基于D-半乳糖衍生的小分子半乳糖凝集素抑制剂的合成及活性研究进展

doi:10.6023/cjoc202110036

摘要/Abstract

半乳糖凝集素是一类能够特异性识别β-半乳糖苷结构的可溶性蛋白, 广泛分布于正常组织和病变组织中, 在细胞黏附、细胞凋亡、炎症反应和肿瘤转移等过程具有重要作用, 是治疗肿瘤、炎症及神经性疾病等多种疾病的潜在靶点. 根据衍生位点的差异, 按照半乳糖单取代、双取代和多取代衍生物的顺序对近十多年来基于D-半乳糖衍生的小分子半乳糖凝集素抑制剂进行分类, 总结了这些抑制剂的化学合成方法及活性研究进展, 期望能为高活性和高选择性的半乳糖凝集素抑制剂的设计提供思路, 为靶向半乳糖凝集素的新型药物开发提供参考.

关键词: 半乳糖凝集素, 抑制剂, 合成, 生物活性, 研究进展

Galectins are a family of soluble proteins which can specifically recognize the structure of β-galactoside. It is widely distributed in normal and diseased tissues, and plays an important role in cell adhesion, cell apoptosis, inflammatory response, tumor metastasis and other related processes. Galectin is a promising target for the treatment of many diseases, such as tumor, inflammation and neurological diseases. Herein, the synthesis and biological activities of small galectin inhibitors derived from D-galactose are reviewed according to the difference of derivatization sites, which are expected to provide research thought for designing galectin inhibitors with high affinity and high selectivity, and afford reference for development of new drug candidates targeting galectins.

Key words: galectin, inhibitor, synthesis, biological activity, research progress

引用此文

雍灿, 李芸, 毕涛, 陈国凤, 郑东霞, 王周玉, 张园园. 基于D-半乳糖衍生的小分子半乳糖凝集素抑制剂的合成及活性研究进展[J]. 有机化学, 2022, 42(5): 1307-1325.

Can Yong, Yun Li, Tao Bi, Guofeng Chen, Dongxia Zheng, Zhouyu Wang, Yuanyuan Zhang. Research Progress on the Synthesis and Activity of D-Galactose Derived Small Galectin Inhibitors[J]. Chinese Journal of Organic Chemistry, 2022, 42(5): 1307-1325.

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图/表 40

图1. 三类不同的半乳糖凝集素结构

Figure 1. Three different structures of Galectins

Galectin	Related physiological process	Related disease	Ref.
Galectin-1	参与细胞生长、迁移、粘附、运动等过程; 诱导T 细胞死亡, 促进T细胞介导的肿瘤免疫逃逸.	胰腺癌、肺癌、甲状腺癌、胶质瘤、结肠癌、淋巴癌等	[7]
Galectin-3	参与细胞的增殖、凋亡, 以及免疫系统的调节.	心脏病、脑炎、乳腺癌、结肠癌、甲状腺癌、前列腺癌膀胱癌、黑色素瘤等	[7a, 8]
Galectin-4	诱导CD⁺T细胞产生炎性细胞因子白介素-6(IL-6), 同时抑制CD⁺T细胞凋亡.	肠炎、结肠癌等	[8c, 9]
Galectin-7	参与角质形成以及细胞存活、生长、分化的调控过程.	皮肤癌、头颈部鳞状细胞癌等	[10]
Galectin-8	调节细胞黏附、生长等过程, 促使调节T细胞分泌白介素-10(IL-10), 以限制免疫反应; 增加骨骼吸收因子的表达.	骨质流失、肾炎、乳腺癌、骨髓瘤等	[8c, 11]
Galectin-9	参与耐受巨噬细胞编程和适应性免疫抑制、细胞因子产生以及T细胞信号转导和凋亡.	病毒感染(如艾滋病病毒、登革热病毒、基孔肯雅热病毒、新型冠状病毒), 疟疾, 胰腺癌等	[12]

表1. 半乳糖凝集素及其生物学功能

Table 1. Physiological functions of Galectin

图2. TD-139结构式

Figure 2. Structures of TD-139

图3. 乳糖与Galectin-3的结合示意图[18a]

Figure 3. Diagram of binding mode between lactose and Galectin-3

图4. β-硫代苯基半乳糖苷衍生物的合成

Figure 4. Synthesis of β-thiophenylgalactoside derivatives

图5. 端基肟醚半乳糖衍生物的合成

Figure 5. Synthesis of oxime ether galactose derivatives

图6. C(2')-酰胺二糖衍生物的合成

Figure 6. Synthesis of C(2')-amide disaccharide derivatives

图7. 端基半乳糖苷衍生物的合成

Figure 7. Synthesis of terminal galactose derivatives

图8. 噻唑类半乳糖苷衍生物的合成

Figure 8. Synthesis of thiazole galactoside derivatives

图9. 杂环类半乳糖苷衍生物的合成

Figure 9. Synthesis of heterocycle galactoside derivatives

图10. 芳基三唑半乳糖苷衍生物的合成

Figure 10. Synthesis of aryl triazole galactoside derivatives

图11. 肟醚半乳糖衍生物的合成

Figure 11. Synthesis of oxime ether galactose derivatives

图12. C(3)三唑基乳糖胺衍生物的合成

Figure 12. Synthesis of triazole lactosamine derivatives

图13. C(3)-三唑半乳糖基芳基磺酰胺衍生物的合成

Figure 13. Synthesis of C(3)-triazole galactose aryl sulfonamide derivatives

图14. C(3)-喹啉/中氮茚半乳糖衍生物的合成

Figure 14. Synthesis of C(3)-quinoline/indolizine galactose derivatives

图15. 氨基嘧啶半乳糖甲基苷衍生物的合成

Figure 15. Synthesis of aminopyrimidine methyl galactose derivatives

图16. C(3)-炔基苄基醚类半乳糖衍生物的合成

Figure 16. Synthesis of C(3)-alkynyl benzyl ether galactose derivatives

图17. 3-O-异丙基-β-甲基吡喃半乳糖化合物的合成

Figure 17. Synthesis of 3-O-isopropyl-β-methylpyranyl galactose derivatives

图18. 丙二酸酯半乳糖衍生物的合成

Figure 18. Synthesis of malonate galactose derivatives

图19. 化合物129和Galectin-8N复合物的晶体结构[33]

Figure 19. Complex of compound 129 with Galectin-8N

图20. 3-O-芳基半乳糖苷衍生物的合成

Figure 20. Synthesis of 3-O-aryl galactoside derivatives

图21. C(3)-三氮唑半乳糖衍生物的合成

Figure 21. Synthesis of C(3)-triazole galactose derivatives

图22. 硫代二半乳糖衍生物的合成

Figure 22. Synthesis of thiodigalactose derivatives

图23. C(3)优化的乳糖胺衍生物的合成

Figure 23. Synthesis of C(3)-lactosamine derivatives

图24. C(3)-三唑半乳糖苷衍生物的合成路线

Figure 24. Synthesis of C(3)-triazole galactoside derivatives

图25. 硫代二半乳糖衍生物的合成

Figure 25. Synthesis of thiodigalactose derivatives

图26. 化合物169 (A)和170 (B)与Galectin-3复合物的晶体结构[38]

Figure 26. Crystal structure of compounds 169 (A) and 170 (B) with Galectin-3

图27. C(1), C(3)取代的三唑基半乳糖衍生物的合成

Figure 27. Synthesis of C(1), C(3) substituted galactose derivatives

图28. 喹啉半乳糖衍生物的合成

Figure 28. Synthesis of quinoline galactose derivatives

图29. C(3)-香豆素-1,2,3-三氮唑半乳糖衍生物的合成

Figure 29. Synthesis of C(3)-coumarin-1,2,3-triazole galactose derivatives

图30. 三唑基半乳糖苷衍生物的合成

Figure 30. Synthesis of triazolyl galactoside derivatives

图31. 化合物186与Galectin-3复合物的晶体结构[40]

Figure 31. Crystal structure of compound 186 with Galectin-3

图32. 氨基嘧啶衍生物的合成

Figure 32. Synthesis of arylaminopyrimidines derivatives

图33. 苯并咪唑半乳糖衍生物的合成

Figure 33. Synthesis of benzoimidazole galactose derivatives

图34. 三取代的半乳糖衍生物的合成

Figure 34. Synthesis of trisubstituted galactose derivatives

图35. 塔罗糖衍生物的合成

Figure 35. Synthesis of talose derivatives

图36. C(3)-香豆素半乳糖衍生物的合成

Figure 36. Synthesis of C(3)-coumarin galactose derivatives

图37. 糖-芳基三环杂合物的合成

Figure 37. Synthesis of galactose-aryl tricyclic compounds

图38. 四氢吡喃半乳糖衍生物的合成

Figure 38. Synthesis of tetrahydropyran galactose derivatives

图39. 基于D-半乳糖衍生的小分子半乳糖凝集素抑制剂

Figure 39. D-galactose derived small galectin inhibitors

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