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Novel topoisomerase I inhibitors. Syntheses and biological evaluation of phosphorus substituted quinoline derivates with antiproliferative activity

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  • Concepción Alonso, University of the Basque Country (UPV/EHU)
  • ,
  • María Fuertes, University of the Basque Country (UPV/EHU)
  • ,
  • Endika Martín-Encinas, University of the Basque Country (UPV/EHU)
  • ,
  • Asier Selas, University of the Basque Country (UPV/EHU)
  • ,
  • Gloria Rubiales, University of the Basque Country (UPV/EHU)
  • ,
  • Cinzia Tesauro
  • Birgitta K. Knudssen
  • Francisco Palacios, University of the Basque Country (UPV/EHU)

This work describes the synthesis of 1,2,3,4-tetrahydroquinolinylphosphine oxides, phosphanes and phosphine sulfides as well as that of quinolinylphosphine oxides and phosphine sulfides, which were synthesized in good to high overall yield. The synthetic route involves a multicomponent reaction of (2-phosphine-oxide)-, 2-phosphine- or (2-phosphine-sulfide)-aniline, aldehydes and olefins and allows the selective generation of two stereogenic centres in a short, efficient and reliable synthesis. The selective dehydrogenation of 1,2,3,4-tetrahydroquinolinylphosphine oxides and phosphine sulfides leads to the formation of corresponding phosphorus substituted quinolines. Some of the products which were prepared showed excellent activity as topoisomerase I (Top1) inhibitors. In addition, prolonged effect of the most potent compounds is maintained with the same intensity even after 3 min of the beginning of the enzymatic reaction. The cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV03) and human embryonic kidney (HEK293) was also screened. 1,2,3,4-Tetrahydroquinolinylphosphine oxide 6g with an IC50 value of 0.25 +/- 0.03 mu M showed excellent activity against the A549 cell line in vitro, while 1,2,3,4-tetrahydroquinolinylphosphane 9c with an IC50 value of 0.08 +/- 0.01 mu M and 1,2,3,4-tetrahydroquinolinylphosphine sulfide derivative 10f with an IC50 value of 0.03 +/- 0.04 mu M are more active against the A549 cell line. Moreover, selectivity towards cancer cell (A549) over non-malignant cells (MRC5) has been observed. According to their structure, they may be excellent antiproliferative candidates. (C) 2018 Elsevier Masson SAS. All rights reserved.

Original languageEnglish
JournalEuropean Journal of Medicinal Chemistry
Volume149
Pages (from-to)225-237
Number of pages13
ISSN0223-5234
DOIs
Publication statusPublished - 10 Apr 2018

    Research areas

  • Antiproliferative effect, Enzyme inhibition, Phosphorated quinolines, Topoisomerase I, MEDICINAL CHEMISTRY, MULTICOMPONENT REACTIONS, DESIGN, COMPLEXES, DNA TOPOISOMERASES, CANCER, DISCOVERY, Quinolines/chemistry, Humans, Antineoplastic Agents, Topoisomerase I Inhibitors/chemical synthesis, Structure-Activity Relationship, Hydrogenation, Phosphorus/chemistry, Cell Line, Tumor, Cell Proliferation/drug effects, Phosphines, Drug Screening Assays, Antitumor

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