Design, Synthesis And Activity Study Of Arylpiperazines As Integrin αvβ3 Antagonists

Inhibiting angiogenesis is a promising strategy for treatment of cancer and several other disorders. Contrast with chemotherapy, anti-angiogenesis therapy was more merits. As an important vascular target in tumor angiogenesis, Integrinα_vβ₃ promotes endothelial cell migration and survival during angiogenesis and lymphangiogenesis which facilitate tumor metastasis. Through cutting down nutrition of tumor,α_vβ₃ antagonists would hungry tomor tissue. An excellent prettyα_vβ₃ antagonist may deal cancer.In our study, a three-dimensional pharmacophore models of integrinα_vβ₃ receptor antagonists were constructed based on currently available 30 inhibitors with highly inhibitory activity against integrinα_vβ₃ receptor (IC50<110 nmol?L-1) in Catalyst software. The pharmacophore model we established well fit active compounds. according to the pharmacophore model, fifiteen anded compounds were rational designed. Sixteen midway compounds and fifity target compounds IA～ID, IIA～IID,â…¢A～ⅢE andâ…£A,â…£C were synthesized, some of them were whole new and not reported. The antitumor activity of target compounds were determined in vitro using ECV304 and H1299 cells by MTT method with 5-FU as a positive contrast. Preliminary bioassay suggests that some target compounds in 50μmol/L inhibit ECV304 more than 60%.Comparing the results of our activity with the predictive values of pharmacophore model, the pharmacophore model showed excellent reliability and forecast ability. It contributes to design the nicerα_vβ₃ antagonists and will be helpful in identifying novel lead compounds and providing a valuable tool in designing new integrinα_vβ₃ inhibitors.