Study On The Bag And Behavior Of Cordycepin And Cyclodextrin And The Design, Synthesis And Antitumor Activity Of VEGFR-2 Inhibitors

Cordycepin, as an active ingredient of traditional Chinese medicine Cordyceps militaris, has been widely used in medicine, especially in the field of traditional Chinese medicine. It was the first deoxy-nucleoside antibiotic isolated from the fungus and possessd a variety of excellent biological activity and pharmacological effects. However, the use of cordycepin as a natural herbal medicine is greatly limited by its low water solubility and bioavailability.The cyclodextrin has made tremendous progress in pharmaceutics field as a polymer compound. This usually enhances drug solubility in aqueous solutions and affects the chemical characteristics of the encapsulated drug in the pharmaceutical industry. Therefore, it is very important to study the cyclodextrin inclusion behavior of cordycepin molecule.Cancer is a common disease which seriously threatens human health and life. As the development direction of modern novel antineoplastic agents, specific targeting molecule drug is a new research direction, and wherein VEGFR-2kinase inhibitor which aims to realize the anti-angiogenic therapy has become one of the hot currents of medicinal chemistry.This study contains two main parts:Part I:The inclusion complex of cordycepin with the three common cyclodextrin (a-CD, P-CD and y-CD) were prepared and their behavior, characterization, and binding ability were investigated in both solution and the solid state by means of NMR, UV-vis, SEM, DSC, FT-IR, XRD, ESI-MS and Molecular Modelling. The results showed that: Cordycepin can be well formed between a-, p-or y-CD of1:1binding models; the physical and chemical properties of Cordycepin can be improved through the inclusion, especially the water solubility and thermal stability. Part â…¡:A class of the pharmacophore of benzoxazoles as the basic structure of arylureas VEGFR-2kinase inhibitors was designed. From the raw material2,4-diaminophenol hydrochloride which can get from easy way, the inhibitors were synthesized through a two-steps reaction with simple post-processing. In this way, a total of23compounds were synthesized and their structures were confirmed by IR,1H NMR,13C NMR and HRMS. The anti-tumor activity of these compounds were tested by growth inhibition experients in vitro tumor cell lines (H1975, A549, Hela), and we found that more than one compounds having a good cytotoxic activity. Among them, the cytotoxic activity of compound5-14is nearly an order of magnitude higher than the positive control sorafenib and sunitinib.