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

Authors
  • Barbaraci, Carla1, 2
  • Giurdanella, Giovanni1
  • Leotta, Claudia Giovanna2
  • Longo, Anna1
  • Amata, Emanuele1
  • Dichiara, Maria1
  • Pasquinucci, Lorella1
  • Turnaturi, Rita1
  • Prezzavento, Orazio1
  • Cacciatore, Ivana3
  • Zuccarello, Elisa4
  • Lupo, Gabriella1
  • Pitari, Giovanni Mario2
  • Anfuso, Carmelina Daniela1
  • Marrazzo, Agostino1
  • 1 University of Catania, Italy , (Italy)
  • 2 Vera Salus Ricerca S.r.l., Italy , (Italy)
  • 3 “G. D’Annunzio” University of Chieti-Pescara, Italy , (Italy)
  • 4 Columbia University, United States , (United States)
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Sep 03, 2021
Volume
64
Issue
18
Pages
13622–13632
Identifiers
DOI: 10.1021/acs.jmedchem.1c00995
PMID: 34477381
PMCID: PMC8474110
Source
PubMed Central
Disciplines
  • Article
License
Unknown

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.

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