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

Zeise’s salt derivatives of the potassium trichlorido[η(2)-((prop-2-en/but-3-en)-1-yl)-2-acetoxybenzoate]platinate(II) type (ASA-Prop-PtCl(3)/ASA-But-PtCl(3) derivatives) were synthesized and characterized regarding their structure, stability, and biological activity. It is proposed that the leads ASA-Prop-PtCl(3) and ASA-But-PtCl(3) 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 CH(3) substituents were introduced into the acetylsalicylic acid (ASA) moiety. Each structural modification improved COX-2 inhibition. Especially compounds with F substituents at ASA-But-PtCl(3) reached the maximum achievable inhibition of about 70% already at 1 µM. The PGE(2) formation in COX-1/2-positive HT-29 cells was suppressed by all F/Cl/CH(3) derivatives, indicating COX inhibitory potency in cellular systems. The CH(3)-bearing complexes showed the highest cytotoxicity in COX-1/2-positive HT-29 cells with IC(50) 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-PtCl(3) and ASA-But-PtCl(3) derivatives by enhancing COX-2 inhibition.