2. Academic Validation
  3. Targeting topoisomerase II with trypthantrin derivatives: Discovery of 7-((2-(dimethylamino)ethyl)amino)indolo[2,1-b]quinazoline-6,12-dione as an antiproliferative agent and to treat cancer

Targeting topoisomerase II with trypthantrin derivatives: Discovery of 7-((2-(dimethylamino)ethyl)amino)indolo[2,1-b]quinazoline-6,12-dione as an antiproliferative agent and to treat cancer

  • Eur J Med Chem. 2020 Sep 15;202:112504. doi: 10.1016/j.ejmech.2020.112504.
Elena Catanzaro 1,  Nibal Betari 1,  Jose M Arencibia 2,  Serena Montanari 1,  Claudia Sissi 3,  Angela De Simone 4,  Ivano Vassura 5,  Alan Santini 1,  Vincenza Andrisano 1,  Vincenzo Tumiatti 1,  Marco De Vivo 2,  Dmitri V Krysko 6,  Marco B L Rocchi 7,  Carmela Fimognari 8,  Andrea Milelli 9
Affiliations

Affiliations

  • 1 Department for Life Quality Studies, Alma Mater Studiorum-Università di Bologna, Corso D'Augusto 237, 47921, Rimini, Italy.
  • 2 Molecular Modeling and Drug Discovery Lab, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genova, Italy.
  • 3 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo, 5, 35131, Padova, Italy.
  • 4 Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125, Torino, Italy.
  • 5 Department of Industrial Chemistry "Toso Montanari", Alma Mater Studiorum-Università di Bologna, Viale Del Risorgimento, 4, 40136, Bologna, Italy.
  • 6 Cell Death Investigation and Therapy Laboratory, Department of Human Structure and Repair, Ghent University, 9000, Ghent, Belgium; Cancer Research Institute Ghent, 9000, Ghent, Belgium; Department of Pathophysiology, Sechenov First Moscow State Medical University (Sechenov University), 119146 Moscow, Russia.
  • 7 Department of Biomolecular Sciences, Campus Scientifico "E. Mattei", University of Urbino Carlo Bo, Via Ca' Le Suore 2, Urbino, Italy.
  • 8 Department for Life Quality Studies, Alma Mater Studiorum-Università di Bologna, Corso D'Augusto 237, 47921, Rimini, Italy. Electronic address: carmela.fimognari@unibo.it.
  • 9 Department for Life Quality Studies, Alma Mater Studiorum-Università di Bologna, Corso D'Augusto 237, 47921, Rimini, Italy. Electronic address: andrea.milelli3@unibo.it.
PMID: 32712536 DOI: 10.1016/j.ejmech.2020.112504
Abstract

Drugs targeting human Topoisomerase II (topoII) are used in clinical practice since decades. Nevertheless, there is an urgent need for new and safer topoII inhibitors due to the emergence of secondary malignancies and the appearance of resistance mechanisms upon treatment with topoII-targeted Anticancer drugs. In the present investigation, we report the discovery of a new topoII inhibitor, whose design was based on the structure of the natural product trypthantrin, a natural alkaloid containing a basic indoloquinazoline moiety. This new topoII inhibitor, here numbered compound 5, is found to inhibit topoII with an IC50 of 26.6 ± 4.7 μM. Notably, compound 5 is more potent than the template compound trypthantrin, and even than the widely used topoII-targeted clinical drug etoposide. In addition, compound 5 also exhibits high water solubility, and a promising antiproliferative activity on different tumor cell lines such as acute leukemia, colon, and breast Cancer. In LIGHT of these results, compound 5 represents a promising lead for developing new topoII inhibitors as anti-cancer therapeutic agents.

Keywords

Anticancer agents; Drug design; Topoisomerase II; Tryptanthrin.

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