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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040763n

[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.