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

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

  • J Med Chem. 2021 Sep 23;64(18):13622-13632. doi: 10.1021/acs.jmedchem.1c00995.
Carla Barbaraci 1 2,  Giovanni Giurdanella 3,  Claudia Giovanna Leotta 2,  Anna Longo 3,  Emanuele Amata 1,  Maria Dichiara 1,  Lorella Pasquinucci 1,  Rita Turnaturi 1,  Orazio Prezzavento 1,  Ivana Cacciatore 4,  Elisa Zuccarello 5,  Gabriella Lupo 3,  Giovanni Mario Pitari 2,  Carmelina Daniela Anfuso 3,  Agostino Marrazzo 1
Affiliations

Affiliations

  • 1 Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
  • 2 Vera Salus Ricerca S.r.l., Via Sigmund Freud 62/B, 96100 Siracusa, Italy.
  • 3 Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Via S. Sofia 97, 95123 Catania, Italy.
  • 4 Department of Pharmacy, "G. D'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo, Italy.
  • 5 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York 10032, United States.
PMID: 34477381 DOI: 10.1021/acs.jmedchem.1c00995
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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