Show simple item record

dc.contributor.authorStacy, Alexandra E
dc.contributor.authorPalanimuthu, Duraippandi
dc.contributor.authorBernhardt, Paul V
dc.contributor.authorKalinowski, Danuta S
dc.contributor.authorJansson, Patric J
dc.contributor.authorRichardson, Des R
dc.date.accessioned2021-07-29T01:30:10Z
dc.date.available2021-07-29T01:30:10Z
dc.date.issued2016
dc.identifier.issn0022-2623
dc.identifier.doi10.1021/acs.jmedchem.6b01050
dc.identifier.urihttp://hdl.handle.net/10072/406443
dc.description.abstractMultidrug resistance (MDR) mediated by P-glycoprotein (Pgp) represents a significant impediment to successful cancer treatment. The compound, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), has been shown to induce greater cytotoxicity against resistant cells than their nonresistant counterparts. Herein, the structure-activity relationships of selected thiosemicarbazones are explored and the novel mechanism underlying their ability to overcome resistance is further elucidated. Only thiosemicarbazones with electron-withdrawing substituents at the imine carbon mediated Pgp-dependent potentiated cytotoxicity, which was reversed by Pgp inhibition. Treatment of resistant cells with these thiosemicarbazones resulted in Pgp-dependent lysosomal membrane permeabilization (LMP) that relied on copper (Cu) chelation, reactive oxygen species generation, and increased relative lipophilicity. Hence, this study is the first to demonstrate the structural requirements of these thiosemicarbazones necessary to overcome MDR. We also demonstrate the mechanism that enables the targeting of resistant tumors, whereby thiosemicarbazones "hijack" lysosomal Pgp and form redox-active Cu complexes that mediate LMP and potentiate cytotoxicity.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherAMER CHEMICAL SOC
dc.relation.ispartofpagefrom8601
dc.relation.ispartofpageto8620
dc.relation.ispartofissue18
dc.relation.ispartofjournalJournal of Medical Chemistry
dc.relation.ispartofvolume59
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchOrganic chemistry
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3404
dc.subject.fieldofresearchcode3405
dc.subject.fieldofresearchcode3214
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsChemistry, Medicinal
dc.subject.keywordsPharmacology & Pharmacy
dc.subject.keywordsPyridoxal Isonicotinoyl Hyrdrazone
dc.titleStructure-Activity Relationships of Di-2-pyridylketone, 2-Benzoylpyridine, and 2-Acetylpyridine Thiosemicarbazones for Overcoming Pgp-Mediated Drug Resistance
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationStacy, AE; Palanimuthu, D; Bernhardt, PV; Kalinowski, DS; Jansson, PJ; Richardson, DR, Structure-Activity Relationships of Di-2-pyridylketone, 2-Benzoylpyridine, and 2-Acetylpyridine Thiosemicarbazones for Overcoming Pgp-Mediated Drug Resistance, Journal of Medical Chemistry, 2016, 59 (18), pp. 8601-8620
dc.date.updated2021-07-29T01:26:44Z
gro.hasfulltextNo Full Text
gro.griffith.authorRichardson, Des R.


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record