Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation: A new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6

被引：175

作者：

Kozikowski, Alan P. ^{[1
]}

Tapadar, Subhasish ^{[1
]}

Luchini, Doris N. ^{[2
]}

Kim, Ki Hwan ^{[1
]}

Billadeau, Daniel D. ^{[2
]}

机构：

[1] Univ Illinois, Dept Med Chem & Pharmacognosy, Drug Discovery Program, Chicago, IL 60612 USA

[2] Mayo Clin, Coll Med, Div Oncol Res, Rochester, MN 55905 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 15期

关键词：

D O I：

10.1021/jm8002894

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of hydroxamate based HDAC inhibitors containing a phenylisoxazole as the CAP group has been synthesized using nitrile oxide cycloaddition chemistry. An HDAC6 selective inhibitor having a potency of -2 picomolar was identified. Some of the compounds were examined for their ability to block pancreatic cancer cell growth and found to be about 10-fold more potent than SAHA. This research provides valuable, new molecular probes for use in exploring HDAC biology.

引用

页码：4370 / 4373

页数：4

共 25 条

[1] Anticancer activities of histone deacetylase inhibitors [J].

Bolden, Jessica E. ;

Peart, Melissa J. ;

Johnstone, Ricky W. .

NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (09) :769-784

[2] HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination [J].

Boyault, C. ;

Sadoul, K. ;

Pabion, M. ;

Khochbin, S. .

ONCOGENE, 2007, 26 (37) :5468-5476

[3]

Butler KV, 2008, CURR PHARM DESIGN, V14, P505

[4]

Carducci MA, 2001, CLIN CANCER RES, V7, P3047

[5]

CHEN YF, 2008, J MED CHEM IN PRESS

[6] Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation [J].

Dompierre, Jim P. ;

Godin, Juliette D. ;

Charrin, Benedicte C. ;

Cordelieres, Fabrice P. ;

King, Stephen J. ;

Humbert, Sandrine ;

Saudou, Frederic .

JOURNAL OF NEUROSCIENCE, 2007, 27 (13) :3571-3583

[7] A new simple and high-yield synthesis of suberoylanilide hydroxamic acid and its inhibitory effect alone or in combination with retinoids on proliferation of human prostate cancer cells [J].

Gediya, LK ;

Chopra, P ;

Purushottamachar, P ;

Maheshwari, N ;

Njar, VCO .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (15) :5047-5051

[8] Histone acetylation in chromatin structure and transcription [J].

Grunstein, M .

NATURE, 1997, 389 (6649) :349-352

[9] New perspectives in the management of pancreas cancer [J].

Haller, DG .

SEMINARS IN ONCOLOGY, 2003, 30 (04) :3-10

[10]

Kelly WK, 2003, CLIN CANCER RES, V9, P2098

← 1 2 3 →