Synthesis And Cytotoxic Activity Against Cancer Cells Of Pyrazolo[1, 5-a] Indole Derivatives

It was first reported by Hajime Katayama that pyrazolo[1,5-a]indole derivatives have potent inhibitory activity against DNA topoisomerases I and II and have strong cytotoxic activity against cancer cells. Katayama's group also reported methods of synthesizing the skeleton and derivatives of pyrazolo[1,5-a]indole. Inspired by reports of Cu(I)-catalyzed intermolecular C-N coupling Reaction, we were thinking about using a new method of Cu(I)-catalyzed intramolecular amination reaction to synthesize pyrazolo[1,5-a]indole derivatives in order to introduce diverse substituents to the pyrazolo[1,5-a]indole skeleton and study structure activity relationship. Substituted 2-bromophenylacetic acids were converted to acid chlorides, which immediately reacted with anions derived from ketones to form 1, 3-diketones. By addition of hydrazine, 1, 3-diketones were rapidly converted into pyrazoles. Pyrazolo[1,5-a]indole intermediates were synthesized by Cu(I)-catalyzed C-N coupling reaction. Targeting products were obtained by pyrazolo[1,5-a]indole intermediates reacting with methyl trifluoromethanesulfonate and 4-(dimethylamino) benzaldehyde. Nineteen Pyrazolo[1,5-a]indole intermediates and twelve targeting derivatives were synthesized. Some targeting derivatives show potent anticancer activity.