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

• Published in: Bioorganic & medicinal chemistry letters 1997-04, Vol.7 (8), p.1065-1070
• Main Authors: Lee, Moses, Simpson, Jacob E., Woo, Shirley, Kaenzig, Crystal, Anlezark, Gill M., Eno-Amooquaye, Ebun, Burke, Philip J.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; General aspects; Medical sciences; Pharmacology. Drug treatments
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(97)00162-5

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 IC 50 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. Compound 1, an analog of tallimustine that contains an aminopropyl group at the C-terminus, and its 4-nitrobenzylcarbamoyl prodrug 2 have been prepared. The prodrug 2 is significantly less cytotoxic than the parent drug 1. However, in the presence of nitroreductase and NADH prodrug 2 is as active as compound 1.