Novel topoisomerase I-targeting antitumor agents synthesized from the NNN-trimethylammonium derivative of ARC-111 5H-23-dimethoxy-89-methylenedioxy-5-(2-NNN-trimethylammonium)ethyldibenzoch16-naphthyridin-6-one iodide

摘要

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, 1H-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.