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.
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry
Feng, W., Satyanarayana, M., Tsai, Y. C., Liu, A. A., Liu, L. F., & LaVoie, E. J. (2009). Novel topoisomerase I-targeting antitumor agents synthesized from the N,N,N-trimethylammonium derivative of ARC-111, 5H-2,3-dimethoxy-8,9-methylenedioxy-5-[(2-N,N,N-trimethylammonium)ethyl]dibenzo[c,h][1,6]naphthyridin-6-one iodide. European Journal of Medicinal Chemistry, 44(9), 3433-3438. https://doi.org/10.1016/j.ejmech.2009.02.004