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Structure-Activity Relationships of Di-2-pyridylketone, 2-Benzoylpyridine, and 2-Acetylpyridine Thiosemicarbazones for Overcoming Pgp-Mediated Drug Resistance.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2016 Sep 22; Vol. 59 (18), pp. 8601-20. Date of Electronic Publication: 2016 Aug 30. - Publication Year :
- 2016
-
Abstract
- Multidrug 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.
- Subjects :
- Cell Line, Tumor
Copper metabolism
Drug Resistance, Multiple
Humans
Lysosomes drug effects
Lysosomes metabolism
Lysosomes pathology
Models, Molecular
Permeability drug effects
Reactive Oxygen Species metabolism
Structure-Activity Relationship
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Thiosemicarbazones chemistry
Thiosemicarbazones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 59
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27524608
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.6b01050