Pyrimidinedione-mediated selective histone deacetylase 6 inhibitors with antitumor activity in colorectal cancer HCT116 cells.

Abstract

We synthesized a series of pyrimidinedione derivatives and evaluated their activities. The results indicate that compound 6, 4-[5-fluoro-2,6-dioxo-3-(tetrahydro-furan-2-yl)-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-N-hydroxy-benzamide, exhibits potent antiproliferative activity, apoptosis induction with cleavage of caspase and PARP, and enhanced tendency to inhibit HDAC6 (IC50 = 12.4 nM) activity over HDAC1 (IC50 = 1710 nM) and HDAC2 (IC50 = 5500 nM). Compound 6 also inhibits tumor growth and is less toxic than parent 4 in vivo. These data provide compelling evidence that compound 6 is a potential antitumor compound with HDAC6 targeted inhibitory activity and may be tested for preclinical investigation for cancer treatment.

• Authors: Yi-Min Liu, Hsueh-Yun Lee, Mei-Jung Lai, Shiow-Lin Pan, Hsiang-Ling Huang, Fei-Chiao Kuo, Mei-Chuan Chen, Jing-Ping Liou
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 13 Issue 40 Pg. 10226-35 (Oct 28 2015) ISSN: 1477-0539 [Electronic] England
• PMID: 26309122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Pyrimidinones
• HDAC6 protein, human
• Histone Deacetylase 6
• Histone Deacetylases

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• HCT116 Cells
• Histone Deacetylase 6
• Histone Deacetylase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Histone Deacetylases (metabolism)
• Humans
• Mice
• Mice, Nude
• Molecular Structure
• Neoplasms, Experimental (drug therapy, pathology)
• Pyrimidinones (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship