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

Author: Scherfler, Amelie ; Varbanov, Hristo P ; Kircher, Brigitte ; Kapitza, Paul ; Zwerger, Michael ; Hermann, Martin ; Hörmann, Nikolas ; Gust, Ronald ; Baecker, Daniel ; Grabher, Patricia

28 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Gust, Ronald ; Hörmann, Nikolas ; Baecker, Daniel ; Hermann, Martin ; Grabher, Patricia ; Varbanov, Hristo P ; Zwerger, Michael ; Kapitza, Paul ; Kircher, Brigitte ; Scherfler, Amelie

(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.

13 May 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

Heterodimeric GW7604 Derivatives: Modification of the Pharmacological Profile by Additional Interactions at the Coactivator Binding Site

Q1 · MEDICINE

Article

Author: Schuster, Daniela ; Kalchschmid, Christina ; Gust, Ronald ; Knox, Alexandra K. ; Gaggia, Francesca

(E/Z)-3-(4-((E)-1-(4-Hydroxyphenyl)-2-phenylbut-1-enyl)phenyl)acrylic acid (GW7604) as a derivative of (Z)-4-hydroxytamoxifen (4-OHT) was linked by diaminoalkane spacers to molecules that are known binders to the coactivator binding site (benzimidazole or thioxo-quinazolinone scaffolds). With this modification, an optimization of the pharmacological profile was achieved. The most active thioxo-quinazolinone derivative 16 showed extraordinarily high affinity to the estrogen receptor (ER) β (RBA = 110%), inhibited effectively the coactivator recruitment (IC₅₀ = 20.88 nM (ERα) and 28.34 nM (ERβ)), acted as a pure estradiol (E2) antagonist in a transactivation assay (IC₅₀ = 18.5 nM (ERα) and 7.5 nM (ERβ)), and downregulated the ERα content in MCF-7 cells with an efficacy of 60% at 1 μM. The cytotoxicity was restricted to hormone-dependent MCF-7 (IC₅₀ = 4.2 nM) and tamoxifen-resistant MCF-7TamR cells (IC₅₀ = 476.6 nM). The compounds bearing a thioxo-quinazolinone moiety can therefore be assigned as pure E2-antagonistic selective ER degraders/downregulators. By contrast, the benzimidazole derivatives acted solely as pure antagonists without degradation of the ER.

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