Kiakos, K;
Englinger, B;
Yanow, SK;
Wernitznig, D;
Jakupec, MA;
Berger, W;
Keppler, BK;
... Patil, PC; + view all
(2018)
Design, synthesis, nuclear localization, and biological activity of a fluorescent duocarmycin analog, HxTfA.
Bioorganic & Medicinal Chemistry Letters
, 28
(8)
pp. 1342-1347.
10.1016/j.bmcl.2018.03.016.
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Abstract
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®. HxTfA contains a p-anisylbenzimidazole 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 γH2AX observed by confocal microscopy and immunoblotting studies, and ultimately induces apoptosis.
Type: | Article |
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Title: | Design, synthesis, nuclear localization, and biological activity of a fluorescent duocarmycin analog, HxTfA |
Location: | England |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1016/j.bmcl.2018.03.016 |
Publisher version: | http://doi.org/10.1016/j.bmcl.2018.03.016 |
Language: | English |
Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
Keywords: | Adenine-N3, Alkylating agent, Antimalarial, Cytotoxic, Duocarmycins, Minor groove, Tafuramycin A, Vaccine |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
URI: | https://discovery.ucl.ac.uk/id/eprint/10046563 |
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