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Design, synthesis, and characterization of new iron chelators with anti-proliferative activity: structure-activity relationships of novel thiohydrazone analogues.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2007 Nov 29; Vol. 50 (24), pp. 6212-25. Date of Electronic Publication: 2007 Oct 27. - Publication Year :
- 2007
-
Abstract
- Di-2-pyridylketone isonicotinoyl hydrazone Fe chelators utilize the N,N,O-donor set and have moderate anti-proliferative effects. Their closely related N,N,S-thiosemicarbazone analogues, namely, the di-2-pyridylketone thiosemicarbazones, exhibit markedly increased anti-proliferative and redox activity, and this was thought to be due to the inclusion of a sulfur donor atom (Richardson, D. R. et al. J. Med. Chem. 2006, 49, 6510-6521). To further examine the effect of donor atom identity on anti-proliferative activity, we synthesized thiohydrazone analogues of extensively examined aroylhydrazone chelators. The O,N,S-thiohydrazones exhibited decreased anti-proliferative effects compared to their parent aroylhydrazones and reduced redox activity. In contrast, the N,N,S-thiohydrazones showed vastly increased anti-proliferative activity compared to their hydrazone analogues, being comparable to potent thiosemicarbazones. Additionally, N,N,S-thiohydrazone complexes had reversible FeIII/II couples and exhibited increased redox activity. These observations demonstrate that the N,N,S-donor set is critical for potent anti-proliferative efficacy.
- Subjects :
- Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Ascorbic Acid metabolism
Benzoates metabolism
Cell Line
Cell Line, Tumor
Crystallography, X-Ray
Drug Design
Drug Screening Assays, Antitumor
Electrochemistry
Ferrous Compounds chemistry
Ferrous Compounds pharmacology
Humans
Hydrazones chemistry
Hydrazones pharmacology
Hydroxylation
Iron metabolism
Iron Chelating Agents chemistry
Iron Chelating Agents pharmacology
Ligands
Molecular Structure
Oxidation-Reduction
Structure-Activity Relationship
Thiones chemistry
Thiones pharmacology
Transferrin metabolism
Antineoplastic Agents chemical synthesis
Ferrous Compounds chemical synthesis
Hydrazones chemical synthesis
Iron Chelating Agents chemical synthesis
Thiones chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 50
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17963372
- Full Text :
- https://doi.org/10.1021/jm070839q