A-ring and E-ring modifications of the cytotoxic alkaloid Luotonin A: Synthesis, computational and biological studies. Issue 9 (1st May 2020)

• Record Type: Journal Article
• Authors: Ibric, Amra; Battisti, Verena; Deckardt, Sophie; Haller, Anna Veronika; Lee, Calvin; Prötsch, Corinna; Langer, Thierry; Heffeter, Petra; Schueffl, Hemma Henrike; Marian, Brigitte; Haider, Norbert
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 9(2020)
• Publication Date: 2020-05-01
• Subjects: Luotonin A -- Topoisomerase I -- Cytotoxicity -- Docking -- G2/M arrest; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115443
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.