title: Dual targeting of histone deacetylase and topoisomerase II with novel bifunctional inhibitors.
abstract: Strategies to ameliorate the flaws of current chemotherapeutic agents, while maintaining potent anticancer activity, are of particular interest. Agents which can modulate multiple targets may have superior utility and fewer side effects than current single-target drugs. To explore the prospect in cancer therapy of a bivalent agent that combines two complementary chemo-active groups within a single molecular architecture, we have synthesized dual-acting histone deacetylase and topoisomerase II inhibitors. These dual-acting agents are derived from suberoylanilide hydroxamic acid (SAHA) and anthracycline daunorubicin, prototypical histone deacetylase (HDAC) and topoisomerase II (Topo II) inhibitors, respectively. We report herein that these agents present the signatures of inhibition of HDAC and Topo II in both cell-free and whole-cell assays. Moreover, these agents potently inhibit the proliferation of representative cancer cell lines.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, United States.
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: Adegboyega K
authors.initials: AK
authors.lastname: Oyelere
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002474:Cell-Free System; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D059003:Topoisomerase Inhibitors; D014404:Tubulin; D000077337:Vorinostat; D006655:Histone Deacetylases; D004250:DNA Topoisomerases, Type II; D003630:Daunorubicin