Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors
Alexander Weninger,
Jessica Sagasser,
Victoria Obermoser,
Josef Egger,
Susanna Wisboeck,
Qianqian Qiu,
Miriam Ladstaetter,
Andrea Cucchiaro,
Klaus Wurst,
Daniel Baecker,
Ronald Gust
Affiliations
Alexander Weninger
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Jessica Sagasser
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Victoria Obermoser
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Josef Egger
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Susanna Wisboeck
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Qianqian Qiu
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Miriam Ladstaetter
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Andrea Cucchiaro
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Klaus Wurst
Department of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Daniel Baecker
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Ronald Gust
Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Zeise’s salt derivatives of the potassium trichlorido[η2-((prop-2-en/but-3-en)-1-yl)-2-acetoxybenzoate]platinate(II) type (ASA-Prop-PtCl3/ASA-But-PtCl3 derivatives) were synthesized and characterized regarding their structure, stability, and biological activity. It is proposed that the leads ASA-Prop-PtCl3 and ASA-But-PtCl3 interfere with the arachidonic acid cascade as part of their mode of action to reduce the growth of COX-1/2-expressing tumor cells. With the aim to increase the antiproliferative activity by strengthening the inhibitory potency against COX-2, F, Cl, or CH3 substituents were introduced into the acetylsalicylic acid (ASA) moiety. Each structural modification improved COX-2 inhibition. Especially compounds with F substituents at ASA-But-PtCl3 reached the maximum achievable inhibition of about 70% already at 1 µM. The PGE2 formation in COX-1/2-positive HT-29 cells was suppressed by all F/Cl/CH3 derivatives, indicating COX inhibitory potency in cellular systems. The CH3-bearing complexes showed the highest cytotoxicity in COX-1/2-positive HT-29 cells with IC50 values of 16–27 µM. In COX-negative MCF-7 cells, they were 2–3-fold less active. These data clearly demonstrate that it is possible to increase the cytotoxicity of ASA-Prop-PtCl3 and ASA-But-PtCl3 derivatives by enhancing COX-2 inhibition.
