基于二肽基肽酶4 (DPP-4)靶点设计的五种降糖活性杂环合成及构效关系研究进展

doi:10.6023/cjoc202107001

摘要/Abstract

糖尿病是我国慢性疾病中威胁人类健康的主要疾病, 治疗糖尿病的药物作用靶点主要有二肽基肽酶4 (DPP-4)、单磷酸腺苷活化蛋白激酶(AMPK)、过氧化物酶体增殖物激活受体γ (PPARγ)受体等, 其中以DPP-4为靶点的靶向药物研究是近几年的热点. DPP-4抑制剂是治疗2型糖尿病的药物, 其最大的优点是不易诱发低血糖和增加体重. 据报道, 目前已上市的DPP-4靶向药物可引起胰腺炎和超敏等不良反应, 因此继续开发新型DPP-4抑制剂的降糖药物, 以避免不良反应发生值得进一步深入研究. 在系统的文献调研基础上, 总结出具有潜在的降糖活性杂环结构, 并通过计算机分子模拟对接, 针对DPP-4靶点, 最终筛选出5种易合成且降糖活性较高的杂环结构, 并对其合成路线及构效关系进行归纳总结分析, 为今后开发安全高效、结构新颖的DPP-4抑制剂的降糖药物提供研究基础.

关键词: 糖尿病, 二肽基肽酶4 (DPP-4)抑制剂, 分子对接, 合成方法, 构效关系

Recently, diabetes has gradually become a main life-threatening disease in China. Drug targets for the treatment of diabetes mainly include dipeptidyl peptidase 4 (DPP-4), adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma (PPARγ) receptor and so on, in which targeted drug research targeting DPP-4 is a hot spot in recent years. DPP-4 inhibitor is a drug for the treatment of type 2 diabetes, and its biggest advantage is that it is not easy to induce hypoglycemia and increase weight. It is reported that the currently available DPP-4 targeted drugs can cause adverse reactions, such as pancreatitis and hypersensitivity. Therefore, it is worth further studying to continue to develop new hypoglycemic drugs for DPP-4 inhibitors to avoid adverse reactions. According to the systematic literature review, the potential heterocyclic structures with hypoglycemic activity are summarized and through computer molecular simulation docking, five kinds of heterocyclic structures with high hypoglycemic activity and easy synthesis are finally screened out based on DPP-4 target design. The synthesis routes and structure-activity relationships are summarized and analyzed, which provides a research basis for the development of safe, efficient and novel hypoglycemic drugs for DPP-4 inhibitors in the future.

Key words: diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitor, molecular docking, synthesis methods, structure-activity relationship

引用此文

孔媛芳, 杨彬, 庄严, 张京玉, 孙德梅, 董春红. 基于二肽基肽酶4 (DPP-4)靶点设计的五种降糖活性杂环合成及构效关系研究进展[J]. 有机化学, 2022, 42(3): 770-784.

Yuanfang Kong, Bin Yang, Yan Zhuang, Jingyu Zhang, Demei Sun, Chunhong Dong. Research Progress on the Synthesis and Structure-Activity Relationship of Five Hypoglycemic Active Heterocycles Based on Dipeptidyl Peptidase 4 (DPP-4) Target Design[J]. Chinese Journal of Organic Chemistry, 2022, 42(3): 770-784.

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图/表 45

Figure 1. Chemical structures of 12 hypoglycemic compounds

Compd.	IC₅₀/(mg•L^–1)
Compd.	α-Glucosidase inhibitory activity	AGEs forming free radical activity
1a	>1000	5.247±0.519
1b	>1000	6.567±0.456
1c	>1000	3.239±0.713
1d	>1000	2.346±0.188
2a	>1000	4.223±0.268
2b	0.469±0.042	2.453±0.069
2c	0.250±0.042	1.132±0.141
2d	1.020±0.062	0.623±0.016
Acarbose	0.042±0.002	—
Aminoguanidine Hydrochloride	—	28.255±0.657

Table 1. In vitro hypoglycemic activity of compounds 1a~1d and 2a~2d

Figure 2. Structure of compound 3

Compd.	R¹	R²	n	Decrease in blood glucose/%
Compd.	R¹	R²	n	18 h	21 h
4a	Me	H	0	-7.0±4.8	3.6±0.7
4b	Me	H	1	24.7±9.1	27.6±5.9
4c	Me	H	2	-5.6±6.2	13.0±9.3
4d	Me	H	3	-3.0±6.1	-9.3±18.3
4e	H	H	1	13.9±12.7	7.4±3.0
4f	Et	H	1	-19.5±8.7	2.4±8.3
4g	Ph	H	1	3.9±5.6	-3.4±22.4
4h	4-ClC₆H₄CH₂	H	1	24.5±8.2	-8.5±19.0
4i	4-PhC₆H₄CH₂	H	1	3.8±13.4	11.4±6.0
4j	Me	Cl	1	37.1±7.7	47.6±6.9

Table 2. Hypoglycemic differentiation activities of thiazole-2,4-dione derivatives

Entry	FPG/(mol•L^–1)		2 h PBG/(mol•L^–1)
Entry	Before treatment	Post treatment	Before treatment	Post treatment
1	7.43±0.70	5.30±0.39	11.33±1.24	6.80±0.53
t	0.569	12.010	0.105	8.000
P	0.285	0.000	0.458	0.000

Table 3. Blood glucose indexes of patients [(x±s), n=82]

Entry	Compound	Binding energy/(kJ•mol^–1)
1	a	–25.62
2	g	–22.68
3	j	–22.68
4	b	–21.84
5	i	–21.42
6	e	–21
7	l	–20.58
8	h	–20.16
9	d	–19.32
10	c	–17.64
11	k	–17.64
12	f	–13.86

Table 4. Computer simulation results

Figure 3. Complexes of five hypoglycemic heterocyclic compounds and DPP-4 (a) Complex of DPP-4 and benzopyran-2-one a; (b) Complex of DPP-4 and hexahydropyrrolo[2,1-b]oxazole c; (c) Complex of DPP-4 and pyrano[3,2- c]pyridine g; (d) Complex of DPP-4 and pyrrolotriazine j; (e) Complex of DPP-4 and triazolopyrazine l.

Figure 4. Skeleton of benzopyran-2-one (chromen-2-one, Coumarin)

Figure 5. Various biological activities of benzopyran- 2-one ring

Scheme 1. Synthetic route of compound 7

Scheme 2. Synthetic route of compound 10

Scheme 3. Synthetic route of compound 13

Scheme 4. Synthetic route of compounds 15a and 15b

Scheme 5. Synthetic route of compounds 16 and 17

Figure 6. Structure-activity relationship of benzopyran-2-one

Figure 7. Skeleton of hexahydropyrrolo[2,1-b]oxazole

Figure 8. Various biological activities of hexahydropyrrolo[2,1- b]oxazole

Scheme 6. Synthetic route of compound 21

Scheme 7. Synthetic route of compounds 23a~23c

Scheme 8. Synthetic route of compound 25

Figure 9. Structure-activity relationship of hexahydropyrrolo[2,1-b]oxazole

Figure 10. Skeleton of pyrano[3,2-c]pyridine

Figure 11. Various biological activities of pyrano[3,2-c]pyridine

Scheme 9. Synthetic route of compound 28

Scheme 10. Synthetic route of compound 31

Scheme 11. Synthetic route of compound 34

Scheme 12. Synthetic route of compound 37

Scheme 13. Synthetic route of compound 41

Figure 12. Structure-activity relationship of pyrano[3,2- c]pyridone

Figure 13. Skeleton of pyrrolotriazine

Scheme 14. Synthetic route of compound 49

Scheme 15. Synthetic route of compound 53

Scheme 16. Synthetic route of compound 57

Scheme 17. Synthetic route of compound 60

Scheme 18. Synthetic route of compound 63

Figure 14. Structure-activity relationship of pyrrolotriazine

Figure 15. Skeleton of triazolopyrazine

Scheme 19. Synthetic route of compound 70

Scheme 20. Synthetic route of compound 74

Scheme 21. Synthetic route of compound 80

Scheme 22. Synthetic route of compound 85

Scheme 23. Synthetic route of compound 88

Figure 16. Structure-activity relationship of triazolopyrazine

Figure 17. Research on five heterocyclic synthesis methods with hypoglycemic activity

Figure 18. In vitro and in vivo activities of five hypoglycemic heterocyclic compounds

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