Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 40, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2021.116177
Keywords
Naphthyridines; Intramolecular[4+2]-cycloaddition; Topoisomerase I; Enzyme inhibition; Antiproliferative effect
Funding
- Ministerio de Ciencia, Innovacion y Universidades (MCIU), Agencia Estatal de Investigacion (AEI) [RTI2018-101818-B-I00]
- Fondo Europeo de Desarrollo Regional (FEDER) [RTI2018-101818-B-I00]
- Gobierno Vasco, Universidad del Pais Vasco (GV) [IT 992-16]
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The synthesis and behavior of 1,8-naphthyridine derivatives fused with other heterocycles, such as chromenes and quinolines, as topoisomerase I inhibitors were studied. It was found that quinolino[4,3-b][1,8]naphthyridine derivatives exhibited strong inhibitory activity against topoisomerase I enzyme, similar to camptothecin.
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, ob-tained 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 qui-nolino[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.
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