Design, Synthesis And Antitumor Activity Research Of Integrin α_vβ₃ Antagonists

Integrinα_vβ₃, was expressed in many cell types, including osteoclasts, leukocytes, vascular smooth muscle cells, and endothelial cells. It had been implicated in a variety of therapies for cancer, macular degeneration, and arthritis among others. Integrinα_vβ₃ was associated with adhesion and migration of vascular smooth muscle cells and leukocytes. Antagonism of integrinα_vβ₃ lead to apoptosis of endothelial cells, blocks the tumor growth, even tumor elapsed. Integrinα_vβ₃ receptor had been considered as a new target of anti-blood in anti-tumor research. Excellentα_vβ₃ antagonists may deal cancer. Computer aided drug design had been used to design new compounds that strongly inhibitα_vβ₃ receptor in our study.The contents of this study were as followed:I. Generated a pharmacophore model of integrinα_vβ₃ receptor antagonistsTwenty two compounds of four categories with highly inhibitory activity of integrinα_vβ₃ receptor (IC50<1.5 nmol·L-1) were selected as a training set, to develop a pharmacophore model with the Catalyst software. The pharmacophore model of integrinα_vβ₃ receptor antagonists consisted of four features, namely, two hydrogen-bonding acceptors, an aliphatic hydrophobic core and an aromatic ring center. RMS=0.44, Correl=0.90, Weight=1.31, Config=16.26. The pharmacophore model that we established well fit activate compounds. It was better than other known ones. It would contribute to the design and screening of integrinα_vβ₃ receptor antagonists.II. Design and synthesis of target compoundsThe tripeptide RGD sequence, which was identified and combined toα_vβ₃ receptor, was considered as the lead compound in this study. Compounds were rational designed according to the lead compound RGD by bioisostere principle. Activities of which were estimated by matching the pharmacophore model. Target compounds Ia～Id and IIa～IId were screened out.Thirteen midway compounds and eight target compounds were synthesized. The target compounds were not reported, structures of which were corroborated by spectra of UV, IR, 1H-NMR, and 13C-NMR.How to synthesize one of the actants 3-phenylpentanoic acid, an important medical staple was particular discussed.III. Determination of antitumor activity in vitroThe antitumor activity of target compounds were determined in vitro using ECV304 and Hela cells by MTT method with 5-FU as positive contrast. Preliminary bioassay suggests that target compounds of 50μmol/L inhibit ECV304 more than 50%, while more than 40% of Hela cells were inhibited, even 78%.All in all, the new points of this study was to have generated an advancedα_vβ₃ receptor pharmaphore model, given a new basic structure as lead compound ofα_vβ₃ receptor antagonists, and synthesized eight unreported compounds.IV. Prospect ionDue to significant expression of integrinα_vβ₃ receptor on the surface of vascular endothelial cells of malignancy tumors, only entirely occupancy ofα_vβ₃ receptor on cell membrane surface lead to growth inhibition of vascular endothelial cells. It is the reason why inhibitory activities of target compounds were not so high. As a result, selectivity is an important indicator of evaluation of integrinα_vβ₃ receptor antagonists.Efficiently inhibition of angiogenesis was probably deal with malignancy tumor. Antagonism ofα_vβ₃ receptors lead to inhibition of angiogenesis. Integrinα_vβ₃ receptors were seldom expressed in normal tissues. Highly selectiveα_vβ₃ receptor antagonists would be important in anti-tumor.These researches established base for the searching of nonpeptide antagonists.