Design, Synthesis And Activity Research Of Integrin ?v?3-based On Antitumor Drugs

Integrins are important adhesion molecules located on cell surface,which can mediate cell to cell and cell to extracellular matrix(ECM) interaction through bidirectional signal transduction and plays an important role in tumor ce lls migration, adhesion, invasion and angiogenesis. Integrin ?v?3 overexpressed in many tumor cell surface while low or no expression in normal cells, when its function is inhibited, vascular endothelial cell apoptosis, tumor growth was inhibited, and e ven tumor regression. The research using integrins ?v?3 as targets on anti- tumor drug design and the corresponding treatment strategy has been a hot point in recent years.In our study, a pharmacophore model of integrin ?v?3 receptor inhibitors were constructed based on currently available 30 inhibitors with highly inhibitory activity against integrin ?v?3 receptor in Catalyst software. The tripeptide RGD sequence were chosen as a scaffold for further chemical modification by phamacophore model to explore ?v?3 inhibitors. Finally,sixteen novel target compounds have been designed and synthesized after further modification of the structure of the leading compounds and sixteen were whole new and not reported. 16 target compounds were synthesized by conventional methods or microwave-catalized organic synthesis method. UV?IR?1H-NMR?13C-NMR ?ESI-MS? HPLC were applied to confirm the structure and purity of target compounds. Integrin ?v?3 overexpressed in tumor angiogenesis process, so this experiment, HUVEC as useful primary indicator. To further verify the antitumor effect of the target compound, the paper also selected ?v?3 expression higher tumor cells PANC-1, A375, the inhibitory activity to three cells of target compounds was evaluated by MTT. The results of antitumor activities show that the majority of the target compounds have good inhibitory activity, some of the compounds have higher activity than the positive control. Compound E2 has the maximum inhibition of A375 and HUVEC with the IC50 value of 0.41 ?mol/L, 0.023 ?mol/L.In conclusion, the innovate points of this research was to have built an optimum integrin ?v?3 receptor antagonist pharmaphore model, design and synthesis sixteen unreported compounds of phenylpiperazine derivatives which have better antagonism forintegrin ?v?3 receptor. Pharmacology experiments indicated that those compounds have certain inhibition for some cancer cell growth. The results have provide a theoretical and experimental basis of small molecule antagonists of the ?v?3 active drug design and renovation.