Antitumor-Active Cobalt−Alkyne Complexes Derived from Acetylsalicylic Acid:  Studies on the Mode of Drug Action

• Published in: Journal of medicinal chemistry Vol. 48; no. 2; pp. 622 - 629
• Main Authors: Ott, Ingo, Schmidt, Kathrin, Kircher, Brigitte, Schumacher, Petra, Wiglenda, Thomas, Gust, Ronald
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 27.01.2005
• Subjects: Alkynes - chemical synthesis; Alkynes - chemistry; Alkynes - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Aspirin - analogs & derivatives; Aspirin - chemical synthesis; Aspirin - chemistry; Aspirin - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Nucleus - metabolism; Cobalt; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; DNA - chemistry; Drug Screening Assays, Antitumor; Enzyme-Linked Immunosorbent Assay; General aspects; Humans; Medical sciences; Membrane Proteins; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - metabolism; Antineoplastic agent; Acetylenic compound; Glutathione reductase (NADPH); Cyclooxygenase 2; Cyclooxygenase 1; Cytotoxicity; Molecular interaction; Structure activity relation; Mammary gland; Salicylates; Mechanism of action; Chemical synthesis; Tumor cell; Human; Enzyme; Cobalt Carbonyl Complexes; Organic ligand; Enzyme inhibitor; Transition metal Carbonyl Complexes; Epithelium; In vitro; Biological fixation; Cell line; DNA; Property structure relationship; Oxidoreductases; Lipophilicity; Physicochemical properties
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049326z

Cobalt−alkyne complexes are drugs with remarkable cytotoxicity. From the complexes tested up to now we selected the aspirin derivative [2-acetoxy-(2-propynyl)benzoate]hexacarbonyldicobalt (Co-ASS) as the lead compound. To get more insight into the mode of action, we systematically modified the alkyne ligand and determined the cytotoxic properties of the resulting cobalt complexes. Further investigations were performed on the drug lipophilicity, the cellular uptake into MCF-7 and MDA-MB 231 breast cancer cells, the DNA-binding efficacy, and the nuclear drug content. The ability to inhibit glutathione reductase and cyclooxygenase (COX) enzymes, the binding to the estrogen receptor, and the induction of apoptotic processes were examined for selected compounds. Interestingly, the most antitumor active compounds were potent COX inhibitors (COX-1 and COX-2). The presented results indicate that cobalt−alkyne complexes of the Co-ASS type, represent a new class of organometallic cytostatics with a mode of drug action in which COX inhibition probably plays a major role.