Research Progress in Chemical Semi-synthetic Modification of Thiopeptide Antibiotics

doi:10.6023/A22060276

Acta Chimica Sinica ›› 2022, Vol. 80 ›› Issue (10): 1448-1462.DOI: 10.6023/A22060276 Previous Articles

Review

硫肽类抗生素化学半合成修饰研究进展

朱凤巧^a, 王文贵^a, 瞿旭东^b^,^*(), 王守锋^a^,^*()

a 济南大学化学化工学院山东省氟化学化工材料重点实验室济南 250022
b 上海交通大学生命科学技术学院微生物代谢国家重点实验室上海 200240

投稿日期:2022-06-27 发布日期:2022-08-09
通讯作者: 瞿旭东, 王守锋

作者简介:

朱凤巧, 女, 济南大学化学化工学院在读硕士研究生, 主要从事硫肽类抗生素化学半合成修饰研究.

王文贵, 男, 济南大学化学化工学院讲师, 硕士生导师, 毕业于中国科学院上海有机化学研究所. 承担山东省自然基金面上项目、山东省重点研发项目以及企业委托研发等项目. 主要从事有机氟化学研究, 包括单电子转移、金属催化、可见光催化的含氟化合物的合成、氟利昂的转化及天然产物的修饰等.

瞿旭东, 男, 上海交通大学生命科学技术学院教授, 博士生导师, 毕业于中国科学院上海有机化学研究所, 美国麻省理工学院化学系博士后. 国家自然科学基金“优秀青年科学基金”获得者、教育部“新世纪优秀人才支持计划”、武汉大学“珞珈学者特聘教授”. 承担国家自然基金面上项目、国家重点研发计划. 主要研究天然产物碳骨架的生物合成与编辑: 研究聚酮、含氮杂环和甾体三大类药用分子碳骨架的形成机制, 发展高效的生物合成方法用于碳骨架合成和结构修饰, 开发创新药物和实现药物的高效生产, 解决新药研发和工业生产过程中的瓶颈问题.

王守锋, 男, 济南大学化学化工学院教授, 济南大学化学化工学院化学系系主任, 博士生导师, 毕业于中国科学院上海有机化学研究所, 英国曼彻斯特大学访问学者. 承担国家自然基金面上项目、国家自然基金青年基金、“973”项目子课题、山东省自然基金面上项目、山东省重点研发项目以及企业委托研发等项目. 主要研究天然产物修饰: 抗生素的半合成, 药物化学生物学: 抗生素的传输, 以及含氟精细化学品的合成. 在含氟化合物的合成、复杂天然产物的生物合成及其类似物的突变生物合成研究中取得一系列成果.

基金资助:
国家自然科学基金(31972850); 微生物代谢国家重点实验室开放课题(MMLKF21-09)

Research Progress in Chemical Semi-synthetic Modification of Thiopeptide Antibiotics

Fengqiao Zhu^a, Wengui Wang^a, Xudong Qu^b(), Shoufeng Wang^a()

a Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials, College of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022
b State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240

Received:2022-06-27 Published:2022-08-09
Contact: Xudong Qu, Shoufeng Wang
Supported by:
National Natural Science Foundation of China(31972850); Open Funding Project of State Key Laboratory of Microbial Metabolism(MMLKF21-09)

Thiopetheride antibiotics are a class of ribosomal peptides that are produced by microbial secondary metabolism, rich in sulfur, and highly modified amino acid residues. Thiopeptide antibiotics have a series of very important biological activities, including anti-infection, anti-tumor and immunosuppression, and their mechanism of action targeting ribosomes is different from those commonly used in clinical practice, which makes thiopeptide antibiotics have great development potential, but their poor water solubility and low bioavailability limit their clinical application. In order to improve the physicochemical properties of thiopeptide antibiotics, researchers tried to modified the structure of thiopeptide antibiotics by means of chemosemi-synthesis, combinatorial biosynthesis and precursors directed mutation biosynthesis. The complex structure of thiopeptide antibiotics provides many modification sites for its chemical semi-synthetic modification. In recent years, research on the chemical semi-synthetic modification of thiopeptide antibiotics has developed rapidly. In this paper, the research progress of thiopeptide antibiotic analogues obtained by chemical semi-synthetic modification in recent ten years is reviewed.

Key words: dehydropyridine thiopeptide antibiotics, trisubstituted pyridine thiopeptide antibiotics, hydroxylated pyridine thiopeptide antibiotics, chemical semi-synthetic modification

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Fengqiao Zhu, Wengui Wang, Xudong Qu, Shoufeng Wang. Research Progress in Chemical Semi-synthetic Modification of Thiopeptide Antibiotics[J]. Acta Chimica Sinica, 2022, 80(10): 1448-1462.

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Fig. & Tab. 22

Figure 1. Structure and classification of thiopeptide antibiotics

Figure 2. Mechanism of action of thiopeptide antibiotics

Figure 3. Miller’s group proposed the Thiostrepton chemical semi-synthetic reaction a ND: Products arising from reaction at 2D and 3D could not be separated completely.

Condition	Additive	Conversions to 2A+3B (2A∶3B)	d.r. (2)
1	None	22% (10∶1)	1∶1
2	K₂CO₃	62% (5∶1)	3∶1
3	Na₂CO₃	84% (9∶1)	4∶1
4	KCl	30% (8∶1)	3∶1
5	NaCl	43% (8∶1)	3∶1

Table 1. Reaction for diastereoselective conjugate additions between aryl boronic acids and Thiostrepton

Condition	Additive	Conversions	e.r.
1	None	>99%	83∶17
2	K₂CO₃	95%	10∶90
3	Na₂CO₃	98%	9∶91
4	KCl	18%	15∶85
5	NaCl	42%	21∶79

Table 2. Outcome of conjugate addition reactions between protected Dha monomers and aryl boronic acids

Compound	MIC^a/(µg•mL^–1)
Compound	S. aureus	E. faecalis	S. pneumoniae	S. pyogenes
1	0.5	0.25	0.002	0.002
2a	1	1	0.008	0.004
2a’	0.5	1	0.002	0.002
2b	1	1	0.008	0.008
2b’	2	2	0.015	0.008
2c	4	2	0.015	0.015
2c’	2	1	0.008	0.004
2d	32	4	0.03	0.03
2d’	64	4	0.015	0.015
4a	2	1	0.008	0.002
4b	2	2	0.004	0.004
4c	0.5	0.25	<0.001	0.002
4d	4	4	0.06	0.06
4e	1	1	0.015	0.00

Table 3. Antibacterial activity of Thiostrepton and its analogues

Compound	Solubility^a/(μg•mL^–1)
1	3.0±0.2
4a	<1.0
4c	<1.0
4d	83±5
4e	28±4

Table 4. Water solubility of Thiostrepton and its analogues after the introduction of amides

Figure 4. Roelfes’s group proposed the Thiostrepton chemical semi-synthetic reaction *: Conversion rate of single modification. **: Conversion rate of double modification

Compound	MIC^a/(µg•mL^–1)		Solubility/(µg•mL^–1) in ddH₂O
Compound	S. aureus	E. faecalis	Solubility/(µg•mL^–1) in ddH₂O
1	0.5	0.25	6.4±0.1
7	2	2	—^b
8	2	1	—^b
10	64	64	169.7±2.6 (27×^c)

Table 5. Antibacterial activity and water solubility of Thiostrepton and its analogues

Figure 5. Ring skeleton modification of Thiostrepton

Figure 6. Jacobs’s group proposed the GE2270A chemical semi-synthetic reaction

Figure 7. LaMarche’s group proposed the GE2270A chemical semi-synthetic reaction

Figure 8. The synthetic route of NAI003

Figure 9. LaMarche’s group proposed the Thiomuracin chemical semi-synthetic reaction

Figure 10. Structure of Nocathiacin (I/II/III/IV/V)

Figure 11. Naidu’s group proposed the Nocathiacin chemical semi-synthetic reaction

NR¹R²	MIC^a/(µg•mL^–1)			PD50^b/(mg•kg^–1)
NR¹R²	S. aureus A15090	S. pneumo A28272	E. faecalis A20688	PD50^b/(mg•kg^–1)
35	0.25	0.06	2	1.65
	0.007	0.003	0.06	4.35
	0.25	0.03	0.25	5
	0.5	0.125	1	>10

Table 6. In vitro and in vivo antibacterial activity of Nocathiacin and its analogues

Figure 12. Xu’s group proposed the Nocathiacin chemical semi-synthetic reaction

Figure 13. Gerard Roelfes's group proposed the Nosiheptide chemical semi-synthetic reaction

Figure 14. Wang's group proposed the Nosiheptide chemical semi-synthetic reaction

Compound	MIC^a/(µg•mL^–1)			Yield/%
Compound	S. aureus	E. faecalis	ATCC 25923	Yield/%
Nosiheptide (47)	0.0078	0.031	0.062	—
56	<0.0039	0.015	0.015	91
57	<0.0039	0.0078	0.030	87
58	0.015	0.031	0.031	90
59	<0.0039	0.015	0.031	83
60	<0.0039	0.015	0.031	92

Table 7. Antibacterial activity and yield of Nosiheptide and its analogues

Figure 15. Chemical semi-synthetic modification of the amide moiety of the dehydroalanine side chain (A: Thiostrepton analog; B: Nocathiacin analogue; C: Nosiheptide analogue)

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硫肽类抗生素化学半合成修饰研究进展

Research Progress in Chemical Semi-synthetic Modification of Thiopeptide Antibiotics

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