基于点击化学反应的半乳糖糖基化马蹄金素衍生物的合成及抗HBV活性

Synthesis and Anti-HBV Activity Evaluation of the Galactopyranosyl Derivatives of MTS Based on Click Reaction

以D-半乳糖和二缩三乙二醇为原料,经乙酰化、糖基化和叠氮化钠取代等反应合成了带叠氮连接臂的半乳糖配基,通过点击化学反应将其与炔丙基修饰的马蹄金素(MTS)衍生物进行连接,设计合成了6个具有潜在肝靶向性的半乳糖糖基化MTS衍生物.通过1H NMR,13C NMR,1H-1H COSY,HMQC,DEPT和ESI-MS对其结构进行了表征;采用Hep G2 2.2.15细胞模型初步评价了目标化合物的抗乙型肝炎病毒(HBV)活性.结果表明,所有目标化合物对HBV DNA的复制均有抑制作用,且具有一定的量效关系;化合物15f在50μg/m L浓度下对Hep G2 2.2.15细胞株的抑制率为83%,具有进一步研究的价值.

Matijin-Su [N-（ N-benzoyl-L-phenylalanyl）-O-acetyl-L-phenylalanol,MTS],a dipeptide derivative,was isolated from a Chinese ethnic drug Matijin（ Dichondra repens Forst.） which has been widely used in the treatment of chronic liver disease as folk medicine in China. A series of MTS derivatives with anti-hepatitis B virus（ HBV） activitiy was synthesized by structural modification of MTS. One of MTS derivatives named＂Tyrophentide＂had been finished pre-clinical research and has been approved to do clinical study of phase Ⅰby China Food and Drug Administration（ CFDA）. The preliminary pharmacokinetic experiments showed that it was widely distributed in many organs,and the concentration in liver was low. To improve the concentration in liver lesion tissue and increase the anti-HBV activity of MTS derivatives,a series of hepatic targeting galactopyranosyl derivatives of MTS 15a—15f was designed according to asialoglycoprotein receptor（ ASGP-R）mediation and synthesized. Starting from unexpensive and commercially available galactose and triethylene glycol,the glycosyl donor with azide linker was achieved via acetylation,glycosylation and azidation reaction. At the same time,propargylated MTS derivatives using L-phenylalaninol,L-tyrosine methyl ester hydrochloride,benzoic acid and its derivatives as the starting materials were prepared by acylation,hydrolysis,alkylation,condensation reactions and so on. Then compounds 15a—15f with a 1,2,3-triazole unit were obtained from＂click＂chemistry reaction using copper（ Ⅰ） catalyst in high yield（ over 85%）,which were deacetylated in the 0. 41 mol / L solution of sodium methoxide to give target compounds. The structures of target compounds were confirmed by1 H NMR,13 C NMR,1H-1H COSY,HMQC,DEPT and ESI-MS. The anti-HBV activities of target compounds were evaluated in Hep G2 2. 2. 15 cells. The screening results showed that all target compounds had inhibitory effect on HBV DNA replication in Hep G2 2. 2. 15 cells. Compound 15 f showed inhibition rate anti-HBV activity of 83% at 50 μg / m L and could be worthy of further research.