Dual-acting histone deacetylase-topoisomerase I inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Guerrant, William¹  Patil, Vishal¹  Canzoneri, Joshua C.¹  Yao, Li-Pan¹  Hood, Rebecca¹  Oyelere, Adegboyega K.^1,2 

[1] Georgia Inst Technol, Sch Chem & Biochem, Atlanta, GA 30332 USA

[2] Georgia Inst Technol, Parker H Petit Inst Bioengn & Biosci, Atlanta, GA 30332 USA

关键词: Histone deacetylase;    Histone deacetylase inhibitors;    Topoisomerase I;    Camptothecin;    Suberoylanilide hydroxamic acid;   

DOI  :  10.1016/j.bmcl.2013.03.108

来源: Elsevier

【 摘 要 】

Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands that can modulate multiple targets while avoiding the toxicity of a single-targeted agent. Two attractive targets, histone deacetylase (HDAC) and topoisomerase I (Topo I), are cellular modulators that can broadly arrest cancer proliferation through a range of downstream effects. Both are clinically validated targets with multiple inhibitors in therapeutic use. We describe herein the design and synthesis of dual-acting histone deacetylase-topoisomerase I inhibitors. We also show that these dual-acting agents retain activity against HDAC and Topo I, and potently arrest cancer proliferation. Published by Elsevier Ltd.

【 授权许可】

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