Research Progress on the Synthesis and Activity of D-Galactose Derived Small Galectin Inhibitors

doi:10.6023/cjoc202110036

Abstract

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

Cite this article

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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Fig. & Tab. 40

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]

Table 1. Physiological functions of Galectin

Figure 2. Structures of TD-139

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

Figure 4. Synthesis of β-thiophenylgalactoside derivatives

Figure 5. Synthesis of oxime ether galactose derivatives

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

Figure 7. Synthesis of terminal galactose derivatives

Figure 8. Synthesis of thiazole galactoside derivatives

Figure 9. Synthesis of heterocycle galactoside derivatives

Figure 10. Synthesis of aryl triazole galactoside derivatives

Figure 11. Synthesis of oxime ether galactose derivatives

Figure 12. Synthesis of triazole lactosamine derivatives

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

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

Figure 15. Synthesis of aminopyrimidine methyl galactose derivatives

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

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

Figure 18. Synthesis of malonate galactose derivatives

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

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

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

Figure 22. Synthesis of thiodigalactose derivatives

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

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

Figure 25. Synthesis of thiodigalactose derivatives

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

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

Figure 28. Synthesis of quinoline galactose derivatives

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

Figure 30. Synthesis of triazolyl galactoside derivatives

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

Figure 32. Synthesis of arylaminopyrimidines derivatives

Figure 33. Synthesis of benzoimidazole galactose derivatives

Figure 34. Synthesis of trisubstituted galactose derivatives

Figure 35. Synthesis of talose derivatives

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

Figure 37. Synthesis of galactose-aryl tricyclic compounds

Figure 38. Synthesis of tetrahydropyran galactose derivatives

Figure 39. D-galactose derived small galectin inhibitors

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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