Synthesis of an aminopropyl analog of the experimental anticancer drug tallimustine, and activation of its 4-nitrobenzylcarbamoyl prodrug by nitroreductase and NADH

Compound 1, an analog of tallimustine that contains an aminopropyl group at the C-terminus, and its 4-nitrobenzylcarbamoyl prodrug 2 have been prepared. Analog 1 binds preferentially to the minor groove of poly(dA-dT) over poly(dG-dC), and is cytotoxic against the growth of LS1747 and SW1116 human colon cancer cells, with IC50 values of 0.02 μM and 10.0 μM, respectively. The prodrug 2 is significantly less cytotoxic (2.3 and 22.9 μM, respectively) than the parent drug 1. However, in the presence of nitroreductase and NADH prodrug 2 is as active as compound 1.