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. Epub 2021 Sep 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / pharmacology*
  • Butyrophenones / chemical synthesis
  • Butyrophenones / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Humans
  • Melanoma / drug therapy*
  • Pentanoic Acids / chemical synthesis
  • Pentanoic Acids / pharmacology*
  • Piperidines / cerebrospinal fluid
  • Piperidines / pharmacology*
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology*
  • Stereoisomerism
  • Uveal Neoplasms / drug therapy*
  • Valerates / cerebrospinal fluid
  • Valerates / pharmacology*

Substances

  • Angiogenesis Inhibitors
  • Butyrophenones
  • MRJF22
  • Pentanoic Acids
  • Piperidines
  • Prodrugs
  • Valerates

Supplementary concepts

  • Uveal melanoma