1. A-ring and E-ring modifications of the cytotoxic alkaloid Luotonin A: Synthesis, computational and biological studies
- Author
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Hemma Schueffl, Verena Battisti, Anna Veronika Haller, Calvin Lee, Corinna Prötsch, Amra Ibric, Norbert Haider, Sophie Deckardt, Petra Heffeter, Thierry Langer, and Brigitte Marian
- Subjects
Stereochemistry ,Cell Survival ,In silico ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Humans ,Pyrroles ,Mode of action ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Topoisomerase ,Organic Chemistry ,Quinones ,Biological activity ,Stereoisomerism ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Docking (molecular) ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Camptothecin ,DNA ,medicine.drug - 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.
- Published
- 2020