Selective cytotoxicity of azatyrosinamides against ras-transformed NIH 3T3 cells

• Published in: Bioorganic & medicinal chemistry letters 2005-10, Vol.15 (19), p.4272-4274
• Main Authors: Wang, H.P., Hwang, T.L., Lee, On, Tseng, Y.J., Shu, C.Y., Lee, S.J.
• Format: Article
• Language: English
• Subjects: Alanine - analogs & derivatives; Alanine - chemical synthesis; Alanine - pharmacology; Amides; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cell Line, Transformed; General aspects; Inhibitory Concentration 50; Medical sciences; Mice; NIH 3T3 Cells; Pharmacology. Drug treatments; ras Proteins; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.06.048

Synthesis and cytotoxicity of novel azatyrosinamides structurally modified from ras-specific antioncogenic azatyrosine are reported. Compound 12 (IC 50 16.5 ± 2.2 μM) exhibited selective toxicity on ras-transformed NIH 3T3 cells over wild-type cells. The inhibitory activity of this compound was 458-fold higher than that of azatyrosine. This study aims to develop novel azatyrosinamide compounds structurally modified from ras-specific antioncogenic azatyrosine. Analogues 4– 15 were prepared and their inhibition on the growth of wild-type and ras-transformed NIH 3T3 cell lines was compared. Compound 12 was found to be the most active with IC 50 16.5 ± 2.2 μM which is 458-fold more potent than that of azatyrosine. The selective toxicity, defined as IC 50 wild-type/IC 50 ras-transformed for this compound was 138.5.