Synthesis, Characterization And In Vitro Anti-proliferative Testing Of Guanidyl Modified 5-methyl-indolo[2,3-b]Quinolines

objective:Indoloquinoline is a main structure of many natural products formed by tetracyclic heteroaromatic, which is an extremely important part in many drugs. In recent years, researches show that indoloquinolines not only possess antimalarial and antifungal activities but also have anti-proliferative activity. And 5-methyl-indolo[2,3-b]quinoline have received lot attentions because of its brief method to synthesize, high selectivity and good activity to cancer cell. However, few article has reported about 5-methyl-indolo[2,3-b]quinoline connected with guanidine group. In order to find more 5-methyl-indolo[2,3-b]quinoline derivatives for cure of cancer, we want to synthesize some 5-methyl-indolo[2,3-b]quinoline derivatives by referencing methods of others. Method:The time of reaction, temperature and feeding ratio were screened to obtain a best method to synthesize some 5-methyl-indolo[2,3-b]quinoline derivatives using indolo-3-carboxylate as a starting material. Then the intermediate 4 and 6 were obtained by modifying the C-11 with diamine and reacted with 1H-pyrazole-l-carboxamidine hydrochloride to obtain a 5-methyl-indolo[2,3-b]quinolone derivative modified with guanidine group. The target products were characterize by 1H NMR,13C NMR, IR test and their anticancer activity against A549 cell, H460 cell and DU145 cell was tested. Result:A good method to achieve a high yield of guanidyl modified 5-methyl-indolo[2,3-b]quinolines has been established and three derivatives of 5-methyl-indolo[2,3-b]quinolone (5a,5b,7) have been obtained. Then the spectrum of 1H NMR,13C NMR, IR and the data of melting point which show that three hybrids with high purity and good yield have been obtained. On this basis, the anticancer activity against A549 cell, H460 cell and DU145 cell was tested. The IC50 of 5a,5b,7 against A549 cell, H460 cell and DU145 cell are orderly 5a(0.78±0.09μM,26.10±2.26μM,10.50±2.26μM); 5b(1.04±0.21μM, 38.90±9.82μM,25.80±2.19μM);7(3.70±0.31μM,15.90±1.19μM, 14.60±5.12μM). Conclusion:5-methyl-indolo[2,3-b]quinoline could be efficiently and easily obtained by the method we screened.Then the preliminary tests of their anti-proliferative activity were preceded. The result shows all the hybrids have shown antitumor activity against A549 and H460 and DU145 tumor cell line.5a was evaluated the most potential compound with the IC50 of 0.78±0.09μM,26.10±2.26μM,10.50±0.87μM compared with 5b and 7. Thus, we can make a conclusion that indoloquinolines modified with guandyl has a potential antitumor activity.