Synthesis and in vitro antitumor activity of novel naphthyridinone derivatives

A series of naphthyridinone derivatives based on 1a (a precursor of Voreloxin) were designed and synthesized. Seven compounds having >70% inhibition against HL60 at 30 μmol/L were further evaluated for their in vitro antitumor activity by SRB assay. Results reveal that thiazol-2-yl and 3-aminomethyl-4-benzyloxyimino-3-methylpyrrolidin-1-yl groups are optimal at the N-1 and C-7 positions of naphthyridinone core, respectively. 10j exhibits broad-spectrum activity (IC₅₀:<0.5-6.25 μmol/L) against all of the tested cell lines including Etoposide- and/or 1a-resistant ones, and is 1.3-fold to >100-fold more potent than the two references against eight of these cell lines.