title: Synthesis, characterization and antineoplastic activity of bis-aziridinyl dimeric naphthoquinone - A novel class of compounds with potent activity against acute myeloid leukemia cells.
abstract: The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported. Bis-dimethylamine BiQ, as the isostere of bis-aziridinyl BiQ but without the alkylating moiety did not show as potent anti-AML activity. Systemic administration of bis-aziridinyl BiQ was well tolerated in NSG mice.
authors.affiliation: University of Maryland School of Medicine, Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Carter-Cooper
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.affiliation: Department of Chemistry, McDaniel College, Westminster, MD, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Ferraris
authors.affiliation: University of Maryland School of Medicine, Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.
authors.forename: Eun Yong
authors.initials: EY
authors.lastname: Choi
authors.affiliation: University of Maryland School of Medicine, Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.
authors.forename: Dahlia
authors.initials: D
authors.lastname: Kronfli
authors.affiliation: University of Maryland School of Medicine, Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.
authors.forename: Smaraki
authors.initials: S
authors.lastname: Dash
authors.affiliation: Department of Chemistry, McDaniel College, Westminster, MD, United States.
authors.forename: Phuc
authors.initials: P
authors.lastname: Truong
authors.affiliation: University of Maryland School of Medicine, Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.affiliation: University of Maryland School of Medicine, Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.
authors.forename: Rena G
authors.initials: RG
authors.lastname: Lapidus
authors.affiliation: University of Maryland School of Medicine, Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States. Electronic address: aemadi@umm.edu.
authors.forename: Ashkan
authors.initials: A
authors.lastname: Emadi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D017382:Reactive Oxygen Species
keywords: Acute myeloid leukemia; Aziridine; DNA damage; Naphthoquinone; Reactive oxygen species