Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile

Monofunctional platinum(II) complexes of general formula cis -[Pt(NH ₃) ₂(N -heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that o...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-07, Vol.109 (30), p.11987-11992
Main Authors: Park, Ga Young, Wilson, Justin J, Song, Ying, Lippard, Stephen J
Format: Article
Language:English
Subjects:
Adducts
ammonia
Antineoplastic Agents - chemistry
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Antineoplastics
Binding sites
Biological Sciences
Cell culture techniques
Cell lines
Chemical compounds
Chemistry
cisplatin
cross-linking reagents
crosslinking
Crystallography, X-Ray
Deoxyguanine Nucleotides - metabolism
Deoxyribonucleic acid
DNA
DNA - metabolism
DNA-directed RNA polymerase
Drug Discovery - methods
drug resistance
Gene Expression Regulation, Neoplastic - drug effects
Genetic Vectors
HT29 cells
hydrophobicity
Inhibitory Concentration 50
Kinetics
Ligands
luciferase
Luciferases
mammals
methionine
Models, Molecular
Molecular Structure
nitrates
Organoplatinum Compounds - chemistry
Organoplatinum Compounds - metabolism
Organoplatinum Compounds - pharmacokinetics
Organoplatinum Compounds - pharmacology
Pharmaceuticals
Phenanthridines - chemistry
Phenanthridines - metabolism
Phenanthridines - pharmacokinetics
Phenanthridines - pharmacology
Physical Sciences
Platinum
Platinum Compounds - chemistry
Platinum Compounds - metabolism
Platinum Compounds - pharmacokinetics
Platinum Compounds - pharmacology
pyridines
Reactivity
RNA polymerase
X-radiation
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Summary:Monofunctional platinum(II) complexes of general formula cis -[Pt(NH ₃) ₂(N -heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N -heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N -heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis -[Pt(NH ₃) ₂(phenanthridine)Cl]NO ₃, which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5′-deoxyguanosine monophosphate than to N -acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1207670109