Design, Synthesis And Anti-Tumor Activities Of Novel 1-Anilino-5H-Pyridazino[4, 5-b]Indole Derivatives

It was well known that cancer was the second leading causes of death in the world.In recent years,a large number of compounds with novel structures and targeted strategies were developed and evaluated as potential anticancer drugs;in which small-molecular epidermal growth factor receptor（EGFR）and vascular endothelial growth factor receptor（VEGFR） tyrosine kinases inhibitors are among the hottest races in pharmaceutical development.In this paper we focused on the structure,function of EGFR and VEGFR,and advance of their inhibitors.In accordance with the previous structure-activity relationship（SAR）of 4-anilinoquinazoline and 4-anilinopyrimido[4,5-b]indole derivatives,a novel series of 1-anilino-5H-pyridazino[4,5-b]indole derivatives were designed as the "bioisosteres" of 4-anilinopyrimido[4,5-b]indoles.Different substituted aminoalkoxy moieties were introduced into 8-position,and various anilines were introduced into 1-position in order to investigate their influence on anti-tumor activity.88 Novel 1-anilino-5H-pyridazino[4,5-b]indole derivatives were synthesized and their structures were confirmed by MS and ¹H NMR.The anti-tumor activities of 88 novel compounds were tested by the MTT method in vitro against two cancer cell lines（Bel-7420 and HT-1080）,with Gefitinib as the positive control. 47 Compounds exhibited potent anti-tumor activity.Among them,compound L-08、L-15、L-30、L-36、L-64、L-87 showed an five-fold increase in potent anti-tumor activity against the cancer cell lines Bel-7402 and HT-1080 relative to the positive control.Compound L-30 displayed the most potent anti-tumor activity with IC₅₀values of 4.2μM and 2.1μM against Bel-7402 and HT- 1080,respectively.The preliminary structure-activity relationship of the compounds were discussed.