间接糖基化马蹄金素衍生物的合成及抗乙肝病毒活性研究

doi:10.7503/cjcu20160222

高等学校化学学报 ›› 2016, Vol. 37 ›› Issue (8): 1451.doi: 10.7503/cjcu20160222

间接糖基化马蹄金素衍生物的合成及抗乙肝病毒活性研究

徐广灿^1,², 袁洁^1,⁴, 刘青川³, 黄正明³, 梁光义^1,²(), 徐必学¹()

1. 贵州省中国科学院天然产物化学重点实验室, 贵阳 550002
2. 贵阳中医学院药学院, 贵阳 550002
3. 中国人民解放军第三○二医院, 北京 100039
4. 新疆医科大学厚博学院, 克拉玛依 834000

收稿日期:2016-05-20 出版日期:2016-07-19 发布日期:2016-07-19
作者简介:
联系人简介: 梁光义, 男, 博士, 教授, 博士生导师, 主要从事天然产物化学方面的研究. E-mail: guangyi_liang@126.com. 徐必学, 男, 博士, 副研究员, 主要从事药物化学方面的研究. E-mail: bixue_xu@126.com
基金资助:
国家自然科学基金(批准号: 81360472)资助

Synthesis and Anti-HBV Activities of the Indirect Galactopyranosyl Derivatives of Matijin-Su^†

XU Guangcan^1,², YUAN Jie^1,⁴, LIU Qingchuan³, HUANG Zhengming³, LIANG Guangyi^1,^2,^*(), XU Bixue^1,^*()

1. The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences,Guiyang 550002, China
2. College of Pharmacy, Guiyang College of Traditional Chinese Medicine, Guiyang 550002, China
3. 302 Hospital of PLA, Beijing 100039, China
4. HouBo College of Xinjiang Medical University, Karamay 834000, China

Received:2016-05-20 Online:2016-07-19 Published:2016-07-19
Contact: LIANG Guangyi,XU Bixue E-mail:guangyi_liang@126.com;bixue_xu@126.com
Supported by:
Supported by the National Natural Science Foundation of China(No.81360472)

摘要/Abstract

摘要：

以二缩三乙二醇或三缩四乙二醇为连接臂, 通过间接引入具有肝靶向性的D-半乳糖配基的方法, 设计合成了6个半乳糖糖基化修饰的肝靶向马蹄金素(MTS)衍生物; 通过¹H NMR, ¹³C NMR, ¹H-¹H COSY, HMQC和ESI-MS对其结构进行了表征; 并以HepG2 2.2.15为细胞模型初步评价了目标化合物的抗乙肝病毒(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15b的体外抗HBV活性最好, 后期研究将选用其进行小鼠体内组织分布实验, 并与原型化合物以及Y101体内组织分布情况进行比较研究, 以验证半乳糖基的引入能否提高MTS衍生物的肝靶向性.

关键词: 肝靶向, 半乳糖, 马蹄金素衍生物, 抗HBV活性

Abstract:

To explore the effect of the length of the linker on the activities of the derivatives of Matijin-Su(MTS) with potential for hepatic targeting, six galactosyl derivatives of MTS with potential for hepatic targeting were synthesized by binding galactosyl to derivatives of MTS using triethylene glycol or tetraethylene glycol as a linking arm, and their structures were confirmed by means of ¹H NMR, ¹³C NMR, ¹H-¹H COSY, HMQC and ESI-MS. The anti-HBV activities of those compounds were evaluated using HepG2 2.2.15 cells. The screening results showed that all the target compounds had inhibitory effect on HBV DNA replication in HepG2 2.2.15 cells in a dose-response manner. The inhibition rates of compounds 15b(72.24%), 15c(56.49%), 15f(65.24%) on the replication of HBV DNA were better than other tested compounds, when the in concentration of the drug was 50 μg/mL. The results can provide reference for further research of hepatic targeting MTS derivatives. For the evaluation of the hepatic target distribution of galactopyranosyl derivatives of MTS, compound 15b with best anti HBV activity will be selected to do tissue distribution experiments in vivo and comparative study with derivative of MTS(13b) and Y101.

Key words: Hepatic targeting, Glacatose, Derivatives of Matijin-Su(MTS), Anti-hepatitis B virus activity

中图分类号:

O629

TrendMD:

徐广灿, 袁洁, 刘青川, 黄正明, 梁光义, 徐必学. 间接糖基化马蹄金素衍生物的合成及抗乙肝病毒活性研究. 高等学校化学学报, 2016, 37(8): 1451.

XU Guangcan,YUAN Jie,LIU Qingchuan,HUANG Zhengming,LIANG Guangyi,XU Bixue. Synthesis and Anti-HBV Activities of the Indirect Galactopyranosyl Derivatives of Matijin-Su^†. Chem. J. Chinese Universities, 2016, 37(8): 1451.

图/表 10

Fig.1 Chemical structures of MTS(A) and Y101(B)

Fig.2 General structure of hepatic targeting MTS derivatives

Scheme 1 Synthetic routes of target compounds 15a—15f (1) Ac2O, CH3COONa, 140 ℃; (2) 4-methylphenylsulfonyl chloride, pyridine, r.t.; (3) 0.4 nm molecular sieves, BF3·Et2O, CH2Cl2, 0 ℃ to r.t.; (4) phthalimide potassium, DMF, 110 ℃; (5) N2H4·H2O, MeOH, H2O, 80 ℃; (6)(Boc)2O, NaHCO3, EtOH, r.t.; (7) Ac2O, pyridine, r.t.; (8) TFA, CH2Cl2, 0 ℃; (9) IBCF, NMM, CH2Cl2/DMF, 0 ℃ to r.t.; (10) (a) NaOH, DMF, r.t.; (b) IBCF, NMM, CH2Cl2/DMF, 0 ℃ to r.t.; (11) NaOH, DMF, r.t.; (12) IBCF, NMM, CH2Cl2/DMF, 0 ℃ to r.t.; (13) CH3ONa, CH3OH/CH2Cl2, r.t..

Table 1 Appearance, yields, melting points, specific rotation and ESI-MS data for all the intermediates*

Compd.	Appearance	Yield(%)	m.p./℃	[α $] D 20$ /(°)(c=0.5, CH₃OH)	ESI-MS, m/z
3a	Pale oil	40
3b	Pale oil	55
4a	Pale oil	49			657.0[M+Na]⁺
4b	Pale oil	45
5a	Pale oil	87
5b	Pale oil	84
8a	Pale oil	79			580.1[M+H]⁺
8b	Pale oil	82			626.5[M+Na]⁺
9a	Pale oil				502.0[M+Na]⁺
9b	Pale oil				524.1[M+H]⁺
14a	White solid	79	130—132	-29.89	896.4[M+H]⁺
14b	White solid	83	133—134	-31.37	1026.3[M+Na]⁺
14c	White solid	65	145—146	-43.17	978.4[M+Na]⁺
14d	White solid	97	128—129	-27.82	962.2[M+Na]⁺
14e	White solid	79	132—135	-33.39	1048.3[M+H]⁺
14f	White solid	68	146—148	-34.68	1022.3[M+Na]⁺

Table 1 Appearance, yields, melting points, specific rotation and ESI-MS data for all the intermediates*

Compd.	Appearance	Yield(%)	m.p./℃	[α $] D 20$ /(°)(c=0.5, CH₃OH)	ESI-MS, m/z
3a	Pale oil	40
3b	Pale oil	55
4a	Pale oil	49			657.0[M+Na]⁺
4b	Pale oil	45
5a	Pale oil	87
5b	Pale oil	84
8a	Pale oil	79			580.1[M+H]⁺
8b	Pale oil	82			626.5[M+Na]⁺
9a	Pale oil				502.0[M+Na]⁺
9b	Pale oil				524.1[M+H]⁺
14a	White solid	79	130—132	-29.89	896.4[M+H]⁺
14b	White solid	83	133—134	-31.37	1026.3[M+Na]⁺
14c	White solid	65	145—146	-43.17	978.4[M+Na]⁺
14d	White solid	97	128—129	-27.82	962.2[M+Na]⁺
14e	White solid	79	132—135	-33.39	1048.3[M+H]⁺
14f	White solid	68	146—148	-34.68	1022.3[M+Na]⁺

Table 2 1H NMR data for intermediates 3 and 4*

Compd.	¹H NMR(CDCl₃), δ
3a	7.80(d, J=8.3 Hz, 2H), 7.35(d, J=8.0 Hz, 2H), 4.17(t, J=4.8 Hz, 2H), 3.75—3.68(m, 4H), 3.63—3.55(m, 6H), 2.45(s, 3H)
3b	7.79(d, J=8.3 Hz, 2H), 7.33(d, J=8.0 Hz, 2H), 4.15(t, J=4.8 Hz, 2H), 3.75—3.56(m, 14H), 2.44(s, 3H)
4a	7.79(d, J=8.3 Hz, 2H), 7.34(d, J=7.9 Hz, 2H), 5.38(dd, J=3.4, 1.0 Hz, 1H), 5.20(dd, J=10.5, 8.0 Hz, 1H), 5.02(dd, J=10.5, 3.4 Hz, 1H), 4.56(d, J=8.0 Hz, 1H), 4.20—4.09(m, 4H), 3.98—3.89(m, 2H), 3.73(ddd, J=11.0, 7.0, 3.9 Hz, 1H), 3.70—3.55(m, 8H), 2.45(s, 3H), 2.15(s, 3H), 2.05(s, 3H), 2.05(s, 3H), 1.99(s, 3H)
4b	7.79(d, J=8.3 Hz, 2H), 7.35(d, J=8.1 Hz, 2H), 5.38(dd, J=2.6, 0.8 Hz, 1H), 5.19(dd, J=10.5, 8.0 Hz, 1H), 5.01(dd, J=10.5, 3.4 Hz, 1H), 4.56(d, J=8.0 Hz, 1H), 4.19—4.08(m, 4H), 4.00—3.84(m, 2H), 3.80—3.55(m, 13H), 2.44(s, 3H), 2.14(s, 3H), 2.04(d, J=3.1 Hz, 6H), 1.97(s, 3H)

Table 3 1H NMR and 13C NMR data for intermediates 5, 8 and 14

Compd.	¹H NMR(400 MHz, CDCl₃), δ	¹³C NMR(100 MHz, CDCl₃), δ
5a	7.84(dd, J=5.5, 3.0 Hz, 2H), 7.71(dd, J=5.5, 3.0 Hz, 2H), 5.38(dd, J=3.4, 0.9 Hz, 1H), 5.19(dd, J=10.5, 8.0 Hz, 1H), 5.02(dd, J=10.5, 3.4 Hz, 1H), 4.55(d, J=8.0 Hz, 1H), 4.20—4.08(m, 2H), 3.95—3.52(m, 13H), 2.14(s, 3H), 2.04(s, 6H), 1.97(s, 3H)	170.6, 170.4, 170.3, 169.7, 168.4, 168.4, 134.1, 132.2, 123.4, 101.5, 71.0, 70.8, 70.7, 70.5, 70.2, 69.2, 69.0, 68.1, 67.2, 61.5, 37.3, 20.9, 20.8, 20.8, 20.8
5b	7.85(dd, J=5.5, 3.0 Hz, 2H), 7.74(dd, J=5.5, 3.0 Hz, 2H), 5.40(dd, J=3.4, 0.8 Hz, 1H), 5.21(dd, J=10.5, 8.0 Hz, 1H), 5.03(dd, J=10.5, 3.4 Hz, 1H), 4.59(d, J=8.0 Hz, 1H), 4.22—4.13(m, 2H), 4.03—3.52(m, 17H), 2.15(s, 3H), 2.06(s, 3H), 2.05(s, 3H), 1.99(s, 3H)	170.6, 170.4, 170.3, 169.7,168.43, 168.39, 134.1, 132.2, 123.4, 101.5, 71.0, 70.79, 70.76 70.7, 70.5, 70.3, 70.2, 69.2, 69.0, 68.1, 67.2, 61.5, 37.3, 20.9, 20.84, 20.82, 20.8
8a	5.26(t, J=8.6 Hz, 1H), 5.10(s, 1H), 4.94(dd, J=10.2, 3.2 Hz, 1H), 4.54(d, J=7.8 Hz, 1H), 4.32(dd, J=6.3, 4.5 Hz, 2H), 4.05(d, J=2.8 Hz, 1H), 3.81—3.51(m, 12H), 2.11(s, 3H), 2.09(s, 3H), 2.06(s, 3H), 1.84(s, 3H),1.45(s, 9H)	170.6, 170.4, 170.3, 169.6, 156.1, 101.58, 71.0, 70.8, 70.8,70.72, 70.65, 69.2, 69.0, 67.2, 61.4, 40.5, 28.6, 28.0, 21.0, 19.8, 19.7
8b	5.37(dd, J=8.4, 1.0 Hz, 1H), 5.20(dd, J=10.5, 8.0 Hz, 1H), 5.01(dd, J=10.5, 3.4 Hz, 1H), 4.56(d, J=8.0 Hz, 1H), 4.21—4.07(m, 2H), 4.00—3.87(m, 2H), 3.81—3.70(m, 1H), 3.70—3.30(m, 14H), 2.14(s, 3H), 2.05(s, 3H), 2.04(s, 3H), 1.97(s, 3H), 1.43(s, 9H)	170.5, 170.4, 170.3, 169.6, 156.1, 101.5, 71.0, 70.83, 70.77, 70.72, 70.65, 70.41, 70.37, 69.2, 69.0, 67.2, 61.4, 40.5, 28.6, 28.0, 20.9, 20.8, 20.7
14a	7.68(dd, J=8.8, 5.3 Hz, 2H), 7.31—7.04(m, 12H), 6.75—6.65(m, 2H), 6.39(t, J=4.4 Hz, 1H), 5.39(d, J=2.6 Hz, 1H), 5.22(dd, J=10.5, 7.9 Hz, 1H), 5.04(dd, J=10.5, 3.4 Hz, 1H), 4.87—4.77(m, 1H), 4.64—4.53(m, 2H), 4.22—4.07(m, 2H), 4.00—3.89(m, 2H), 3.77—3.68(m, 1H), 3.67—3.42(m, 7H), 3.42—3.31(m, 3H), 3.13(d, J=7.1 Hz, 2H), 3.01(d, J=6.9 Hz, 2H), 2.12(s, 3H), 2.04(s, 3H), 2.02(s, 3H), 1.98(s, 3H)	170.6,170.41, 170.36, 170.3, 169.8, 166.3, 166.2, 163.8, 136.6, 136.4, 129.93, 129.90, 129.7, 129.6, 129.44, 129.42, 128.9, 128.6, 127.3, 127.0, 115.9, 115.7, 101. 4, 71.0, 70.8, 70.7, 70.3, 70.3, 69.7, 69.2, 69.0, 67.2, 61.4, 54.8, 54.6, 39.4, 38.1, 38.2, 20.9, 20.8, 20.80, 20.75
14b	7.98(s, 1H), 7.81(d, J=8.1 Hz, 1H), 7.61(d, J=7.9 Hz, 1H), 7.30—7.04(m, 11H), 6.94—6.86(m, 2H), 6.47(t, J=4.9 Hz, 1H), 5.38(d, J=3.3 Hz, 1H), 5.21(dd, J=10.5, 8.0 Hz, 1H), 5.04(dd, J=10.5, 3.4 Hz, 1H), 4.92—4.83(m, 1H), 4.69—4.59(m, 1H), 4.55(d, J=8.0 Hz, 1H), 4.21—4.07(m, 2H), 4.00—3.88(m, 2H), 3.77—3.67(m, 1H), 3.66—3.41(m, 7H), 3.40—3.29(m, 3H), 3.11(d, J=6.9 Hz, 2H), 3.00(d, J=7.0 Hz, 2H), 2.12(s, 3H), 2.03(s, 3H), 2.02(s, 3H), 1.98(s, 3H)	170.5, 170.4, 170.3,170.21, 170.16, 169.7, 165.6, 140.6, 136.4, 136.3, 136.2, 135.6, 130.1, 129.3, 128.6, 128.4, 127.0, 126.8, 126.2, 101.2, 94.1, 70.8, 70.6, 70.5, 70.1, 70.1, 69.5, 69.0, 68.8, 67.0, 61.2, 54.7, 54.5, 39.2, 38.6, 38.1, 20.8, 20.64, 20.61, 20.57
14c	7.61(d, J=8.6 Hz, 2H), 7.39(d, J=8.5 Hz, 2H), 7.20—7.07(m, 7H), 6.80(d, J=8.6 Hz, 2H), 6.71(d, J=7.3 Hz, 1H), 6.62(d, J=7.8 Hz, 1H), 6.37(t, J=4.9 Hz, 1H), 5.39(d, J=2.6 Hz, 1H), 5.22(dd, J=10.5, 8.0 Hz, 1H), 5.05(dd, J=10.5, 3.4 Hz, 1H), 4.80—4.68(m, 1H), 4.63—4.53(m, 2H), 4.23—4.08(m, 2H), 4.02—3.90(m, 4H), 3.77—3.67(m, 1H), 3.65—3.33(m, 10H), 3.10—3.05(m, 2H, 3a-H), 3.02(d, J=6.8 Hz, 2H), 2.13(s, 3H), 2.04(s, 3H), 2.03(s, 3H,), 1.99(s, 3H), 1.39(t, J=7.0 Hz, 3H)	170.61, 170.59, 170.41, 170.35,170.3, 169.8, 166.2, 158.2, 138.3, 136.6, 132.2, 130.5 129.4, 129.0, 128.7, 128.6, 128.0, 127.0, 114.9, 101.5, 71.0, 70.81, 70.75, 70.4, 70.3, 69.7, 69.3, 69.0, 67.2, 63.5, 61.4, 55.0, 54.6, 39.4, 38.5, 37.3, 21.0, 20.83, 20.80, 20.75, 15.0
14d	7.69(dd, J=8.8, 5.3 Hz, 2H), 7.31—7.05(m, 12H), 6.77(d, J=7.6 Hz, 2H), 6.43(t, J=4.3 Hz, 1H), 5.38(d, J=3.4 Hz, 1H,), 5.21(dd, J=10.5, 7.9 Hz, 1H), 5.05(dd, J=10.5, 3.4 Hz, 1H) 4.87—4.77(m, 1H), 4.63—4.55(m, 2H), 4.20—4.08(m, 2H), 3.98—3.90(m, 2H), 3.79—3.69(m, 1H), 3.66—3.43(m, 11H), 3.42—3.30(m, 3H), 3.13(d, J=6.9 Hz, 2H), 3.01(d, J=6.9 Hz, 2H), 2.13(s, 3H), 2.03(s, 3H), 2.02(s, 3H), 1.97(s, 3H)	170.63, 170.57, 170.41, 170.38,170.3, 169.7, 166.3, 166.2, 163.8, 136.6, 136.5, 129.98, 129.95, 129.7, 129.6, 129.4, 129.0, 128.6, 127.2, 126.9, 115.8, 115.6, 101.3, 71.0, 70.8, 70.7, 70.61, 70.58, 70.32, 70.29, 69.7, 69.1, 68.9, 67.2, 61.4, 54.8, 54.6, 39.4, 38.7, 38.2, 20.9, 20.80, 20.78, 20.75
Compd.	¹H NMR(400 MHz, CDCl₃), δ	¹³C NMR(100 MHz, CDCl₃), δ
14e	7.98(s, 1H), 7.81(d, J=8.1 Hz, 1H), 7.61(d, J=7.9 Hz, 1H), 7.30—7.04(m, 11H), 6.92(d, J=7.8 Hz, 2H), 6.49(t, J=5.0 Hz, 1H), 5.38(d, J=3.3 Hz, 1H), 5.20(dd, J=10.5, 8.0 Hz, 1H), 5.05(dd, J=10.5, 3.4 Hz, 1H), 4.91—4.82(m, 1H), 4.67—4.56(m, 2H), 4.20—4.07(m, 2H), 3.98—3.90(m, 2H), 3.77—3.69(m, 1H), 3.67—3.48(m, 10H), 3.48—3.29(m, 4H), 3.11(d, J=6.9 Hz, 2H), 3.01(dd, J=6.9, 1.5 Hz, 2H), 2.12(s, 3H), 2.03(s, 3H), 2.01(s, 3H), 1.97(s, 3H)	170.5, 170.4, 170.23, 170.21, 170.19, 169.5, 165.6, 140.5, 136.4, 136.3, 136.2, 135.7, 130.1, 129.3, 129.2, 128.7, 128.3, 127.0, 126.7, 126.3, 101.1, 94.1, 70.8, 70.5, 70.5, 70.41, 70.38, 70.12, 70.09, 69.4, 68.9, 68.8, 67.0, 61.2, 54.7, 54.4, 39.2, 38.6, 38.1, 20.7, 20.62, 20.60, 20.58
14f	7.63(d, J=8.7 Hz, 2H), 7.39(d, J=8.7 Hz, 2H), 7.19—7.06(m, 7H), 6.79(d, J=8.6 Hz, 2H), 5.39(dd, J=3.4, 1.0 Hz, 1H), 5.22(dd, J=10.5, 7.9 Hz, 1H), 5.06(dd, J=10.5, 3.4 Hz, 1H), 4.83—4.76(m, 1H), 4.65—4.57(m, 2H), 4.20—4.09(m, 2H), 4.01—3.92(m, 4H), 3.78—3.70(m, 1H), 3.67—3.29(m, 14H), 3.07(dd, J=6.7, 2.3 Hz, 2H), 3.02(d, J=6.9 Hz, 2H), 2.13(s, 3H), 2.05(s, 3H), 2.03(s, 3H), 1.98(s, 3H), 1.38(t, J=7.0 Hz, 3H)	170.7, 170.6, 170.39, 170.36, 170.3, 169.7, 166.2, 158.2, 138.2, 136.6, 132.2, 130.4, 129.4, 128.9, 128.7, 128.68, 128.1, 127.0, 114.8, 101.4, 71.0, 70.8, 70.7, 70.6, 70.6, 70.3, 70.3, 69.6, 69.1, 68.9, 67.2, 63.5, 61.4, 55.0, 54.6, 39.3, 38.6, 37.4, 20.9, 20.80, 20.78, 20.7, 15.0

Table 3 1H NMR and 13C NMR data for intermediates 5, 8 and 14

Compd.	¹H NMR(400 MHz, CDCl₃), δ	¹³C NMR(100 MHz, CDCl₃), δ
5a	7.84(dd, J=5.5, 3.0 Hz, 2H), 7.71(dd, J=5.5, 3.0 Hz, 2H), 5.38(dd, J=3.4, 0.9 Hz, 1H), 5.19(dd, J=10.5, 8.0 Hz, 1H), 5.02(dd, J=10.5, 3.4 Hz, 1H), 4.55(d, J=8.0 Hz, 1H), 4.20—4.08(m, 2H), 3.95—3.52(m, 13H), 2.14(s, 3H), 2.04(s, 6H), 1.97(s, 3H)	170.6, 170.4, 170.3, 169.7, 168.4, 168.4, 134.1, 132.2, 123.4, 101.5, 71.0, 70.8, 70.7, 70.5, 70.2, 69.2, 69.0, 68.1, 67.2, 61.5, 37.3, 20.9, 20.8, 20.8, 20.8
5b	7.85(dd, J=5.5, 3.0 Hz, 2H), 7.74(dd, J=5.5, 3.0 Hz, 2H), 5.40(dd, J=3.4, 0.8 Hz, 1H), 5.21(dd, J=10.5, 8.0 Hz, 1H), 5.03(dd, J=10.5, 3.4 Hz, 1H), 4.59(d, J=8.0 Hz, 1H), 4.22—4.13(m, 2H), 4.03—3.52(m, 17H), 2.15(s, 3H), 2.06(s, 3H), 2.05(s, 3H), 1.99(s, 3H)	170.6, 170.4, 170.3, 169.7,168.43, 168.39, 134.1, 132.2, 123.4, 101.5, 71.0, 70.79, 70.76 70.7, 70.5, 70.3, 70.2, 69.2, 69.0, 68.1, 67.2, 61.5, 37.3, 20.9, 20.84, 20.82, 20.8
8a	5.26(t, J=8.6 Hz, 1H), 5.10(s, 1H), 4.94(dd, J=10.2, 3.2 Hz, 1H), 4.54(d, J=7.8 Hz, 1H), 4.32(dd, J=6.3, 4.5 Hz, 2H), 4.05(d, J=2.8 Hz, 1H), 3.81—3.51(m, 12H), 2.11(s, 3H), 2.09(s, 3H), 2.06(s, 3H), 1.84(s, 3H),1.45(s, 9H)	170.6, 170.4, 170.3, 169.6, 156.1, 101.58, 71.0, 70.8, 70.8,70.72, 70.65, 69.2, 69.0, 67.2, 61.4, 40.5, 28.6, 28.0, 21.0, 19.8, 19.7
8b	5.37(dd, J=8.4, 1.0 Hz, 1H), 5.20(dd, J=10.5, 8.0 Hz, 1H), 5.01(dd, J=10.5, 3.4 Hz, 1H), 4.56(d, J=8.0 Hz, 1H), 4.21—4.07(m, 2H), 4.00—3.87(m, 2H), 3.81—3.70(m, 1H), 3.70—3.30(m, 14H), 2.14(s, 3H), 2.05(s, 3H), 2.04(s, 3H), 1.97(s, 3H), 1.43(s, 9H)	170.5, 170.4, 170.3, 169.6, 156.1, 101.5, 71.0, 70.83, 70.77, 70.72, 70.65, 70.41, 70.37, 69.2, 69.0, 67.2, 61.4, 40.5, 28.6, 28.0, 20.9, 20.8, 20.7
14a	7.68(dd, J=8.8, 5.3 Hz, 2H), 7.31—7.04(m, 12H), 6.75—6.65(m, 2H), 6.39(t, J=4.4 Hz, 1H), 5.39(d, J=2.6 Hz, 1H), 5.22(dd, J=10.5, 7.9 Hz, 1H), 5.04(dd, J=10.5, 3.4 Hz, 1H), 4.87—4.77(m, 1H), 4.64—4.53(m, 2H), 4.22—4.07(m, 2H), 4.00—3.89(m, 2H), 3.77—3.68(m, 1H), 3.67—3.42(m, 7H), 3.42—3.31(m, 3H), 3.13(d, J=7.1 Hz, 2H), 3.01(d, J=6.9 Hz, 2H), 2.12(s, 3H), 2.04(s, 3H), 2.02(s, 3H), 1.98(s, 3H)	170.6,170.41, 170.36, 170.3, 169.8, 166.3, 166.2, 163.8, 136.6, 136.4, 129.93, 129.90, 129.7, 129.6, 129.44, 129.42, 128.9, 128.6, 127.3, 127.0, 115.9, 115.7, 101. 4, 71.0, 70.8, 70.7, 70.3, 70.3, 69.7, 69.2, 69.0, 67.2, 61.4, 54.8, 54.6, 39.4, 38.1, 38.2, 20.9, 20.8, 20.80, 20.75
14b	7.98(s, 1H), 7.81(d, J=8.1 Hz, 1H), 7.61(d, J=7.9 Hz, 1H), 7.30—7.04(m, 11H), 6.94—6.86(m, 2H), 6.47(t, J=4.9 Hz, 1H), 5.38(d, J=3.3 Hz, 1H), 5.21(dd, J=10.5, 8.0 Hz, 1H), 5.04(dd, J=10.5, 3.4 Hz, 1H), 4.92—4.83(m, 1H), 4.69—4.59(m, 1H), 4.55(d, J=8.0 Hz, 1H), 4.21—4.07(m, 2H), 4.00—3.88(m, 2H), 3.77—3.67(m, 1H), 3.66—3.41(m, 7H), 3.40—3.29(m, 3H), 3.11(d, J=6.9 Hz, 2H), 3.00(d, J=7.0 Hz, 2H), 2.12(s, 3H), 2.03(s, 3H), 2.02(s, 3H), 1.98(s, 3H)	170.5, 170.4, 170.3,170.21, 170.16, 169.7, 165.6, 140.6, 136.4, 136.3, 136.2, 135.6, 130.1, 129.3, 128.6, 128.4, 127.0, 126.8, 126.2, 101.2, 94.1, 70.8, 70.6, 70.5, 70.1, 70.1, 69.5, 69.0, 68.8, 67.0, 61.2, 54.7, 54.5, 39.2, 38.6, 38.1, 20.8, 20.64, 20.61, 20.57
14c	7.61(d, J=8.6 Hz, 2H), 7.39(d, J=8.5 Hz, 2H), 7.20—7.07(m, 7H), 6.80(d, J=8.6 Hz, 2H), 6.71(d, J=7.3 Hz, 1H), 6.62(d, J=7.8 Hz, 1H), 6.37(t, J=4.9 Hz, 1H), 5.39(d, J=2.6 Hz, 1H), 5.22(dd, J=10.5, 8.0 Hz, 1H), 5.05(dd, J=10.5, 3.4 Hz, 1H), 4.80—4.68(m, 1H), 4.63—4.53(m, 2H), 4.23—4.08(m, 2H), 4.02—3.90(m, 4H), 3.77—3.67(m, 1H), 3.65—3.33(m, 10H), 3.10—3.05(m, 2H, 3a-H), 3.02(d, J=6.8 Hz, 2H), 2.13(s, 3H), 2.04(s, 3H), 2.03(s, 3H,), 1.99(s, 3H), 1.39(t, J=7.0 Hz, 3H)	170.61, 170.59, 170.41, 170.35,170.3, 169.8, 166.2, 158.2, 138.3, 136.6, 132.2, 130.5 129.4, 129.0, 128.7, 128.6, 128.0, 127.0, 114.9, 101.5, 71.0, 70.81, 70.75, 70.4, 70.3, 69.7, 69.3, 69.0, 67.2, 63.5, 61.4, 55.0, 54.6, 39.4, 38.5, 37.3, 21.0, 20.83, 20.80, 20.75, 15.0
14d	7.69(dd, J=8.8, 5.3 Hz, 2H), 7.31—7.05(m, 12H), 6.77(d, J=7.6 Hz, 2H), 6.43(t, J=4.3 Hz, 1H), 5.38(d, J=3.4 Hz, 1H,), 5.21(dd, J=10.5, 7.9 Hz, 1H), 5.05(dd, J=10.5, 3.4 Hz, 1H) 4.87—4.77(m, 1H), 4.63—4.55(m, 2H), 4.20—4.08(m, 2H), 3.98—3.90(m, 2H), 3.79—3.69(m, 1H), 3.66—3.43(m, 11H), 3.42—3.30(m, 3H), 3.13(d, J=6.9 Hz, 2H), 3.01(d, J=6.9 Hz, 2H), 2.13(s, 3H), 2.03(s, 3H), 2.02(s, 3H), 1.97(s, 3H)	170.63, 170.57, 170.41, 170.38,170.3, 169.7, 166.3, 166.2, 163.8, 136.6, 136.5, 129.98, 129.95, 129.7, 129.6, 129.4, 129.0, 128.6, 127.2, 126.9, 115.8, 115.6, 101.3, 71.0, 70.8, 70.7, 70.61, 70.58, 70.32, 70.29, 69.7, 69.1, 68.9, 67.2, 61.4, 54.8, 54.6, 39.4, 38.7, 38.2, 20.9, 20.80, 20.78, 20.75
Compd.	¹H NMR(400 MHz, CDCl₃), δ	¹³C NMR(100 MHz, CDCl₃), δ
14e	7.98(s, 1H), 7.81(d, J=8.1 Hz, 1H), 7.61(d, J=7.9 Hz, 1H), 7.30—7.04(m, 11H), 6.92(d, J=7.8 Hz, 2H), 6.49(t, J=5.0 Hz, 1H), 5.38(d, J=3.3 Hz, 1H), 5.20(dd, J=10.5, 8.0 Hz, 1H), 5.05(dd, J=10.5, 3.4 Hz, 1H), 4.91—4.82(m, 1H), 4.67—4.56(m, 2H), 4.20—4.07(m, 2H), 3.98—3.90(m, 2H), 3.77—3.69(m, 1H), 3.67—3.48(m, 10H), 3.48—3.29(m, 4H), 3.11(d, J=6.9 Hz, 2H), 3.01(dd, J=6.9, 1.5 Hz, 2H), 2.12(s, 3H), 2.03(s, 3H), 2.01(s, 3H), 1.97(s, 3H)	170.5, 170.4, 170.23, 170.21, 170.19, 169.5, 165.6, 140.5, 136.4, 136.3, 136.2, 135.7, 130.1, 129.3, 129.2, 128.7, 128.3, 127.0, 126.7, 126.3, 101.1, 94.1, 70.8, 70.5, 70.5, 70.41, 70.38, 70.12, 70.09, 69.4, 68.9, 68.8, 67.0, 61.2, 54.7, 54.4, 39.2, 38.6, 38.1, 20.7, 20.62, 20.60, 20.58
14f	7.63(d, J=8.7 Hz, 2H), 7.39(d, J=8.7 Hz, 2H), 7.19—7.06(m, 7H), 6.79(d, J=8.6 Hz, 2H), 5.39(dd, J=3.4, 1.0 Hz, 1H), 5.22(dd, J=10.5, 7.9 Hz, 1H), 5.06(dd, J=10.5, 3.4 Hz, 1H), 4.83—4.76(m, 1H), 4.65—4.57(m, 2H), 4.20—4.09(m, 2H), 4.01—3.92(m, 4H), 3.78—3.70(m, 1H), 3.67—3.29(m, 14H), 3.07(dd, J=6.7, 2.3 Hz, 2H), 3.02(d, J=6.9 Hz, 2H), 2.13(s, 3H), 2.05(s, 3H), 2.03(s, 3H), 1.98(s, 3H), 1.38(t, J=7.0 Hz, 3H)	170.7, 170.6, 170.39, 170.36, 170.3, 169.7, 166.2, 158.2, 138.2, 136.6, 132.2, 130.4, 129.4, 128.9, 128.7, 128.68, 128.1, 127.0, 114.8, 101.4, 71.0, 70.8, 70.7, 70.6, 70.6, 70.3, 70.3, 69.6, 69.1, 68.9, 67.2, 63.5, 61.4, 55.0, 54.6, 39.3, 38.6, 37.4, 20.9, 20.80, 20.78, 20.7, 15.0

Table 4 Appearance, yields, melting points, specific rotation, MS and IR data for the target compounds 15a—15f

Compd.	Appearance	Yield (%)	m.p./℃	[α $] D 20 a$ /(°) (c=0.5)	HRMS(calcd.)^b, m/z	IR(KBr), $ν ˙$ /cm^-1
15a	White solid	88	156—157	-80.73	750.3010(750.3014)	3283, 2880, 1634, 1542, 1507, 1076, 700
15b	White solid	89	168—169	-46.64	858.2074(858.2075)	3278, 2875, 1635, 1540, 1508, 1075, 698
15c	White solid	88	182—184	-36.09	810.3001(810.2981)	3284, 2924, 1632, 1542, 1512, 1073, 677
15d	White solid	74	151—152	-36.99	794.3265(794.3276)	3282, 2875, 1635, 1542, 1506, 1077, 699
15e	White solid	73	166—167	-39.71	902.2334(902.2337)	3273, 2873, 1635, 1534, 1506, 1077, 698
15f	White solid	78	186—189	-43.17	832.3429(832.3423)	3279, 2873, 1632, 1539, 1512, 1091, 702

Table 4 Appearance, yields, melting points, specific rotation, MS and IR data for the target compounds 15a—15f

Compd.	Appearance	Yield (%)	m.p./℃	[α $] D 20 a$ /(°) (c=0.5)	HRMS(calcd.)^b, m/z	IR(KBr), $ν ˙$ /cm^-1
15a	White solid	88	156—157	-80.73	750.3010(750.3014)	3283, 2880, 1634, 1542, 1507, 1076, 700
15b	White solid	89	168—169	-46.64	858.2074(858.2075)	3278, 2875, 1635, 1540, 1508, 1075, 698
15c	White solid	88	182—184	-36.09	810.3001(810.2981)	3284, 2924, 1632, 1542, 1512, 1073, 677
15d	White solid	74	151—152	-36.99	794.3265(794.3276)	3282, 2875, 1635, 1542, 1506, 1077, 699
15e	White solid	73	166—167	-39.71	902.2334(902.2337)	3273, 2873, 1635, 1534, 1506, 1077, 698
15f	White solid	78	186—189	-43.17	832.3429(832.3423)	3279, 2873, 1632, 1539, 1512, 1091, 702

Table 5 1H NMR and 13C NMR data for the target compounds 15a—15f

Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ
15a	8.55(d, J=8.4 Hz, 1H), 8.08(d, J=8.2 Hz, 1H), 8.01(t, J=5.5 Hz, 1H), 7.79(dd, J=8.7, 5.6 Hz, 2H), 7.29—7.06(m, 12H), 4.80(d, J=4.3 Hz, 1H), 4.69—4.59(m, 2H), 4.54(t, J=5.7 Hz, 1H), 4.47(dd, J=13.7, 8.3 Hz, 1H), 4.33(d, J=4.5 Hz, 1H), 4.05(d, J=7.0 Hz, 1H), 3.85—3.73(m, 1H), 3.62—3.09(m, 17H), 3.05—2.75(m, 4H)	171.1, 170.8, 165.2, 162.7, 138.3, 137.6, 130.4, 130.1, 130.0, 129.3, 129.2,128.07, 128.05, 126.3, 126.2, 115.3, 115.1, 103.6, 75.2, 73.5, 70.5, 69.78, 69.75, 69.7, 69.0, 68.2, 67.7, 60.5, 54.9, 54.0, 38.7, 37.9, 36.8
15b	8.64(d, J=8.5 Hz, 1H), 8.12—8.05(m, 2H), 8.01(t, J=5.6 Hz, 1H), 7.85(d, J=7.8 Hz, 1H), 7.71(d, J=7.9 Hz, 1H), 7.28—7.08(m, 11H), 4.80(d, J=4.4 Hz, 1H), 4.69—4.60(m, 2H), 4.54(t, J=5.6 Hz, 1H), 4.47(dd, J=13.6, 8.3 Hz, 1H), 4.33(d, J=4.5 Hz, 1H), 4.05(d, J=7.1 Hz, 1H), 3.85—3.75(m, 1H), 3.61—3.10(m, 17H), 3.06—2.76(m, 4H)	170.9, 170.8, 164.8, 139.9, 138.3, 137.6, 136.0, 135.8, 130.5, 129.3, 129.1, 128.1, 128.0, 126.9, 126.3, 103.6, 94.6, 75.2, 73.5, 70.5, 69.8, 69.7, 69.0, 68.2, 67.7, 60.5, 54.8, 54.0, 38.7, 37.9, 36.8
15c	8.58(d, J=8.4 Hz, 1H), 8.10(d, J=8.0 Hz, 1H), 8.01(t, J=5.7 Hz, 1H), 7.77(d, J =8.7 Hz, 2H), 7.52(d, J=8.7 Hz, 2H, 7.21—7.10(m, 7H), 6.75(d, J=8.7 Hz, 2H), 4.81(d, J=4.5 Hz, 1H), 4.68(d, J=5.2 Hz), 4.63—4.56(m, 1H), 4.55(t, J=5.7 Hz, 1H), 4.52—4.48(m,	171.3, 171.0, 165.4, 157.2, 137.8, 136.4, 132.9, 130.3, 130.2, 129.6, 129.5, 128.5, 128.2, 126.5, 114.1, 103.8, 75.4, 73.7, 70.7,69.98, 69.94,
Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ
15c	1H), 4.34(d, J=4.5 Hz, 1H), 4.07(d, J=7.3 Hz, 1H), 3.91(q, J=7.0 Hz, 2Ha), 3.85—3.77(m, 1H), 3.62—3.58(m, 1H), 3.57—3.44(m, 11H), 3.39—3.10(m, 4H), 2.99—2.91(m, 2H), 2.82(dd, J=13.8, 9.4 Hz, 2H), 1.25(t, J=7.0 Hz, 3H)	69.9, 69.2, 68.4, 67.9, 63.0, 60.7, 55.3, 54.2, 39.9, 38.6, 37.9, 36.1
15d	7.74(dd, J=8.7, 5.4 Hz, 2H), 7.30—7.08(m, 12H), 4.79(dd, J=9.4, 5.7 Hz, 1H), 4.60(t, J=7.3 Hz, 1H), 4.24(d, J=7.5 Hz, 1H), 4.02—3.95(m, 1H), 3.83—3.22(m, 21H), 3.21—3.05(m, 2H), 3.03—2.85(m, 2H)	173.3, 173.1, 169.0, 167.5, 165.0, 138.6, 138.2, 131.5, 131.2, 131.1, 130.4, 130.3, 129.5, 129.4, 127.8, 116.4, 116.2, 105.1, 76.7, 74.9, 72.5, 71.6, 71.5, 71.3, 70.4, 70.3, 69.6, 62.5, 56.6, 56.0, 40.4, 39.2, 38.4
15e	8.01(s, 1H), 7.87(d, J=8.0 Hz, 1H), 7.65(d, J=8.2 Hz, 1H), 7.28—7.10(m, 11H), 4.79(dd, J=9.4, 5.6 Hz, 1H, 2-H), 4.61(dd, J=8.1, 6.3 Hz, 1H,), 4.24(d, J=7.5 Hz, 1H), 4.03—3.96(m, 1H), 3.85—3.23(m, 21H), 3.21—3.07(m, 2H), 3.01—2.87(m, 2H)	173.2, 173.1, 168.4, 141.8, 138.6, 138.2, 137.6, 137.2, 131.3, 130.4, 130.3, 129.5, 129.5, 127.8, 105.1, 94.6, 76.7, 74.9, 72.5,71.54, 71.48, 71.3, 70.4, 70.3, 69.6, 62.5, 56.6, 56.0, 40.4, 39.2, 38.3
15f	8.60(d, J=8.4 Hz, 1H), 8.12(d, J=8.0 Hz, 1H), 8.02(t, J=5.4 Hz, 1H), 7.79(d, J=8.6 Hz, 2H), 7.53(d, J=8.6 Hz, 2H), 7.24—7.12(m, 7H), 6.77(d, J=8.6 Hz, 2H), 4.83(d, J=4.4 Hz, 1H), 4.70(d, J=5.0 Hz, 1H), 4.66—4.45(m, 3H), 4.36(d, J=4.6 Hz, 1H), 4.08(d, J=7.0 Hz, 1H), 3.93(q, J=7.0 Hz, 2H), 3.88—3.55(m, 2H), 3.59—3.10(m, 20H), 3.03—2.92(m, 2H), 2.90—2.79(m, 2H), 1.27(t, J=7.0 Hz, 3H)	171.0, 170.7, 165.2, 157.0, 137.5, 136.2, 136.0, 132.7, 130.1, 129.9, 129.3, 129.2, 128.3, 128.0, 126.3, 113.9, 103.6, 75.2, 73.5, 70.5, 69.8, 69.7, 69.6, 68.9, 68.2, 67.7, 62.8, 60.4, 55.1, 54.0, 38.6, 37.9, 36.0, 14.7

Table 5 1H NMR and 13C NMR data for the target compounds 15a—15f

Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ
15a	8.55(d, J=8.4 Hz, 1H), 8.08(d, J=8.2 Hz, 1H), 8.01(t, J=5.5 Hz, 1H), 7.79(dd, J=8.7, 5.6 Hz, 2H), 7.29—7.06(m, 12H), 4.80(d, J=4.3 Hz, 1H), 4.69—4.59(m, 2H), 4.54(t, J=5.7 Hz, 1H), 4.47(dd, J=13.7, 8.3 Hz, 1H), 4.33(d, J=4.5 Hz, 1H), 4.05(d, J=7.0 Hz, 1H), 3.85—3.73(m, 1H), 3.62—3.09(m, 17H), 3.05—2.75(m, 4H)	171.1, 170.8, 165.2, 162.7, 138.3, 137.6, 130.4, 130.1, 130.0, 129.3, 129.2,128.07, 128.05, 126.3, 126.2, 115.3, 115.1, 103.6, 75.2, 73.5, 70.5, 69.78, 69.75, 69.7, 69.0, 68.2, 67.7, 60.5, 54.9, 54.0, 38.7, 37.9, 36.8
15b	8.64(d, J=8.5 Hz, 1H), 8.12—8.05(m, 2H), 8.01(t, J=5.6 Hz, 1H), 7.85(d, J=7.8 Hz, 1H), 7.71(d, J=7.9 Hz, 1H), 7.28—7.08(m, 11H), 4.80(d, J=4.4 Hz, 1H), 4.69—4.60(m, 2H), 4.54(t, J=5.6 Hz, 1H), 4.47(dd, J=13.6, 8.3 Hz, 1H), 4.33(d, J=4.5 Hz, 1H), 4.05(d, J=7.1 Hz, 1H), 3.85—3.75(m, 1H), 3.61—3.10(m, 17H), 3.06—2.76(m, 4H)	170.9, 170.8, 164.8, 139.9, 138.3, 137.6, 136.0, 135.8, 130.5, 129.3, 129.1, 128.1, 128.0, 126.9, 126.3, 103.6, 94.6, 75.2, 73.5, 70.5, 69.8, 69.7, 69.0, 68.2, 67.7, 60.5, 54.8, 54.0, 38.7, 37.9, 36.8
15c	8.58(d, J=8.4 Hz, 1H), 8.10(d, J=8.0 Hz, 1H), 8.01(t, J=5.7 Hz, 1H), 7.77(d, J =8.7 Hz, 2H), 7.52(d, J=8.7 Hz, 2H, 7.21—7.10(m, 7H), 6.75(d, J=8.7 Hz, 2H), 4.81(d, J=4.5 Hz, 1H), 4.68(d, J=5.2 Hz), 4.63—4.56(m, 1H), 4.55(t, J=5.7 Hz, 1H), 4.52—4.48(m,	171.3, 171.0, 165.4, 157.2, 137.8, 136.4, 132.9, 130.3, 130.2, 129.6, 129.5, 128.5, 128.2, 126.5, 114.1, 103.8, 75.4, 73.7, 70.7,69.98, 69.94,
Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ
15c	1H), 4.34(d, J=4.5 Hz, 1H), 4.07(d, J=7.3 Hz, 1H), 3.91(q, J=7.0 Hz, 2Ha), 3.85—3.77(m, 1H), 3.62—3.58(m, 1H), 3.57—3.44(m, 11H), 3.39—3.10(m, 4H), 2.99—2.91(m, 2H), 2.82(dd, J=13.8, 9.4 Hz, 2H), 1.25(t, J=7.0 Hz, 3H)	69.9, 69.2, 68.4, 67.9, 63.0, 60.7, 55.3, 54.2, 39.9, 38.6, 37.9, 36.1
15d	7.74(dd, J=8.7, 5.4 Hz, 2H), 7.30—7.08(m, 12H), 4.79(dd, J=9.4, 5.7 Hz, 1H), 4.60(t, J=7.3 Hz, 1H), 4.24(d, J=7.5 Hz, 1H), 4.02—3.95(m, 1H), 3.83—3.22(m, 21H), 3.21—3.05(m, 2H), 3.03—2.85(m, 2H)	173.3, 173.1, 169.0, 167.5, 165.0, 138.6, 138.2, 131.5, 131.2, 131.1, 130.4, 130.3, 129.5, 129.4, 127.8, 116.4, 116.2, 105.1, 76.7, 74.9, 72.5, 71.6, 71.5, 71.3, 70.4, 70.3, 69.6, 62.5, 56.6, 56.0, 40.4, 39.2, 38.4
15e	8.01(s, 1H), 7.87(d, J=8.0 Hz, 1H), 7.65(d, J=8.2 Hz, 1H), 7.28—7.10(m, 11H), 4.79(dd, J=9.4, 5.6 Hz, 1H, 2-H), 4.61(dd, J=8.1, 6.3 Hz, 1H,), 4.24(d, J=7.5 Hz, 1H), 4.03—3.96(m, 1H), 3.85—3.23(m, 21H), 3.21—3.07(m, 2H), 3.01—2.87(m, 2H)	173.2, 173.1, 168.4, 141.8, 138.6, 138.2, 137.6, 137.2, 131.3, 130.4, 130.3, 129.5, 129.5, 127.8, 105.1, 94.6, 76.7, 74.9, 72.5,71.54, 71.48, 71.3, 70.4, 70.3, 69.6, 62.5, 56.6, 56.0, 40.4, 39.2, 38.3
15f	8.60(d, J=8.4 Hz, 1H), 8.12(d, J=8.0 Hz, 1H), 8.02(t, J=5.4 Hz, 1H), 7.79(d, J=8.6 Hz, 2H), 7.53(d, J=8.6 Hz, 2H), 7.24—7.12(m, 7H), 6.77(d, J=8.6 Hz, 2H), 4.83(d, J=4.4 Hz, 1H), 4.70(d, J=5.0 Hz, 1H), 4.66—4.45(m, 3H), 4.36(d, J=4.6 Hz, 1H), 4.08(d, J=7.0 Hz, 1H), 3.93(q, J=7.0 Hz, 2H), 3.88—3.55(m, 2H), 3.59—3.10(m, 20H), 3.03—2.92(m, 2H), 2.90—2.79(m, 2H), 1.27(t, J=7.0 Hz, 3H)	171.0, 170.7, 165.2, 157.0, 137.5, 136.2, 136.0, 132.7, 130.1, 129.9, 129.3, 129.2, 128.3, 128.0, 126.3, 113.9, 103.6, 75.2, 73.5, 70.5, 69.8, 69.7, 69.6, 68.9, 68.2, 67.7, 62.8, 60.4, 55.1, 54.0, 38.6, 37.9, 36.0, 14.7

Scheme 2 Synthetic route 2 for intermediate 5a

Table 6 Inhibition ratios for the replication of HBV DNA of compounds 15a—15f*

Compd.	Inhibition ratio(%)
Compd.	12.5 μg/mL	25 μg/mL	50 μg/mL
15a	19.08±0.71	40.61±2.13	43.88±0.55
15b	65.57±2.41	70.27±7.73	72.24±2.07
15c	29.89±1.68	25.60±1.04	56.49±0.73
15d	16.48±3.66	29.19±1.90	41.28±1.63
15e	11.04±0.19	12.54±2.60	33.05±1.00
15f	25.07±0.73	16.97±1.12	65.24±2.23
Lamivudine			92.57±1.03

参考文献 28

[1]	Li G. , Viral Hepatitis , People’s Medical Publishing House, Beijing, 2002, 22— 41
	( 李刚. 病毒性肝炎, 北京: 人卫出版社, 2002, 22— 41)
[2]	Zoulim, F. , Liver Int., 2013, 31( S1), 111- 116 doi: 10.1111/liv.12069 URL pmid: 23286855
[3]	Feng D., R. , Liang, S. , Wang Y., Y. , Xu Y., J. , Chem. Res. Chinese Universities, 2014, 30( 5), 749- 754 doi: 10.1016/j.biomaterials.2014.03.014 URL pmid: 24685267
[4]	Pardo, M. , Bartolome, J. , Carreno, V. , Arch. Med. Res., 2007, 38( 6), 661- 677 doi: 10.1016/j.arcmed.2006.12.013 URL pmid: 17613358
[5]	刘玉明, 梁光义, 徐必学. 天然产物研究与开发, 2003, 15( 1), 15- 17 doi: 10.3969/j.issn.1001-6880.2003.01.005 URL
	Liu Y., M. , Liang G., Y. , Xu B., X. , Nat. Prod. Res. Dev., 2003, 15( 1), 15- 17 doi: 10.3969/j.issn.1001-6880.2003.01.005 URL
[6]	Xu B., X. , Huang Z., M. , Liu C., X. , Cai Z., G. , Pan W., D. , Cao P., X. , Hao X., J. , Liang G., Y. , Bioorg. Med. Chem., 2009, 17( 8), 3118- 3125
[7]	Qiu J., Y. , Xu B., X. , Huang Z., M. , Pan W., D. , Cao P., X. , Liu C., X. , Hao X., J. , Song B. A.. Liang G., Y. , Bioorg. Med. Chem., 2011, 19( 18), 5352- 5360
[8]	邱净英, 黄正明, 潘卫东, 曹佩雪, 梁光义. 中国药科大学学报, 2012, 43( 5), 390- 394
	Qiu J., Y. , Huang Z., M. , Pan W., D. , Cao P., X. , Liang G., Y. , J. Chin. Pharm. Univ., 2012, 43( 5), 390- 394
[9]	梁光平, 胡占兴, 刘青川, 黄正明, 张建新, 梁光义, 徐必学. 高等学校化学学报, 2014, 35( 11), 2353- 2359 doi: 10.7503/cjcu20140223
	Liang G., P. , Hu Z., X. , Liu Q., C. , Huang Z., M. , Zhang J., X. , Liang G., Y. , Xu B., X. , Chem. J. Chinese Universities, 2014, 35( 11), 2353- 2359 doi: 10.7503/cjcu20140223
[10]	Ashwell, G. , Harford, J. , Annu. Rev. Biochem., 1982, 51( 4), 531- 554
[11]	Morell A., G. , Gregoriadis, G. , Scheinberg I., H. , Hickman, J. , Ashwell, G. , J. Biol. Chem., 1971, 246( 5), 1461- 1467
[12]	Steirer L., M. , Park E., I. , Townsend R., R. , Jacques U., B. , J. Biol. Chem., 2009, 284( 6), 3777- 3783 doi: 10.1074/jbc.M808689200 URL pmid: 19075021
[13]	Hashida, M. , Nishikawa, M. , Takakura, Y. , J. Controlled Release, 1995, 36( 12), 99- 107 doi: 10.1016/0168-3659(95)00050-I URL
[14]	Wang Y., Q. , Su, J. , Cai W., W. , Lu, P. , Yuan L., F. , Jin, T. , Chen S., Y. , Sheng, J. , Drug, Design , Development and Therapy, 2013, 7( 3), 211- 221
[15]	吴卫, 程怡, 吴琼. 南京医科大学学报, 2012, 32( 2), 168- 171 doi: 10.7655 URL
	Wu, W. , Cheng, Y. , Wu, Q. , J. Nanjing. Med. Univ., 2012, 32( 2), 168- 171 doi: 10.7655 URL
[16]	吴超, 郭伟英. 辽宁医学院学报, 2008, 29( 6), 490- 491 doi: 10.3969/j.issn.1674-0424.2008.06.004 URL
	Wu, C. , Guo W., Y. , J. Liaoning Med. Univ., 2008, 29( 6), 490- 491 doi: 10.3969/j.issn.1674-0424.2008.06.004 URL
[17]	袁洁, 刘青川, 徐广灿, 胡占兴, 梁光平, 黄正明, 刘昌孝, 梁光义, 徐必学. 有机化学, 2015, 35( 10), 2176- 2183 doi: 10.6023/cjoc201505011
	Yuan, J. , Liu Q., C. , Xu G., C. , Hu Z., X. , Liang G., P. , Huang Z., M. , Liu C., X. , Liang G., Y. , Xu B., X. , Chin. J. Org. Chem., 2015, 35( 10), 2176- 2183 doi: 10.6023/cjoc201505011
[18]	Lee Y., C. , Lee R., T. , Carbohydrates in Chemistry and, Biology , Wiley-VCH, Weinheim, 2000, 549-592
[19]	Biessen E., A. , Beuting D., M. , Roelen H., C. , Marel G. A. V., D. , Boom J. H., V. , Berkel T. J., V. , J. Med. Chem., 1995, 38( 9), 1538- 1546
[20]	Dean, B. , Oguchi, H. , Cai, S. , Otsuji, E. , Tashiro, K. , Hakomori, S. , Toyokuni, T. , Carbohydr. Res., 1993, 245( 2), 175- 192 doi: 10.1016/0008-6215(93)80071-L URL pmid: 8370021
[21]	徐广灿, 刘青川, 袁洁, 胡占兴, 马芳芳, 梁光义, 徐必学. 有机化学, 2016, 36( 7), 1617- 1625 doi: 10.6023/cjoc201512051
	Xu G., C. , Liu Q., C. , Yuan, J. , Hu Z., X. , Ma F., F. , Liang G., Y. , Xu B., X. , J. Org. Chem., 2016, 36( 7), 1617- 1625 doi: 10.6023/cjoc201512051
[22]	Percec, V. , Leowanawat, P. , Sun H., J. , Kulikov, O. , Nusbaum C., D. , Tran T., M. , Bertin, A. , Wilson D., A. , Peterca, M. , Zhang S., D. , Kamat N., P. , Vargo, K. , Moock, D. , Johnston E., D. , Hammer D., A. , Pochan D., J. , Chen Y., X. , Chabre Y., M. , Shiao T., C. , Bergeron-Blerk, M. , André, S. , Roy, R. , Gabius H., J. , Heiney P., A. , J. Am. Chem. Soc., 2013, 135( 24), 9055- 9077
[23]	Zhang S., D. , Moussodia R., O , Sun H., J. , Leowanawat, P. , Muncan, A. , Nusbaum C., D. , Chelling K., M. , Heiney P., A. , Klein M., L. , Andre, S. , Roy, R. , Gabius H., J. , Perec, V. , Angew. Chem. Int. Ed., 2014, 53( 41), 10899- 10903
[24]	Ligeour, C. , Dupin, L. , Marra, A. , Eur. J. Org. Chem., 2014, 2014( 34), 7621- 7630 doi: 10.1002/ejoc.201402902 URL
[25]	Li Y., X. , Wang F., J. , Chen, W. , Wan Y., Y. , Li Z., M. , Chem. Res. Chinese Universities, 2015, 31( 6), 952- 957
[26]	Alker, D. , Arrowsmith J., E. , Eur. J. Med. Chem., 1991, 26( 91), 907- 913 doi: 10.1016/0223-5234(91)90132-7 URL
[27]	Chen, N. , Xie, J. , J. Org. Chem., 2014, 79( 21), 10716- 10724 doi: 10.1021/jo502128h URL pmid: 25318074
[28]	Cai M. S., Li Z. J., Carbohydrate Chemistry: Fundamentals, Reactions, Synthesis, Isolation and Structure, Chemical Industry Press, Beijing, 2006, 370— 373
	( 蔡孟深, 李中军. 糖化学基础、反应、合成、分离及结构 , 北京: 化学工业出版社, 2006, 370— 373)

间接糖基化马蹄金素衍生物的合成及抗乙肝病毒活性研究

Synthesis and Anti-HBV Activities of the Indirect Galactopyranosyl Derivatives of Matijin-Su^†

RichHTML

PDF (PC)

可视化

被引次数

摘要/Abstract

引用本文

使用本文

图/表 10

参考文献 28

相关文章 15

编辑推荐

Metrics

本文评价

[1]	赵军强, 闫彩霞, 陈泽, 杨宁, 冯霞, 赵义平, 陈莉. 细胞内氧化还原响应型肝靶向嵌段聚合物的合成及纳米自组装性能[J]. 高等学校化学学报, 2018, 39(7): 1592.
[2]	袁洁, 刘青川, 徐广灿, 梁光义, 徐必学. 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[J]. 高等学校化学学报, 2016, 37(7): 1307.
[3]	王静云, 付雪, 包永明. 原子转移自由基聚合(ATRP)阳离子化菊粉作为非病毒基因载体的研究[J]. 高等学校化学学报, 2014, 35(10): 2124.
[4]	朱建勤, 陈晖, 王少戎, 李燕, 方唯硕. 熊果酸半乳糖苷偶联物的合成及保肝活性[J]. 高等学校化学学报, 2013, 34(7): 1660.
[5]	于雷, 华小辉, 翟延君, 杨丽敏, 赵国忠, 孟田华, 翁诗甫, 徐怡庄, 刘克新, 吴瑾光, 陈佳洱. 两种半乳糖醇氯化钆配合物的制备与表征[J]. 高等学校化学学报, 2011, 32(6): 1244.
[6]	吕丰, 李艳周, 武莉, 刘天军. 用于肿瘤成像的半乳糖/酞菁近红外荧光探针[J]. 高等学校化学学报, 2011, 32(5): 1010.
[7]	高遐张馥陈志春林贤福. 含乳糖聚电解质靶向微胶囊的层层自组装构筑[J]. 高等学校化学学报, 2011, 32(4): 957.
[8]	黄微王平王蔚张玥张闯年田秦王秀华刘媛袁直. 甘草次酸修饰PEG-PLGA纳米粒的制备及与肝癌细胞亲和性[J]. 高等学校化学学报, 2011, 32(2): 416.
[9]	王富强, 郝俊霞, 戴小军, 龚波林. 原子转移自由基聚合制备新型接枝聚α-D-吡喃半乳糖苷色谱固定相及其性能[J]. 高等学校化学学报, 2011, 32(12): 2757.
[10]	贺晓凌, 董友玉, 聂萍萍, 冯霞, 陈莉. 聚苯乙烯细胞培养板表面的糖化温敏修饰及其对细胞行为的影响[J]. 高等学校化学学报, 2009, 30(12): 2502.
[11]	查瑞涛,贺晓婷,杜田,袁直 . 肝靶向甘草次酸修饰的壳聚糖纳米粒子的合成和表征[J]. 高等学校化学学报, 2007, 28(6): 1098.
[12]	王银松,韩月莲,李英霞,王玉玫,李荣珊 . 甲氨喋呤-乳糖酰基壳聚糖的制备及其体外实验[J]. 高等学校化学学报, 2007, 28(6): 1092.
[13]	查瑞涛, 杜田, 袁直 . 端基为肝靶向基团的聚谷氨酸苄酯的合成及表征[J]. 高等学校化学学报, 2006, 27(5): 885.
[14]	杨丽敏, 赵莹, 苏允兰, 王哲明, 严纯华, 吴瑾光. 半乳糖醇与氯化稀土配合物的合成及荧光光谱研究[J]. 高等学校化学学报, 2002, 23(8): 1475.
[15]	丁雄军, 卓仁禧, 付功成. 二乙三胺五乙酸吡哆醇酯配体及其钆配合物的合成、弛豫率和肝靶向性研究[J]. 高等学校化学学报, 2002, 23(1): 49.

间接糖基化马蹄金素衍生物的合成及抗乙肝病毒活性研究

Synthesis and Anti-HBV Activities of the Indirect Galactopyranosyl Derivatives of Matijin-Su†

RichHTML

PDF (PC)

可视化

被引次数

摘要/Abstract

引用本文

使用本文

图/表 10

参考文献 28

相关文章 15

编辑推荐

Metrics

本文评价

Synthesis and Anti-HBV Activities of the Indirect Galactopyranosyl Derivatives of Matijin-Su^†