Antitumor-active cobalt-alkyne complexes derived from acetylsalicylic acid: studies on the mode of drug action.
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.
Ott
Ingo
I
Institute of Pharmacy, Free University of Berlin, Königin Luise Str. 2+4, 14195 Berlin, Germany.
Schmidt
Kathrin
K
Kircher
Brigitte
B
Schumacher
Petra
P
Wiglenda
Thomas
T
Gust
Ronald
R
D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003035:Cobalt; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008565:Membrane Proteins; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D000480:Alkynes; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D009942:Organometallic Compounds; D003035:Cobalt; D004247:DNA; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin