Novel topoisomerase I-targeting antitumor agents synthesized from the N, N, N-trimethylammonium derivative of ARC-111, 5 H-2,3-dimethoxy-8,9-methylenedioxy-5-[(2- N, N, N-trimethylammonium)ethyl]dibenzo[ c, h][1,6]naphthyridin-6-one iodide

Abstract

Several new TOP1-targeting agents were prepared using as an intermediate the N, N, N-trimethyl quaternary ammonium salt 2 of ARC-111. Direct displacement of the quaternary ammonium group with hydroxide, cyclopropylamine, imidazole, 1 H-1,2,3-triazole, alkylethylenediamines, ethanolamine, and polyhydroxylated alkylamines provides a convenient means for furthering insight into the structure–activity relationships within this series of non-camptothecin TOP1-targeting agents. The relative TOP1-targeting activities and cytotoxicities were evaluated in RPMI8402 and P388 cells and their camptothecin-resistant variants. Their potential to serve as substrates for the efflux transporters MDR1 and BCRP, which are associated with multidrug resistance, was also assessed.