Design And Synthesis Of Hypoxic Tissue Targeted Anilinoquinazoline Tyrosine Kinase Inhibitors

Objective: Focusing on the hypoxia phenomenon in tumors, we introduced nitro-imidazole group to the structures of anilinoquinazoline small molecule tyrosine kinase inhibitors by structure modification to obtain new type of hypoxic tissue targeted EGFR/VEGFR-2 tyrosine kinase inhibitors.Methods: Considering the molecular biological mechanism for tumorigenisis and the influence of hypixia towards tumor cell signaling pathways, target compounds in this article were designed with Vandetanib as lead compound according to the exsiting structure-activity relationships of anilinoquinazoline EGFR/VEGFR-2 inhibitors and nitro-imidazole radiosensitizers through molecule splicing and computer-aided drug design methods. Synthesis, structure confirmation and biological activity test for these target compounds have also been completed.Results: In this paper, we have synthesized 37 unreported compounds of 5 types. Molecular structures of these compounds were comfirmed by 1H-NMR/13C-NMR and molecular weights were measured by mass spectrum. Biological activity test for target molecules indicated that some of them showed approximate anti-tumor activities with lead compound and we also have summerazied the preliminary structure-activity relationship for these target molecules.Conclusion: Target compounds synthesized in this paper showed anti-tumor activities in different degrees and some compounds with better tumor cell inhibition could become potential candidates of hypoxic tissue targeted tyrosine kinase inhibitors. Further structure confirmation and pharmacological research for these compounds is worth to be continued.