Synthesis And Cytotoxic Activity Against Cancer Cells For Indolo [1, 2-b] Indazole Derivatives

It was reported by Hajime Katayama that pyrazolo[1,5-a]indole derivatives have strong cytotoxic activity against cancer cells. According to analysis of the structure-activity relationship of these compounds, we figured out a similar structure, indolo[1,2-b]indazole, and have reported a new method to construct this skeleton via a palladium-catalyzed intramolecular aromatic amination reaction. Due to the high cost of palladium metal, the toxicity and instability of the corresponding ligands, this method was limited for further development and application. Recent reports of Cu(I)-catalyzed intermolecular C-N coupling reaction enticed us to search for a new method of Cu(I)-catalyzed intramolecular amination reaction for the synthesis of indolo[1,2-b]indazole structures.The substrate, 1-acetylamino-2-(2-bromophenyl)indoline, was prepared from phenylhydrazine and 2-bromoacetophenone. We explored the effects of metals, ligands, bases and solvents on the typical reaction, and found out that the use of CuI as metal source, 1,10-phenanthroline as ligand, K2CO3 as base, anhydrous 1,4-dioxane as solvent, is the most optimal condition for the synthesis of 1H-indolo[1,2-b]indazole.With the optimal reaction protocol in hand, we then sought to study, and possibly expand the scope of the application of the reaction condition. A diversity of compounds including methyl, methoxy, chloro, and fluoro substituted substrates were investigated and gave the corresponding products in good yields.Based on the above study, target products were obtained by reacting indolo[1,2-b]indazole intermediates with methyl trifluoromethanesulfonate and 4-(dimethylamino)benzaldehyde. Three of the target derivatives were screened for pharmacological activity and showed strong cytotoxic activity against cancer cells.