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Dual-acting histone deacetylase-topoisomerase I inhibitors.

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.

SUBMITTER: Guerrant W

PROVIDER: S-EPMC3657756 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Dual-acting histone deacetylase-topoisomerase I inhibitors.

Guerrant William W Patil Vishal V Canzoneri Joshua C JC Yao Li-Pan LP Hood Rebecca R Oyelere Adegboyega K AK

Bioorganic & medicinal chemistry letters 20130404 11

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 throug ...[more]

PMID: 23622981

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