Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors

Author:

Weninger Alexander1,Sagasser Jessica1,Obermoser Victoria1,Egger Josef1,Wisboeck Susanna1,Qiu Qianqian1,Ladstaetter Miriam1,Cucchiaro Andrea1ORCID,Wurst Klaus2,Baecker Daniel13ORCID,Gust Ronald1ORCID

Affiliation:

1. 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

2. Department of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria

3. Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany

Abstract

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.

Funder

Austrian Science Fund

Publisher

MDPI AG

Subject

Pharmaceutical Science

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