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

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Ingo Ott,^† Kathrin Schmidt,^† Brigitte Kircher,^‡ Petra Schumacher,^‡ Thomas Wiglenda,^† and Ronald Gust*^†

Institute of Pharmacy, Free University of Berlin, Knigin Luise Str. 2+4, 14195 Berlin, Germany, and Laboratory for Tumor and Immunobiology, Department of Hematology and Oncology, University Hospital of Innsbruck, Austria

J. Med. Chem., 2005, 48 (2), pp 622–629

DOI: 10.1021/jm049326z

Publication Date (Web): December 30, 2004

†

Free University of Berlin.

‡

University Hospital of Innsbruck.

Institut für Pharmazie der FU Berlin, Königin Luise Str. 2+4, D-14195 Berlin, Germany. Phone: (030) 838 53272. Telefax: (030) 838 56906. E-mail: rgust@zedat.fu-berlin.de.

Abstract

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.

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Published In Issue January 27, 2005
Received August 13, 2004

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Article

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

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