期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 18, 页码 13622-13632出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00995
关键词
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资金
- PON FSE-FESR RI funds [CUP: E77H18000450006, DOT1708221, 3]
- Italian MUR for supporting grant PRIN [201744BN5T]
- Vera Salus Ricerca S.r.l.
The drug (S)-(-)-MRJF22 shows promising antiangiogenic and antimigratory effects, making it a potential candidate for novel antimetastatic therapy in patients with uveal melanoma.
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 (sigma) 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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