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

Abstract

(E/Z)-3-(4-((E)-1-(4-Hydroxyphenyl)-2-phenylbut-1-enyl)phenyl)acrylic acid (GW7604) as a carrier was esterified with alkenols of various lengths and coordinated through the ethylene moiety to PtCl₃, similar to Zeise's salt (K[PtCl₃(C₂H₄)]). The resulting GW7604-Alk-PtCl₃ complexes (Alk = Prop, But, Pent, Hex) degraded in aqueous solution only by exchange of the chlorido ligands. For example, GW7604-Pent-PtCl₃ coordinated the amino acid alanine in the cell culture medium, bound the isolated nucleotide 5'-GMP, and interacted with the DNA (empty plasmid pSport1). It accumulated in estrogen receptor (ER)-positive MCF-7 cells primarily via cytosolic vesicles, while it was only marginally taken up in ER-negative SKBr3 cells. Accordingly, GW7604-Pent-PtCl₃ and related complexes were inactive in SKBr3 cells. GW7604-Pent-PtCl₃ showed high affinity to ERα and ERβ without mediating agonistic or ER downregulating properties. GW7604-Alk ligands also increased the cyclooxygenase (COX)-2 inhibitory potency of the complexes. In contrast to Zeise's salt, the GW7604-Alk-PtCl₃ complexes inhibited COX-1 and COX-2 to the same extent.