Development of Cobalt(3,4-diarylsalen) Complexes as Tumor Therapeutics

[1,6-Bis(2-hydroxyphenyl)-3,4-diaryl-2,5-diazahexa-1,5-diene]cobalt(II) complexes (cobalt(3,4-diarylsalen)) with 2-, 3-, or 4-OCH3/OH substituents in the 3,4-standing aryl rings were synthesized and tested for antitumor activity in vitro on the MCF-7, MDA-MB 231, and LNCaP/FGC cell lines. The cytoto...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-11, Vol.47 (24), p.5837-5846
Main Authors: Gust, Ronald, Ott, Ingo, Posselt, Diana, Sommer, Klaus
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Aza Compounds - chemical synthesis
Aza Compounds - chemistry
Aza Compounds - pharmacology
Biological and medical sciences
Catalysis
Cell Line, Tumor
Chelating Agents - chemical synthesis
Chelating Agents - chemistry
Cobalt
Drug Screening Assays, Antitumor
General aspects
Humans
Medical sciences
Models, Molecular
Molecular Structure
Organometallic Compounds - chemical synthesis
Organometallic Compounds - chemistry
Organometallic Compounds - pharmacology
Pharmacology. Drug treatments
Stereoisomerism
Structure-Activity Relationship
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Summary:[1,6-Bis(2-hydroxyphenyl)-3,4-diaryl-2,5-diazahexa-1,5-diene]cobalt(II) complexes (cobalt(3,4-diarylsalen)) with 2-, 3-, or 4-OCH3/OH substituents in the 3,4-standing aryl rings were synthesized and tested for antitumor activity in vitro on the MCF-7, MDA-MB 231, and LNCaP/FGC cell lines. The cytotoxicity depended on both the configuration of the diene ligand and the kind of substituents in the 3,4-standing aromatic rings. d,l-7 (2-OCH3), d,l-8 (3-OCH3), and d,l-9 (4-OCH3) were equipotent to cisplatin, while the respective hydroxy-substituted complexes (d,l-10 (2-OH), d,l-11 (3-OH), and d,l-12 (2-OH)) as well as all of the meso-configured compounds (m-7 to m-12) did not influence the cell growth. Interestingly, a high catalytic potency and a rapid and high accumulation in MCF-7 cells (15- to 25-fold compared to the cell culture medium (5 μM)) were demonstrated for m-7 (2-OCH3), m-8 (3-OCH3), and m-9 (4-OCH3). Therefore, a mode of action based on a cobalt-catalyzed oxidative damage of the DNA is not very likely.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm040763n