Synthesis And Virtual Screening Of Neolignan Honokiol Derivatives As Anti-oophoroma Activity

Ovarian cancer is a common gynecologic malignancy, which severely hazards human healthy. Vascular endothelial growth factor was expressed in endothelial cells of ovarian carcinomas, which mainly includes three members called VEGFR-1, VEGFR-2 and VEGFR-3. Activation of VEGFR-2 will stimulate the proliferation of vascular endothelial cells, increase the permeability of microvascular, and then promote angiopoiesis. This signaling pathway has been proved to play an important role in the angiopoiesis of new tumor vessels. Therefore, the current researches focus on the new tumor vessels, which is a specific target of anti-tumor drugs.Honokiol is a biphenolic compound extract from the plant Magnolia granifiloris and has been reported to possess anti-tumor activity. The mechanism of action of Honokiol still remains unclear. With the further study of the mechanism of tumor angiopoiesis inhibition, there are more and more researches on honokiol. University of Emory has been reported that honokiol inhibited the phosphorylation of VEGFR-2 mediated by VEGF dose dependently and showed well tumor angiopoiesis inhibitory activity in vitro and in vivo.Using honokiol as lead compound, three series of compounds were designed and synthesized by computer-assisted drug design combination with principle of hybridization. They are the derivatives of honokiol and substituted 5-FU, dihydroartemisinine-2′- honokiol-1,4-succinic acid diester and honokiol Mannich compounds. Retrievaled by Scifinader, all the target compounds have been unreported and confirmed by 1H-NMR and MS.Virtual screening model was established using protein crystal structure of VEGFR-2 as receptor via Autodock4.0. Three dimensional strucuture of target compounds was set up on line using Online Demos. Molecule docking was carried out and then the interaction between ligand and recptor was analyzed.The potential VEGFR-2 inhibitory activity of dihydroartermisine-2′-honokiol-1, 4-butanedioic acid diester is higher than the other two series. The introduction of artesunate contributes much to activity. Among the derivatives of honokiol, which is substituted 5-FU, the inhibitory activity of compound with chlorine substituent at meta position is best.