Study On Synthesis And Antitumor Activity Of Targeted Drug Delivery System For Combretastatin A4 Using Galactose Units As The Carrier

Combretastatin A-4, a compound isolated from the African tree Combretum caffrum, shows structural similarities to the tubulin binding agent colchicine, and has a higher affinity for the colchicine binding site on tubulin than colchicine itself. There is interest in these compounds as anti-cancer agents since they are able to induce irreversible vascular shutdown in tumours. However, the major disadvantages of CA-4 as a drug candidate are limited bioavailability and poor solubility in aqueous media. Its derivative AC-7739, AVE-8082 and phosphate prodrugs CA-4P, CA-1P had beed in clinic research. Especially, CA-4P is currentiy in phase III clinical trials as tumor vascular targeting agent.In this thesis, Combretastatin A4 was perpared in straightforward and scalable proceduer. Based on their Structure-activity relationship stuies, we retained the important 3,4,5-trimethoxyphenyl pharmacophore and selected the 3'-OH group of Combretastatin A4 for prodrug modification. Galactose was employed as a homing device, because it is well-known that galactose receptors (asialoglycoprotein receptors) were exposed on the surface of liver parenchymal cells. The antennary (branched) structure of derivative was designed based on the fact that a saccharide cluster having a branched structure shows highly effective binding with the saccharide receptors that is a "cluster effect". The derivatives of after glycosylation have targeted, transported to the liver cells can bedirected in an effect to improve the anticancer drug distribution in the body, reducingthe damage to normal organs, improve the effectiveness and reduction of drug to the dose.According to this design, in this thesis, a total of 16 compounds, including Combretastatin A4 were designed, synthesized and tested for their cytotoxicities against A549 cell line and HepG2 cell line in vitro. Results were as follows:in the four Monosaccharide derivatives, the Xylose-based derivative exhibited high cytotoxicities against the A549 cell line and HepG2 cell line, and the reason maybe is that the xylose has smaller polarity, it has little effect on Combretastatin A4; In the three Disaccharide derivatives, the Lactose derivatives did not exhibited high cytotoxicities against the HepG2 cell line, and the reason maybe is that there only one Galactose residues, and the force agent asialoglycoprotein receptors is weak;The NO.9 derivatives show significant targeting and cytotoxicity, in four tetrasaccharide derivatives; For Hexasaccharide derivatives, the cytotoxicities value against the A549 cell line and HepG2 cell line is very close, this may be explained exhibited such cytotoxicities, it may be concern release rate.