2. Academic Validation
  3. Fused chromeno and quinolino[1,8]naphthyridines: Synthesis and biological evaluation as topoisomerase I inhibitors and antiproliferative agents

Fused chromeno and quinolino[1,8]naphthyridines: Synthesis and biological evaluation as topoisomerase I inhibitors and antiproliferative agents

  • Bioorg Med Chem. 2021 Jun 15:40:116177. doi: 10.1016/j.bmc.2021.116177.
Endika Martín-Encinas 1,  Gloria Rubiales 1,  Birgitta R Knudsen 2,  Francisco Palacios 3,  Concepción Alonso 4
Affiliations

Affiliations

  • 1 Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center), Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
  • 2 Department of Molecular Biology and Genetics and Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus 8000, Denmark.
  • 3 Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center), Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain. Electronic address: francisco.palacios@ehu.eus.
  • 4 Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center), Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain. Electronic address: concepcion.alonso@ehu.eus.
PMID: 33962152 DOI: 10.1016/j.bmc.2021.116177
Abstract

The synthesis of 1,8-naphthyridine derivatives fused with Other heterocycles, such as chromenes and quinolines, as well as their behaviour as Topoisomerase I inhibitors is studied. The preparation is carried out through a direct and simple process as an intramolecular [4 + 2] cycloaddition reaction between functionalized aldimines, obtained by the condensation of 2-aminopyridine and unsaturated aldehydes, and olefins. In particular, while no clear inhibitory activity is observed for chromeno[4,3-b][1,8]naphthyridine fused heterocycles, a very different result is observed for quinolino[4,3-b][1,8]naphthyridine derivatives. Experimental assays indicated that quinolino[4,3-b][1,8]naphthyridines inhibited the Topoisomerase I enzymatic reaction behaving like a poison, as occurs with the natural TopI inhibitor, camptothecin. Furthermore, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV3), and on non-cancerous lung fibroblasts cell line (MRC5) was also screened.

Keywords

Antiproliferative effect; Enzyme inhibition; Intramolecular [4+2]-cycloaddition; Naphthyridines; Topoisomerase I.

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