title: 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.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
authors.forename: William
authors.initials: W
authors.lastname: Guerrant
authors.forename: Vishal
authors.initials: V
authors.lastname: Patil
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Canzoneri
authors.forename: Li-Pan
authors.initials: LP
authors.lastname: Yao
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hood
authors.forename: Adegboyega K
authors.initials: AK
authors.lastname: Oyelere
mesh_terms: D002166:Camptothecin / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D059004:Topoisomerase I Inhibitors; D006655:Histone Deacetylases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin