Design, synthesis, nuclear localization, and biological activity of a fluorescent duocarmycin analog, HxTfA

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Kiakos, Kostantinos^1,2,3  Englinger, Bernhard^6,7  Yanow, Stephanie K.⁴  Wernitznig, Debora^2,3  Jakupec, Michael A.^2,3  Berger, Walter^3,6,7  Keppler, Bernhard K.^2,3  Hartley, John A.¹  Lee, Moses^5,8  Patil, Pravin C.⁵ 

[1] UCL Canc Inst, DNA Interact Res Grp, Canc Res UK Drug, London WC1E 6BT, England

[2] Univ Vienna, Inst Inorgan Chem, Waehringer Str 42, A-1090 Vienna, Austria

[3] Univ Vienna, Res Cluster Translat Canc Therapy Res, Waehringer Str 42, A-1090 Vienna, Austria

[4] Univ Alberta, Sch Publ Hlth, Edmonton, AB, Canada

[5] Hope Coll, Dept Chem, Holland, MI 49423 USA

[6] Med Univ Vienna, Inst Canc Res, Borschkegasse 8a, A-1090 Vienna, Austria

[7] Med Univ Vienna, Dept Med 1, Comprehens Canc Ctr, Borschkegasse 8a, A-1090 Vienna, Austria

[8] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA

关键词: Duocarmycins;    Tafuramycin A;    Cytotoxic;    Antimalarial;    Vaccine;    Minor groove;    Adenine-N3;    Alkylating agent;   

DOI  :  10.1016/j.bmcl.2018.03.016

来源: Elsevier

【 摘 要 】

HxTfA 4 is a fluorescent analog of a potent cytotoxic and antimalarial agent, TfA 3, which is currently being investigated for the development of an antimalarial vaccine, PlasProtect (R). HxTfA contains a p-ani-sylbenzimidazole or Hx moiety, which is endowed with a blue emission upon excitation at 318 nm; thus enabling it to be used as a surrogate for probing the cellular fate of TfA using confocal microscopy, and addressing the question of nuclear localization. HxTfA exhibits similar selectivity to TfA for A-tract sequences of DNA, alkylating adenine-N3, albeit at 10-fold higher concentrations. It also possesses in vitro cytotoxicity against A549 human lung carcinoma cells and Plasmodium falciparum. Confocal microscopy studies showed for the first time that HxTfA, and by inference TfA, entered A549 cells and localized in the nucleus to exert its biological activity. At biologically relevant concentrations, HxTfA elicits DNA damage response as evidenced by a marked increase in the levels of gamma H2AX observed by confocal microscopy and immunoblotting studies, and ultimately induces apoptosis. (C) 2018 Elsevier Ltd. All rights reserved.

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