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

Yi-Min Liu; Hsueh Yun Lee; Mei-Jung Lai; Shiow Lin Pan; Hsiang-Ling Huang; Fei-Chiao Kuo; Mei Chuan Chen; Jing Ping Liou

doi:10.1039/c5ob01509j

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

Yi-Min Liu, Hsueh Yun Lee, Mei-Jung Lai, Shiow Lin Pan, Hsiang-Ling Huang, Fei-Chiao Kuo, Mei Chuan Chen, Jing Ping Liou

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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 4in 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.

Original language	English
Pages (from-to)	10226-10235
Number of pages	10
Journal	Organic and Biomolecular Chemistry
Volume	13
Issue number	40
DOIs	https://doi.org/10.1039/c5ob01509j
Publication status	Published - Aug 17 2015

ASJC Scopus subject areas

Biochemistry
Physical and Theoretical Chemistry
Organic Chemistry

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title = "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 4in 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.",

author = "Yi-Min Liu and Lee, {Hsueh Yun} and Mei-Jung Lai and Pan, {Shiow Lin} and Hsiang-Ling Huang and Fei-Chiao Kuo and Chen, {Mei Chuan} and Liou, {Jing Ping}",

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year = "2015",

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doi = "10.1039/c5ob01509j",

language = "English",

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T1 - Pyrimidinedione-mediated selective histone deacetylase 6 inhibitors with antitumor activity in colorectal cancer HCT116 cells

AU - Liu, Yi-Min

AU - Lee, Hsueh Yun

AU - Lai, Mei-Jung

AU - Pan, Shiow Lin

AU - Huang, Hsiang-Ling

AU - Kuo, Fei-Chiao

AU - Chen, Mei Chuan

AU - Liou, Jing Ping

PY - 2015/8/17

Y1 - 2015/8/17

N2 - 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 4in 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.

AB - 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 4in 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.

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DO - 10.1039/c5ob01509j

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VL - 13

SP - 10226

EP - 10235

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

IS - 40

ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

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