Studies on quinones. Part 46. Synthesis and in vitro antitumor evaluation of aminopyrimidoisoquinolinequinones

In the search of structure–activity relationship studies and to explore the antitumor effect associated with the pyrimidoisoquinolinequinone scaffold, several diversily substituted 8-aminopyrimido[4,5-c]isoquinolinequinones were regioselectively synthesized. Variation in the structure of the nitrogen substituent bonded to the 8-position of the pyrimidoisoquinolinequinone system led to a set of alkylamino-, phenylamino- and alkyphenylamino derivatives. The cytotoxic activity of the aminoquinone derivatives was evaluated in vitro using the MTT colorimetric method against one normal cell line (MRC-5 lung fibroblasts) and four human cancer cell lines (AGS human gastric adenocarcinoma; SK-MES-1 human lung cancer cells, and J82 human bladder carcinoma; HL-60 human leukemia) in 72-h drug exposure assays. Among the series, five compounds exhibited interesting antitumor activity against AGS human gastric adenocarcinoma and human lung cancer cells. The SAR studies revealed that both the nature of the nitrogen substituent into the quinone ring and the methyl group at the 6-position play key roles in the antitumor activity.

Graphical abstractA series of aminopyrimido[4,5-c]isoquinoline-7,10-quinones have been synthesized and evaluated for their cytotoxicity against a panel of four human cancer cell lines and normal human lung fibroblasts (MRC-5). Figure optionsDownload full-size imageDownload as PowerPoint slide