2. Academic Validation
  3. A-ring and E-ring modifications of the cytotoxic alkaloid Luotonin A: Synthesis, computational and biological studies

A-ring and E-ring modifications of the cytotoxic alkaloid Luotonin A: Synthesis, computational and biological studies

  • Bioorg Med Chem. 2020 May 1;28(9):115443. doi: 10.1016/j.bmc.2020.115443.
Amra Ibric 1,  Verena Battisti 1,  Sophie Deckardt 1,  Anna Veronika Haller 1,  Calvin Lee 1,  Corinna Prötsch 1,  Thierry Langer 1,  Petra Heffeter 2,  Hemma Henrike Schueffl 2,  Brigitte Marian 2,  Norbert Haider 3
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria.
  • 2 Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
  • 3 Department of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria. Electronic address: norbert.haider@univie.ac.at.
PMID: 32201190 DOI: 10.1016/j.bmc.2020.115443
Abstract

A series of new Luotonin A derivatives with substituents at rings A and E was synthesized, together with some E-ring-unsubstituted derivatives. Subsequently, the compound library was examined in silico for their binding into a previously proposed site in the DNA/Topoisomerase I binary complex. Whereas no convincing correlation between docking scores and biological data from in vitro assays could be found, one novel 4,9-diamino Luotonin A derivative had strong antiproliferative activity based on massive G2/M phase arrest. As this biological activity clearly differs from the reference compound Camptothecin, this strongly indicates that at least some Luotonin A derivatives may be potent antiproliferative agents, however with a different mode of action.

Keywords

Cytotoxicity; Docking; G2/M arrest; Luotonin A; Topoisomerase I.

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