title: Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells.
abstract: Some cancers, like acute myeloid leukemia (AML), use reactive oxygen species to endogenously activate cell proliferation and angiogenic signaling cascades. Thus many cancers display increases in reactive oxygen like hydrogen peroxide concentrations. To translate this finding into a therapeutic strategy we designed new hydrogen peroxide-activated agents with two key molecular pharmacophores. The first pharmacophore is a peroxide-acceptor and the second is a pendant amine. The acceptor is an N-(2,5-dihydroxyphenyl)acetamide susceptible to hydrogen peroxide oxidation. We hypothesized that selectivity between AML and normal cells could be achieved by tuning the pendant amine. Synthesis and testing of fourteen compounds that differed at the pendent amine led to the identification of an agent (14) with 2μM activity against AML cancer cells and an eleven fold-lower activity in healthy CD34+ blood stem cells. Interestingly, analysis shows that upon oxidation the pendant amine cyclizes, ejecting water, with the acceptor to give a bicyclic compound capable of reacting with nucleophiles. Preliminary mechanistic investigations show that AML cells made from addition of two oncogenes (NrasG12D and MLL-AF9) increase the ROS-status, is initially an anti-oxidant as hydrogen peroxide is consumed to activate the pro-drug, and cells respond by upregulating electrophilic defense as visualized by Western blotting of KEAP1. Thus, using this chemical approach we have obtained a simple, potent, and selective ROS-activated anti-AML agent.
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, United States.
authors.forename: Anish K
authors.initials: AK
authors.lastname: Vadukoot
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, United States.
authors.forename: Safnas F
authors.initials: SF
authors.lastname: AbdulSalam
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, United States.
authors.forename: Eboni D
authors.initials: ED
authors.lastname: Pullen
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, United States.
authors.forename: Julio
authors.initials: J
authors.lastname: Landero-Figueroa
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, United States.
authors.forename: Eddie J
authors.initials: EJ
authors.lastname: Merino
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D015195:Drug Design; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007700:Kinetics; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D006861:Hydrogen Peroxide
keywords: Acute myeloid leukemia; Anti-cancer agent; Conjugate addition; Oxidative stress; Reactive oxygen species