Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure

被引：44

作者：

Chen, Liqiang ^{[1
]}

Petrelli, Riccardo ^{[1
,5
]}

Gao, Guangyao ^{[1
]}

Wilson, Daniel J. ^{[1
]}

McLean, Garrett T. ^{[1
]}

Jayaram, Hiremagalur N. ^{[2
,3
]}

Sham, Yuk Y. ^{[1
,4
]}

Pankiewicz, Krzysztof W. ^{[1
]}

机构：

[1] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA

[2] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[3] Richard L Roudebush Vet Affairs Med Ctr, Indianapolis, IN 46202 USA

[4] Univ Minnesota, Biomed Informat & Computat Biol Program, Minneapolis, MN 55455 USA

[5] Univ Camerino, Med Chem Unit, Sch Pharm, I-62032 Camerino, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 16期

关键词：

Inosine monophosphate dehydrogenase; Histone deacetylase; Dual inhibitor; Cinnamic hydroxamic acid; Cancer therapy; Drug resistance; CHRONIC MYELOID-LEUKEMIA; TYROSINE KINASE-INHIBITORS; 5'-MONOPHOSPHATE DEHYDROGENASE; IMP DEHYDROGENASE; POTENT; CANCER; IDENTIFICATION; DISCOVERY; DESIGN; RESISTANCE;

D O I：

10.1016/j.bmc.2010.06.081

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Small molecules that act on multiple biological targets have been proposed to combat the drug resistance commonly observed for cancer chemotherapy. By combining the structural features of known inhibitors of inosine monophosphate dehydrogense (IMPDH) and histone deacetylase (HDAC), dual inhibitors of IMPDH and HDAC based on the scaffold of cinnamic hydroxamic acid (CHA) have been designed, synthesized, and evaluated in biological assays. Key features, including the linker length, linker functionality, substitution position, and interacting groups, have been explored. Their individual contribution to the inhibitory activities against human IMPDH1 and IMPDH2 as well as HDAC has been assessed. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5950 / 5964

页数：15

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