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

Carla Barbaraci,Claudia Giovanna Leotta,Giovanni Giurdanella,Giovanni Mario Pitari,Ivana Cacciatore,Maria Dichiara,Orazio Prezzavento,Elisa Zuccarello,Carmelina Daniela Anfuso,Anna Longo,Lorella Pasquinucci,Rita Turnaturi,Agostino Marrazzo,Emanuele Amata,Gabriella Lupo

doi:10.1021/acs.jmedchem.1c00995

Carla Barbaraci, Claudia Giovanna Leotta + Show 13 more

Open Access

https://doi.org/10.1021/acs.jmedchem.1c00995

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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.

Highlights

Uveal melanoma (UM) is a rare and aggressive intraocular tumor, which arises from melanocytes such as cutaneous melanoma, but presents unique biology and genetic traits.[1]Approximately 90% of all uveal melanoma (UM) involve the choroid, while the rest involve the ciliary body (6%) or iris (4%).[2]
Since (−)-1 has the greatest σ2 binding affinity of the dual-ligand prodrugs (Table 2), these results suggest that σ receptor-mediated regulation of human retinal endothelial cells (HREC) migration by vascular endothelial growth factor (VEGF)-A is principally sensitive to σ2 agonist activity
The results indicate that the three prodrugs exhibit antiangiogenic activity in vitro, comparable to the VEGF-trap AFL but with distinct pharmacological profiles

Summary

Introduction

Uveal melanoma (UM) is a rare and aggressive intraocular tumor, which arises from melanocytes such as cutaneous melanoma, but presents unique biology and genetic traits.[1]Approximately 90% of all UMs involve the choroid, while the rest involve the ciliary body (6%) or iris (4%).[2]. Lacking an intraocular lymphatic system, UM tends to spread via a hematogenous route, and the presence of microvascular loops and networks is clinically related to UM progression and a worse prognosis.[6] Recent studies have shown that different UM cell lines produce a copious amount of vascular endothelial growth factor (VEGF), the primary activator of tumor angiogenesis in mammals.[9] Treatment of inoperable UM patients with the VEGF-trap aflibercept (AFL), a popular drug in ophthalmology, resulted in 50% progressionfree survival at 4 months.[7−9] Intravitreal injection of bevacizumab, an antiangiogenic monoclonal antibody targeting all isoforms of vascular endothelial growth factor A (VEGF-A), is currently under evaluation through a phase II trial for the treatment of UM metastatic disease.[10−12]. Recognized as a biomarker of cell proliferation, Received: June 2, 2021 Published: September 3, 2021

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