苯并咪唑并氮杂糖的设计、合成及其糖苷酶抑制活性

doi:10.6023/cjoc202101055

摘要/Abstract

鉴于前期研究发现的源于D-核糖的苯并咪唑并氮杂糖1和2具有良好的β-葡萄糖糖苷酶抑制活性, 通过关键的Mitsunobu反应, 设计合成了系列新型L-核糖源和2-脱氧-D-核糖源的苯并咪唑并氮杂糖衍生物6a~6c和7a~7c; 并依据电子等排的药物设计方法, 设计了系列新的糖环上2位氨基取代的稠合三环氮杂糖13a、13b和17a~17e; 以及4位烷氧基取代的氮杂糖28a和28b. 化合物13a和13b通过苄胺对甲磺酰化的羟基(OMs)取代合成, 化合物17a~17e通过氨基对三元环氧中间体15的开环制备, 化合物28a和28b通过4-羟基对卤代烃的亲核取代合成. 测试了化合物6a~6c、7a~7c、13a、13b、15、17a~17e、19、28a和28b对α-葡萄糖糖苷酶(黑曲霉)、β-葡萄糖糖苷酶(杏仁)和α-半乳糖糖苷酶(咖啡豆)的抑制活性, 结果显示所测化合物在10 μmol/L时对α-葡萄糖糖苷酶和α-半乳糖糖苷酶没有或微弱的抑制活性, 部分化合物表现出较好的β-葡萄糖糖苷酶抑制活性, 其中环氧中间体15和2-氨基化合物17a活性最好, IC₅₀值分别为10.5和11.7 μmol/L, 但均低于阳性对照品1的活性. 结果表明该类稠合三环氮杂糖是一类良好的选择性β-葡萄糖苷酶抑制剂.

关键词: 稠合三环氮杂糖, Mitsunobu反应, 糖苷酶抑制剂, 苯并咪唑, 环氧中间体

Based on our previous studies that benzimidazole-fused tricyclic iminosugars 1 and 2derived fromD-ribose inhibitedβ-glucosidase significantly, a series of novel tricyclic iminosugars 6a~6c and 7a~7c derived fromL -ribose and 2-deoxy-D-ribose, respectively, were designed and synthesized through the key Mitsunobu reaction. Additionally, based on the drug design method of isosterism, a series of tricyclic iminosugars derivitives 13a,13b and 17a~17e containing amino group on C-2 position, and 28a and 28b with alkoxyl group on C-4 position on sugar ring were designed. Compounds 13a and 13b were synthesized through substitution reaction of benzylamine and methylsulfonide hydroxy (OMs), while compounds 17a~17e were prepared through ring opened reaction of amine and the three-membered epoxy intermediate 15, compounds 28a and 28b were synthesized through nucleophilic substitution reaction of 4-OH and halohydrocarbon. The inhibitory activities of compounds 6a~6c,7a~7c,13a,13b,15,17a~17e,19,28a and 28bagainstα-glucosidase (Aspergillus niger),β-glucosidase (almonds) andα-galatosidase (coffee beans) were tested. The results showed that the tested compounds exhibited no or weakα-glucosidase andα-galatosidase inhibitory activities at 10 μmol/L. Some compounds exhibited good inhibitory activities againstβ-glucosidase. Among them, the epoxy intermediate 15 and compound 17a(2-amino) were the best ones with IC₅₀values of 10.5 and 11.7 μmol/L, respectively, but lower than that of the positive control 1. The results further suggested that such fused tricyclic iminosugars were the excellent and specific inhibitors againstβ-glucosidase.

Key words: fused tricyclic iminosugar, Mitsunobu reaction, glycosidase inhibitors, benzimidazole, epoxy intermediate

引用此文

刘旭, 苏路路, 周昭希, 牛丽萍, 高利刚, 琚欢欢, 李丰兴, 李小六, 陈华. 苯并咪唑并氮杂糖的设计、合成及其糖苷酶抑制活性[J]. 有机化学, 2021, 41(7): 2861-2874.

Xu Liu, Lulu Su, Zhaoxi Zhou, Liping Niu, Ligang Gao, Huanhuan Ju, Fengxing Li, Xiaoliu Li, Hua Chen. Design and Synthesis of Benzimidazole-Iminosugars and Their Inhibitory Activities against Glycosidases[J]. Chinese Journal of Organic Chemistry, 2021, 41(7): 2861-2874.

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图/表 15

图1. β-葡萄糖苷酶抑制剂1和2的结构

Figure 1. Structures of β-glucosidase inhibitors 1 and 2

图式1. L-核糖源的苯并咪唑并氮杂糖6a~6c的合成

Scheme 1. Synthesis of benzimidazole-iminosugars 6a~6c derived from L-ribose

图2. 2-脱氧-D-核糖源的苯并咪唑并氮杂糖7a~7c

Figure 2. Benzimidazole-iminosugars 7a~7c derived from 2-deoxy-D-ribose

C-5 (六元环)	δ	C-4 (五元环)	δ
6a-1	44.3	6a-2	59.8
6b-1	44.5	6b-2	58.9
6c-1	44.2	6c-2	57.9
7a-1	45.9	7a-2	61.0
7b-1	45.9	7b-2	60.1
7c-1	45.6	7c-2	60.0

表1. 化合物6a~6c和7a~7c中关环碳的化学位移

Table 1. Chemical shift of the ring closing carbon in compounds 6a~6c and 7a~7c

图3. 化合物6a-1和6c-2中关键的HMBC和NOESY信号相关

Figure 3. Key HMBC and NOESY correlations of compounds 6a-1 and 6c-2

图式2. 化合物10和11的合成

Scheme 2. Synthesis of compounds 10 and 11

图式3. 化合物13a和13b的合成

Scheme 3. Synthesis of compounds 13a and 13b

图式4. 化合物17a~17e的合成

Scheme 4. Synthesis of compounds 17a~17e

图4. 化合物13a和19的NOESY信号相关及化合物11的X单晶衍射结构

Figure 4. NOESY correlations of compounds 13a and 19, and the X-ray crystallographic structure of compound 11

图式5. 化合物19的合成

Scheme 5. Synthesis of compound 19

图式6. C-2位亲核取代反应的可能机理

Scheme 6. Possible mechanism for the nucleophilic substitution on C-2 position

图5. 化合物17e关键的HMBC和NOESY信号相关

Figure 5. Key HMBC and NOESY correlations of compound 17e

图式7. 甲磺酰化产物22的合成

Scheme 7. Synthesis of mesylated compound 22

图式8. C-4位烷氧基的衍生物28a和28b的合成

Scheme 8. Synthesis of derivatives 28 and 28b with alkoxyl group on C-4 position

化合物	抑制率/%
化合物	α-葡萄糖糖苷酶 (黑曲霉)	β-葡萄糖糖苷酶 (杏仁)	α-半乳糖糖苷酶 (咖啡豆)
6a-1	—^a	—	—
6a-2	—	—	6.4
6b-1	—	—	—
6b-2	—	—	—
6c-1	—	—	—
6c-2	1.2	1.6	—
7a-1	—	2.0	—
7a-2	—	—	8.2
7b-1	—	—	5.2
7b-2	—	—	2.1
7c-1	—	1.4	—
7c-2	—	—	—
13a	—	—	—
13b	—	—	32.6
15	—	54.5 (10.5^b)	9.8
17a	—	50.4 (11.7)	12.2
17b	—	3.4	8.6
17c	—	—	—
17d	—	—	—
17e	—	—	—
19	—	24.1	—
28a	—	—	—
28b	—	—	—
1		70.6 (6.4)

表2. 化合物6a~6c、7a~7c、13a、13b、15、17a~17e、19、28a和28b的糖苷酶抑制活性

Table 2. Inhibitory activities of compounds 6a~6c, 7a~7c, 13a, 13b, 15, 17a~17e, 19, 28a and 28b against glycosidases

参考文献 22

[1]	Schmaltz,R. M.; Hanson,S. R.; Wong,C. H. Chem. Rev. 2011, 111,4259. doi: 10.1021/cr200113w
[2]	Takahashi, M.; Kizuka, Y.; Ohtsubo, K.; Gu,J. G.; Taniguchi, N. Mol. Aspects Med. 2016, 51,56. doi: 10.1016/j.mam.2016.04.008
[3]	Dai,Y. W.; Hartke, R.; Li, Chao.; Yang, Q.; Liu,J. O..; Wang,L. X. ACS Chem. Biol. 2020, 15,2662. doi: 10.1021/acschembio.0c00228
[4]	He,X. P.; Zeng,Y. L.; Zang, Y.; Li, J.; Field,R. A.; Chen,G. R. Carbohydr. Res. 2016, 429,1. doi: 10.1016/j.carres.2016.03.022
[5]	Wei,M. M.; Wang,Y. S.; Ye,X. S. Med. Res. Rev. 2018, 38,1003. doi: 10.1002/med.2018.38.issue-3
[6]	Stutz,A. E. Iminosugars as Glycosidase Inhibitors, Nojirimycin and Beyond, Weinheim, Wiley-VCH, 1999.
[7]	Varrot, A.; Tarling,C. A.; Macdonald,J. M.; Stick,R. V.; Zechel,D. L.; Withers,S. G.; Davies,G. J. J. Am. Chem. Soc. 2003, 125,7496. doi: 10.1021/ja034917k
[8]	Lillelund,V. H.; Jensen,H. H.; Liang,X. F.; Bols, M. Chem. Rev. 2002, 102,515. doi: 10.1021/cr000433k
[9]	Ganem, B. Acc. Chem. Res. 1996, 29,340. doi: 10.1021/ar9502184
[10]	Kiappes,J. L.; Hill,M. L.; Alonzi,D. S.; Miller,J. L.; Iwaki, R.; Sayce,A. C.; Caputo,A. T.; Kato, A.; Zitzmann, N. ACS Chem. Biol. 2018, 13,60. doi: 10.1021/acschembio.7b00870
[11]	Li,Y. X.; Jia,Y. M.; Yu,C. Y. Prog. Chem. 2018, 35,586 (in Chinese).
	( 李意羡, 贾月梅, 俞初一, 化学进展, 2018, 35,586.)
[12]	Sánchez-Fernández,E. M.; García-Moreno,M. I.; Arroba,A. I.; Aguilar-Diosdado, M.; Padrón,J. M.; García-Hernández, R.; Gamarro, F.; Fustero, S.; Sánchez-Aparicio, J.; Masgrau, L.; García-Fernández,J. M.; Mellet,C. O. Eur. J. Med. Chem. 2019, 182,111604. doi: 10.1016/j.ejmech.2019.111604
[13]	Sánchez-Fernández,E. M.; Gonçalves-Pereira, R.; Rísquez-Cuadro, R.; Plata,G. B.; Padrón,J. M.; García-Fernández,J. M.; Mellet,C. O. Carbohydr. Res. 2016, 429,113. doi: 10.1016/j.carres.2016.01.006
[14]	Chen, H.; Hao, L.; Zhu, M.; Yang,T. Y.; Wei,S. N.; Qin,Z. B.; Zhang,P. Z.; Li,X. L. Bioorg. Med. Chem. Lett. 2014, 24,3426. doi: 10.1016/j.bmcl.2014.05.079
[15]	Yin,Z. Q.; Zhu, M.; Wei,S. N.; Shao, J.; Hou,Y. H.; Chen, H.; Li,X. L. Bioorg. Med. Chem. Lett. 2016, 26,1738. doi: 10.1016/j.bmcl.2016.02.049
[16]	Niu,L. P.; Xing,X. K.; Li,X. L.; Chem, H. Chin. J. Org. Chem. 2019, 39,771 (in Chinese). doi: 10.6023/cjoc201807043
	( 牛丽萍, 邢顺凯, 李小六, 陈华, 有机化学, 2019, 39,771.)
[17]	Sun,J. J.; Kang,Y. Q.; Gao,L. G.; Lu, X.; Ju,H. H.; Li,X. L.; Chem, H. Carbohydr. Res. 2019, 478,10. doi: 10.1016/j.carres.2019.04.002
[18]	Yan,L. H.; Lui, H.; Sun,J. J.; Gao,L. G.; Lu, X.; Niu,L. P.; Li,X. L.; Chem, H. Carbohydr. Res. 2019, 485,107807. doi: 10.1016/j.carres.2019.107807
[19]	Kasture,V. M.; Kalamkar,N. B.; Nair,R. J.; Joshi,R. S.; Sabharwal,S. G.; Dhavale,D. D. Carbohydr. Res. 2015, 408,25. doi: 10.1016/j.carres.2015.03.004
[20]	CCDC-2052292 (for 11) and CCDC-2059777 (for 27b) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif
[21]	Compain, P.; Martin,O. R. Iminosugars: From Synthesis to Therapeutic Applications, New York, Wiley, 2007.
[22]	Prasad,S. S.; Reddy,N. R.; Baskaran, S. J. Org. Chem. 2018, 83,9604. doi: 10.1021/acs.joc.8b00748