Haloperidol Metabolite II Valproate Ester (S)-(−)-MRJF22: Preliminary Studies as a Potential Multifunctional Agent Against Uveal Melanoma

Abstract

Increased angiogenesis and vascular endothelial growth factor (VEGF) levels contribute to higher metastasis and mortality in uveal melanoma (UM), an aggressive malignancy of the eye in adults. (±)-MRJF22 , a prodrug of the sigma (σ) ligand haloperidol metabolite II conjugated with the histone deacetylase (HDAC) inhibitor valproic acid, has previously demonstrated a promising antiangiogenic activity. Herein, the asymmetric synthesis of (R)-(+)-MRJF22 and (S)-(−)-MRJF22 was performed to investigate their contribution to (±)-MRJF22 antiangiogenic effects in human retinal endothelial cells (HREC) and to assess their therapeutic potential in primary human uveal melanoma (UM) 92-1 cell line. While both enantiomers displayed almost identical capabilities to reduce cell viability than the racemic mixture, (S)-(−)-MRJF22 exhibited the highest antimigratory effects in endothelial and tumor cells. Given the fundamental contribution of cell motility to cancer progression, (S)-(−)-MRJF22 may represent a promising candidate for novel antimetastatic therapy in patients with UM.

Repurposing Antipsychotics for Cancer Treatment

“…Additionally, the σ receptors decrease the expression of P-glycoprotein, a multidrug-resistant protein (MDR) that is an ATP-dependent efflux pump for several chemotherapeutic drugs. The haloperidol metabolite II is a molecule with such properties (σ1 antagonist/σ2 agonism) and its combination with 4-phenylbutyric acid (a Histone deacetylase inhibitor) in a single-ester molecule, the phenylbutyrate ester of haloperidol metabolite II (+/−MRJF4), or with valproic acid (+/− MRJF22) has been found to have an anti-tumor effect against prostate cancer cell lines (LNCaP, PC3) or rat C6 glioma cells [ 22 , 23 , 24 ], and uveal melanoma [ 25 ], respectively. The antitumor mechanisms of action of haloperidol are summarized in Figure 1 .…”

Synthesis, Computational Insights, and Evaluation of Novel Sigma Receptors Ligands

“…Following up our studies in this field, herein we report the development of a new class of SR ligands designed through the modification of the amino moiety scaffold used for our previously synthesized ligands. Thus, diazabicyclo[4.3.0]­nonane (A) and 2,7-diazaspiro[3.5]­nonane (B) derivatives have been designed (Figure ), where the central core has been flanked with hydrophobic groups at a certain distance to the central basic amine being this a common structural requirement of potent SR ligands as identified by previous works. − A total of 15 compounds with varying distal hydrophobic region and linker portion were evaluated. Herein, we describe the SAfiR studies and subtype preference derived from radioligand binding, the binding mode and the interactions established between the ligands and the S1R and S2R.…”