Straightforward synthesis and biological evaluation as topoisomerase I inhibitors and antiproliferative agents of hybrid Chromeno[4,3-b][1,5]Naphthyridines and Chromeno[4,3-b][1,5]Naphthyridin-6-ones

Endika Martín-Encinas, Gloria Rubiales, Birgitta R. Knudssen, Francisco Palacios*, Concepción Alonso

*Corresponding author for this work

    Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

    Abstract

    This work describes the synthesis of hybrid tetrahydro-1,5-naphthyridine and 1,5-naphthyridine derivatives fused with heterocycles such as chromenes and chromen-2-ones or coumarins, which were synthesized in good to high general yields. The synthetic route involves an intramolecular [4 + 2]-cycloaddition reaction of functionalized aldimines obtained by the condensation of 3-aminopyridine and aldehydes containing a double or triple carbon-carbon bond in orto position and allows the selective generation of three stereogenic centers in a short, efficient and reliable synthesis. The subsequent dehydrogenation of the fused tetrahydrochromeno[4,3-b][1,5]naphthyridines and/or tetrahydrochromeno[4,3-b][1,5]naphthyridin-6-ones leads to the formation of the corresponding tetracyclic chromeno[4,3-b][1,5]naphthyridine derivatives and/or chromeno[4,3-b][1,5]naphthyridin-6-ones in quantitative yields. Some of the prepared products showed activity as inhibitors of Topoisomerase I (TopI). Additionally, the cytotoxic behavior of these compounds has been studied in cell lines derived from human lung adenocarcinoma (A549) and human ovarian carcinoma (SKOV03), and on non-cancerous lung fibroblasts cell line (MRC5) where, on the last ones, the absence of cytotoxicity was observed. 7-Phenyl-6H-6a,7,12,12a-tetrahydrochromeno[4,3-b][1,5]naphthyridine 5a showed excellent cytotoxic activity with a IC50 value of 1.03 ± 0.30 μM against the A549 cell line and a IC50 value of 1.75 ± 0.20 μM against the SKOV03 cell line. The obtained results point to these compounds as good antiproliferative candidates.

    Original languageEnglish
    JournalEuropean Journal of Medicinal Chemistry
    Volume178
    Pages (from-to)752-766
    Number of pages15
    ISSN0223-5234
    DOIs
    Publication statusPublished - Sept 2019

    Keywords

    • Antiproliferative effect
    • chromeno[4,3-b][1,5]naphthyridin-6-ones
    • Chromeno[4,3-b][1,5]naphthyridines
    • Enzyme inhibition
    • Topoisomerase I

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