胆碱酯酶抑制剂萘酰亚胺衍生物的合成与聚集诱导发光性质

doi:10.6023/cjoc202107064

摘要/Abstract

阿尔茨海默症(Alzheimer’s disease, AD)是一种神经退行性疾病, 严重影响老年人的生活质量, 目前治疗AD的药物主要是胆碱酯酶抑制剂, 如多奈哌齐、卡巴拉汀等. 本文基于多奈哌齐结构, 设计合成了一系列新的萘酰亚胺衍生物并进行了活性评价. 结果表明, 所合成的化合物均对乙酰胆碱酯酶(AChE)有选择性抑制, 其中2-((1-(3-甲氧基苄基)哌啶-4-基)甲基)-1H-苯并异喹啉-1,3(2H)-二酮(4k)的抑制活性最强, IC₅₀值为4.43 μmol•L^–1, 优于对照药物卡巴拉汀. 酶动力学及分子对接表明4k能够同时作用于AChE的催化活性位点和外周结合位点, 并且4k对SH-SY5Y和PC12细胞毒性较低. 此外, 这些化合物均显示出典型的聚集诱导发光(AIE)性质, 可能与萘酰亚胺分子内旋转受阻机制有关.

关键词: 萘酰亚胺, 胆碱酯酶, 聚集诱导发光

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by impaired cognitive and memory function, which seriously affects the quality of life of the elderly. At present, the main drugs for the treatment of AD are cholinesterase inhibitors, such as donepezil and rivastigmine. In this paper, a series of novel naphthimide derivatives were designed, synthesized and evaluated based on the structure of donepezil. The results showed that all of the tested compounds were acetylcholinesterase (AChE) selective inhibitors, 2-((1-(3-methoxybenzyl)piperidin-4-yl)methyl)-1H-benzo[de]isoquinoline- 1,3(2H)-dione (4k) exhibited the strongest inhibition to AChE with an IC₅₀ value of 4.43 μmol/L, which was better than the control rivastigmine. Kinetic and molecular modeling studies indicated that 4k targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4k didn’t show obvious cytotoxicity against SH-SY5Y and PC12 cell lines. Besides, these compounds exhibited typical aggregation induced emissions (AIE) properties, which might be controlled by mechanism of restriction of intramolecular rotations.

Key words: naphthalimide, cholinesterase, aggregation induced emission

引用此文

赵永梅, 穆叶舒, 罗稳, 田智勇. 胆碱酯酶抑制剂萘酰亚胺衍生物的合成与聚集诱导发光性质[J]. 有机化学, 2022, 42(3): 819-829.

Yongmei Zhao, Yeshu Mu, Wen Luo, Zhiyong Tian. Synthesis of Naphthalimide Derivatives as Cholinesterase Inhibitors with Aggregation Induced Emission Properties[J]. Chinese Journal of Organic Chemistry, 2022, 42(3): 819-829.

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图/表 12

图1. 多奈哌齐和萘酰亚胺衍生物的结构式

Figure 1. Chemical structures of donepezil and naphthalimide derivatives

图式1. 目标化合物的合成

Scheme 1. Synthesis of the target compounds Reagents and conditions: (a) 1-Boc-4-(aminomethyl)piperidine, EtOH, reflux, 5 h; (b) HCl, EtOH, r.t.,12 h; (c) Benzyl bromide, CH3CN, 60 ℃, 6 h

Compd.	R¹		IC₅₀/(μmol•L^–1) for AChE^a	IC₅₀/(μmol•L^–1) for BChE^b	SI^c
4a	H		18.43±1.96	>100	<0.18
4b	H		12.28±1.79	>100	<0.12
4c	H		9.15±0.55	>100	<0.09
4d	H		11.19±1.13	>100	<0.11
4e	H		4.66±0.54	>100	<0.05
4f	H		12.98±1.78	>100	<0.13
4g	H		8.86±1.05	>100	<0.09
4h	H		7.43±0.71	>100	<0.07
4i	H		12.72±1.92	>100	<0.13
4j	H		11.57±1.06	>100	<0.12
4k	H		4.43±0.45	>100	<0.04
5a	Br		17.14±1.69	>100	<0.17
5b	Br		14.52±0.75	>100	<0.15
5c	Br		9.58±0.81	41.36±2.23	0.23
5d	Br		14.30±1.30	>100	<0.14
Riv.^d	—	—	7.25±0.34	1.85±0.21	3.92
Dpz.^e	—	—	0.027±0.003	1.155±0.03	0.023

表1. 化合物的体外胆碱酯酶抑制活性

Table 1. In vitro ChEs inhibitory activity of the target compounds

图2. 4k的分子对接模型(A)与1EVE蛋白晶体的3D结构(B)

Figure 2. Docking model of 4k with 1EVE (A) and 3D model of 1EVE (B)

图3. 化合物4k与TcAChE的酶动力学曲线

Figure 3. Lineweaver-Burk plots for compound 4k with TcAChE

图4. 化合物4k (20 µmol/L)在不同溶剂中的紫外(A)和荧光光谱(B)

Figure 4. Absorption (A) and FL spectra (B, λex=340 nm, slit: 2.5/5 nm) of 4k (20 µmol/L) in different solvents

图5. 化合物4k (20 µmol/L)在四氢呋喃/水混合液中的紫外(A)和荧光光谱(B)

Figure 5. Absorption (A) and FL spectra (B, λex=340 nm, slit: 2.5/5 nm) of 4k (20 µmol/L) in THF/water mixtures

图6. 化合物4k (20 µmol/L)的荧光强度(394 nm)随含水量的变化图

Figure 6. Changes of FL peak intensities at 394 nm vs the water fraction in the THF/water mixtures Inset: FL photographs under the illumination of a UV lamp (365 nm)

图7. 化合物4k (20 µmol/L)在THF/水混合液中的丁达尔现象(水的比例: 0%, 20%, 40%, 60%, 80%, 100%)

Figure 7. Tyndall effect of 4k (20 μmol/L) in different fraction THF/water mixtures (fw: 0%, 20%, 40%, 60%, 80%, 100%)

图8. 不同浓度的4k THF溶液在紫外灯下(365 nm)的照片

Figure 8. Photograph of different concentrations of 4k in THF under UV lamp (365 nm) Left to right: 1 µmol/L, 10 µmol/L, 100 µmol/L, 1 mmol/L, 10 mmol/L, 100 mmol/L, 125 mmol/L

图9. 化合物4k(20 µmol/L)在甲醇/甘油混合液中的紫外(A)和荧光光谱(B)

Figure 9. Absorption (A) and FL spectra (B, λex=340 nm, slit: 2.5/5 nm) of 4k (20 µmol/L) in MeOH/glycerin mixtures

图10. 化合物4k对SH-SY5Y和PC12细胞株生存能力的影响

Figure 10. Effect of compound 4k on viability of SH-SY5Y and PC12 cell lines

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