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

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.