Synthesis And Anticancer Activity Of New Hybrid 3-Methylidene-2,3-Dihydro-1,8-Naphthyridinones

• Published in: ChemMedChem 2024-04, Vol.19 (7), p.e202300519-e202300519
• Main Authors: Jaskulska, Agata, Szymański, Jacek, Lipiński, Piotr F J, Modranka, Jakub, Janecka, Anna E, Janecki, Tomasz, Gach-Janczak, Katarzyna
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Aldehydes; Anticancer properties; Antitumor activity; Apoptosis; Bioactive compounds; Biocompatibility; Biological activity; Cancer; Carbonyl compounds; Carbonyl groups; Carbonyls; Chemical synthesis; Cytotoxicity; DNA damage; Endothelial cells; Hybrids; Leukemia; Molecular modelling; Promyeloid leukemia; Tumor cell lines; Umbilical vein
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202300519

Synthesis of molecular hybrids, obtained by combination of two or more pharmacophoric groups of different bioactive substances in order to produce more efficient drugs, is now a frequently used approach in medicinal chemistry. Following this strategy, we synthetized a library of 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones, combining a 1,8-naphthyridin-4-one motif with an exo-methylidene bond conjugated with a carbonyl group, pharmacophoric units that are present in many natural, biologically active compounds with anticancer potential. We reasoned that such bifunctional conjugates may have enhanced cytotoxic activity. The title compounds were synthesized in a four step reaction sequence. β-Ketophosphonate, obtained from methyl N-tosylnicotinate and diethyl methylphosphonate, was reacted with various aldehydes giving 3-diethoxyphosphoryl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones as keto-enol tautomers. Later, these compounds were transformed into 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones applying the Horner-Wadsworth-Emmons methodology. Then, the cytotoxicity of the new compounds was assessed on two cancer cell lines, promyelocytic leukemia HL-60 and breast cancer adenocarcinoma MCF-7, and for comparison, on human umbilical vein endothelial cells HUVEC. The most active and selective analog, 2-ethyl-3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one 4 a was chosen for more detailed studies on HL-60 cell line, to determine molecular mechanisms of its anticancer activity. It was shown that 4 a strongly inhibited proliferation and induced apoptosis which could be attributed to its ability to cause DNA damage.