Synthesis Of Novel Galactosylated Lipids, Their Hepatic Targeting Study And "Click Chemistry" Inspired Synthesis Of Glycoconjugates

On the surface of parenchymal cells, there exists an unique receptor protein, the galactose (Gal)- or N-acetylgalactosamine (GalNAc)-recognizing asialoglycoprotein receptor (ASGPr). In view of its exclusive and abundant presence on hepatocytes, and because of its high-affinity and high rate of internalization, the ASGPr was considered a promising candidate target in many drug carrier studies.On this viewpoint, in order to constitute targeted drug delivery system, three series of cholesterylated galactosides were designed as the targetable ligand of liposomal carriers for hepatocytes in this thesis.Monoantennary and diantennary galactoside synthons (6a, 4b and 6c) were obtained through several chemistry reactions (protection, deprotection, glycosidation, conjugation and catalytic hydrogenation et cetera), while 4-(5-cholesten-3-yloxy)-4-oxo-butanoic acid (CHS) was obtained through the reaction of cholesterol with succinic anhydride. After the reaction between galactoside synthons and CHS under the catalysis of NHS, DCC or DIPEA, HOBT and HBTU, three target galactolipids (TM 1~3) were gained. The structures of the synthesized compounds are confirmed by means of IR, 1H-NMR, 13C-NMR, 1H-1H COSY, HSQC and MS. But triantenary galactosylated lipids were not synthesized because of alkaline hydrolysis of peptides. But the data of hepatic targeting test in mouse in vivo show that monoantennary and diantennary galactosylated lipids modified liposomes were better in liver targeting than control liposome. Compared with the injection of doxorubicin (Dox) encapsulated in control liposome (CL DOX), the plasma concentration of DOX encapsulated in monoantennary liposome (MGal DOX) and diantennary liposome (DGal DOX) decreased significantly at 30 min after intravenous injection. In contrast, the liver accumulation of MGal DOX or DGal DOX was up to 41.67% and 66.43% of the total injected dose within 30min, respectively, while the accumulation of CL DOX was relatively lower (23.38%). This shows the hepatic targeting effects of MGal DOX and DGal DOX was significantly higher than that of CL DOX. Moreover, monoantennary and diantennary galactosylated lipids can be facilely and simplely synthesized, so they are more practicable in clinic.Application Cu(I)-mediated 1,3-dipolar cycloaddition to oligosaccharides and glycoconjugates has recently begun, and most of the reports are concerned with the use of anomeric azides. Because of steric hindrance, the yield of such reaction is usually low, which limited its application.Subsequently, we have developed several practical strategies for the ligation of sugar to amino acids, steroidal, aryl or heterocyclic compounds. Eight target compounds were obtained as the mimics of glycopeptide, saponin or other glycoconjugates. The yields of most reactions were more than 85% with complete regioselectivity except for compound g10a. All products were confirmed by IR, 1H NMR, 13C NMR, DEPT, HSQC and EA or Ms; and two intermediate products were cultured to single crystals and confirmed by X-Ray difference reflections.In addition, the synthesis of compound g7a under reflux needs high molar ratio and wastes materials. Moreover, an unexpected side reaction was found in this reaction. The yield (48%) was very low, which is almost equal to the by-product (41%). Then we improved this experiment, proceeded the reaction in Teflon-lined stainless steel autoclave, and compound g7a was synthesized efficiently (87%) with low molar ratio. Meanwhile, a new heterocyclic compound g7a" was unexpectedly discovered and confirmed by 1H NMR, 13C NMR and Ms, and the mechanism of this reaction was studied.