Synthesis, characterization and antineoplastic activity of bis-aziridinyl dimeric naphthoquinone - A novel class of compounds with potent activity against acute myeloid leukemia cells

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Carter-Cooper, Brandon A.¹  Fletcher, Steven²  Ferraris, Dana³  Choi, Eun Yong¹  Kronfli, Dahlia¹  Dash, Smaraki¹  Phuc Truong³  Sausville, Edward A.¹  Lapidus, Rena G.¹  Emadi, Ashkan¹ 

[1] Univ Maryland, Sch Med, Greenebaum Comprehens Canc Ctr, Baltimore, MD 21201 USA

[2] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA

[3] McDaniel Coll, Dept Chem, Westminster, MD USA

关键词: Naphthoquinone;    Acute myeloid leukemia;    DNA damage;    Reactive oxygen species;    Aziridine;   

DOI  :  10.1016/j.bmcl.2016.11.045

来源: Elsevier

【 摘 要 】

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. (C) 2016 Elsevier Ltd. All rights reserved.

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