Dual-acting histone deacetylase-topoisomerase I inhibitors |
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Authors: | William Guerrant Vishal Patil Joshua C Canzoneri Li-Pan Yao Rebecca Hood Adegboyega K Oyelere |
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Institution: | 1. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA;2. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA |
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Abstract: | 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. |
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Keywords: | Histone deacetylase Histone deacetylase inhibitors Topoisomerase I Camptothecin Suberoylanilide hydroxamic acid |
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