UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

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. Green open access

[thumbnail of Kiakos et al HxTfA Manuscript-accepted.pdf]
Preview
Text
Kiakos et al HxTfA Manuscript-accepted.pdf - Accepted Version

Download (4MB) | Preview

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
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
Downloads since deposit
114Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item