number of pages20
JournalJournal of Medicinal Chemistry
Volume59
Issue number10
Publication statusPublished - 2016

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