Click-Inspired Functionalization of Glycans: Rational Design and Efficient Synthesis of C3-OH Specific Derivatives

doi:10.6023/A25030093

Acta Chimica Sinica ›› 2025, Vol. 83 ›› Issue (5): 445-452.DOI: 10.6023/A25030093 Previous Articles Next Articles

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基于点击化学构建的功能化糖分子: 糖C3-OH的衍生化设计及高效合成

张一亮^a^,^b, 武卫龙^b, 许文磊^b, 傅玉琴^b^,^*(), 郭辉^b^,^*(), 卢志强^a^,^b^,^*()

^a 三峡大学生物与制药学院天然产物研究与利用湖北省重点实验室湖北宜昌 443002
^b 洛阳师范学院化学化工学院绿色合成及光功能材料洛阳重点实验室河南洛阳 471934

投稿日期:2025-03-26 发布日期:2025-04-23
基金资助:
国家自然科学基金(U1304206); 国家自然科学基金(21801112); 河南省自然科学基金(212300410374); 河南省自然科学基金(252300420254); 河南省高等学校重点科研项目计划(18A150012); 河南省研究性教学改革研究与实践项目(GJ[2023]388111)

Click-Inspired Functionalization of Glycans: Rational Design and Efficient Synthesis of C3-OH Specific Derivatives

Yiliang Zhang^a^,^b, Weilong Wu^b, Wenlei Xu^b, Yuqin Fu^b^,^*(), Hui Guo^b^,^*(), Zhiqiang Lu^a^,^b^,^*()

^a Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, Hubei Province, China
^b College of Chemistry and Chemical Engineering and Luoyang Key Laboratory of Green Synthesis and Photofunctional Materials, Luoyang Normal University, Luoyang 471934, Henan Province, China

Received:2025-03-26 Published:2025-04-23
Contact: * E-mail: lyfuyuqing@126.com; guohui0319@naikai.edu.cn; zqlu2000@163.com
Supported by:
National Natural Science Foundation of China(U1304206); National Natural Science Foundation of China(21801112); Natural Science Foundation of Henan Province(212300410374); Natural Science Foundation of Henan Province(252300420254); Key Scientific Research Project of Higher Education of Henan Province(18A150012); Research and practice of teaching reform of Henan Province(GJ[2023]388111)

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Abstract

As pivotal functional biomolecules, carbohydrates acquire diverse biological recognition capabilities through structural modifications that fine-tune their interactions with biological systems. Glycan derivatives bearing C3-position modifications have emerged as a focal point in glycochemistry research due to their distinctive physiological and pharmacological activities. This study implemented a modular design strategy to construct multifunctional C3-glycoside scaffolds by synergistically integrating biologically oriented bonding patterns. Three complementary functional motifs—ester linkages (for controlled degradation), perfluoroaryl groups (for hydrophobicity enhancement), and site-specific nucleophilic aromatic substitution (S_NAr)—were strategically incorporated to confer multi-responsive potential. For the synthesis process, we established a highly efficient reaction protocol. Under standard reaction conditions, cesium carbonate was employed as the base, and a tetrahydrofuran (THF)/dimethyl sulfoxide (DMSO) (V/V, 5∶1) mixed solvent system was utilized. Remarkably, the reactions could be completed within as little as 20 s at room temperature, achieving yields exceeding 90%. This rapid and efficient reaction exhibits remarkable versatility and broad substrate tolerance. Taking this reaction as the standard condition, we successfully constructed the efficient synthesis of over 30 related C3-glycan derivatives, demonstrating the robustness and scalability of our developed method. This green synthesis protocol, characterized by mild reaction conditions and a rapid process, represents a significant advancement in achieving efficient C3-site derivatization. Furthermore, we pioneered preliminary investigations on the luminescent signal responses mediated by carbohydrate-lectin recognition interactions using the synthesized C3-modified glycoconjugates, laying groundwork for advanced glycan-based biosensing platforms.

Key words: carbohydrates synthesis, click-inspired glycan-ligation, C3-glycoside derivatization, sugar-lectin recognition signal

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Yiliang Zhang, Weilong Wu, Wenlei Xu, Yuqin Fu, Hui Guo, Zhiqiang Lu. Click-Inspired Functionalization of Glycans: Rational Design and Efficient Synthesis of C3-OH Specific Derivatives[J]. Acta Chimica Sinica, 2025, 83(5): 445-452.

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Fig. & Tab. 6

Figure 1. Some crucial examples of bioactive sugar moiety C3 derivatives (A) and design of ligation patterns based on the C3 position of sugar structure (B)

Entry^a	Base	Solvent (V/V)	Time	Aa-1 Yield^c/%
1	Cs₂CO₃	THF	12 h	33.8
2	Cs₂CO₃	DMSO	12 h	71.5
3	Cs₂CO₃	DMF	12 h	42.6
4	Cs₂CO₃	THF/DMF (5∶1)	12 h	67.3
5	Cs₂CO₃	THF/NMP (5∶1)	12 h	55.2
6	Cs₂CO₃	THF/DMSO (5∶1)	12 h	95.7
7	DBU	THF/DMSO (5∶1)	12 h	NR
8	K₂CO₃	THF/DMSO (5∶1)	12 h	3.0
9	NaHCO₃	THF/DMSO (5∶1)	12 h	14.0
10	NaOAc	THF/DMSO (5∶1)	12 h	3.0
11	Quinine	THF/DMSO (5∶1)	12 h	60.7
12^b	—	THF/DMSO (5∶1)	12 h	NR
13^d	Cs₂CO₃	THF/DMSO (5∶1)	20 s	92.9

Table 1. Reaction condition optimizationa

Figure 2. Scope of phenol for C3-glycan derivatization following the click-inspired glycan ligation

Figure 3. Derivatization and synthetic routes of general sugar molecules at the C3 position: (A) Synthetic route design of Glu C3 beacon; (B) Synthetic route design of Man & Gala C3 beacons

Figure 4. Synthesis of general sugar molecules derivatives at the C3 position bearing luminescent groups

Figure 5. Response of glucose C3 aggregation-induced emission (AIE) molecules with proteins in PBS buffer (10 mmol/L, containing 1 mg/mL CaCl2, 1 mg/mL Mn(NO3)2, pH 7.04). (A) Fluorescence intensity changes (2.2-fold enhancement) of S-Ba-24 (2.5 μmol/L, PBS) upon interaction with different concentrations (0~0.2 μmol/L) of Con A (λex=257 nm, λem=467 nm); (B) Fluorescence intensity changes (1.4-fold enhancement) of S-Ba-24 (2.5 μmol/L, PBS) upon interaction with different concentrations (0~0.2 μmol/L) of PNA; (C) Fluorescence intensity changes (3.1-fold enhancement) of S-di-Ba-26 (2.5 μmol/L, PBS) upon interaction with different concentrations (0~0.2 μmol/L) of Con A

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基于点击化学构建的功能化糖分子: 糖C3-OH的衍生化设计及高效合成

Click-Inspired Functionalization of Glycans: Rational Design and Efficient Synthesis of C3-OH Specific Derivatives

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