Design, synthesis, nuclear localization, and biological activity of a fluorescent duocarmycin analog, HxTfA
- Author(s)
- Konstantinos Kiakos, Bernhard Englinger, Stephanie K. Yanow, Debora Wernitznig, Michael A. Jakupec, Walter Berger, Bernhard K. Keppler, John A. Hartley, Moses Lee, Pravin C. Patil
- 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.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- Medizinische Universität Wien, University of Alberta, Hope College, University College London, University of Vienna
- Journal
- Bioorganic & Medicinal Chemistry Letters
- Volume
- 28
- Pages
- 1342-1347
- No. of pages
- 6
- ISSN
- 0960-894X
- DOI
- https://doi.org/10.1016/j.bmcl.2018.03.016
- Publication date
- 05-2018
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104015 Organic chemistry, 301305 Medical chemistry
- Keywords
- ASJC Scopus subject areas
- Drug Discovery, Molecular Medicine, Molecular Biology, Biochemistry, Clinical Biochemistry, Pharmaceutical Science, Organic Chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/3ec861da-3518-474e-9430-4a747cb74f09