Evaluation of class I HDAC isoform selectivity of largazole analogues

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Kim, Bumki¹  Park, Heekwang¹  Salvador, Lilibeth A.^2,3  Serrano, Patrick E.¹  Kwan, Jason C.²  Zeller, Sabrina L.¹  Chen, Qi-Yin^2,4  Ryu, Soyoung¹  Liu, Yanxia^2,4  Byeon, Seongrim¹  Luesch, Hendrik^2,4  Hong, Jiyong^1,5 

[1] Duke Univ, Dept Chem, Durham, NC 27708 USA

[2] Univ Florida, Coll Pharm, Dept Med Chem, Gainesville, FL 32610 USA

[3] Univ Philippines, Coll Sci, Inst Marine Sci, Quezon City 1100, Philippines

[4] Univ Florida, Ctr Nat Prod Drug Discovery & Dev CNPD3, Gainesville, FL 32610 USA

[5] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA

关键词: Largazole;    HDAC inhibitor;    Class I histone deacetylase;    Isoform selectivity;    Structure-activity relationship;   

DOI  :  10.1016/j.bmcl.2014.07.006

来源: Elsevier

【 摘 要 】

Largazole is a potent class I selective histone deacetylase (HDAC) inhibitor. The majority of largazole analogues to date have modified the thiazole-thiazoline and the warhead moiety. In order to elucidate class I-specific structure-activity relationships, a series of analogues with modifications in the valine or the linker region were prepared and evaluated for their class I isoform selectivity. The inhibition profile showed that the C2 position of largazole has an optimal steric requirement for efficient HDAC inhibition and that substitution of the trans-alkene in the linker with an aromatic group results in complete loss of activity. This data will aid the design of class I isoform selective HDAC inhibitors. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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