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

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.

Development of Cytotoxic GW7604-Zeise’s Salt Conjugates as Multitarget Compounds with Selectivity for Estrogen Receptor- Positive Tumor Cells

“…Optimizing the interference with the COX cascade by linking Zeise’s salt to ASA was already performed. However, the resulting ASA-Alk-PtCl 3 complexes (Chart ) had only slightly higher COX-2 inhibitory activity than Zeise’s salt. , …”

“…However, the resulting ASA-Alk-PtCl 3 complexes (Chart 1) had only slightly higher COX-2 inhibitory activity than Zeise's salt. 33,36 It was also shown that the organometallic substructure determines the efficacy of COX inhibitors. For example, binding to a dicobalt hexacarbonyl cluster strongly enhanced the COX inhibitory effect of ASA-propargyl ligands.…”

“…It was also shown that the organometallic substructure determines the efficacy of COX inhibitors. For example, binding to a dicobalt hexacarbonyl cluster strongly enhanced the COX inhibitory effect of ASA -propargyl ligands. ,− Therefore, it was of interest to evaluate whether the GW7604-Alk-PtCl 3 complexes influence the COX-1/2 inhibition, too.…”

“…As previously published, the resulting ASA-Alk-PtCl 3 complexes (Chart ) exhibited high COX-1 inhibitory activity. The influence on COX-2, however, was only slightly increased compared to Zeise’s salt. , …”

“…The influence on COX-2, however, was only slightly increased compared to Zeise's salt. 33,36 ASA-Alk-PtCl 3 complexes were more stable than Zeise's salt and interestingly degraded by a different route. Redox reactions were not observed in aqueous solutions.…”