合成和评估聚合物-药物共轭物作为神经退行性疾病的潜在抗氧化剂和胆碱酯酶抑制剂

IF 4.4 2区化学 Q2 MATERIALS SCIENCE, MULTIDISCIPLINARY

ACS Applied Polymer Materials Pub Date : 2024-10-23 DOI:10.1021/acs.chemmater.4c01767

Nuruddin Mahadik, Gemma A. Barron, Paul Kong Thoo Lin, Colin J. Thompson

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引用次数: 0

摘要

与单独使用抗氧化剂和胆碱酯酶（ChE）抑制剂相比，聚合物-药物共轭物（PDCs）可提高潜在抗氧化剂和胆碱酯酶（ChE）抑制剂药物的水溶性和体外活性。将这些潜在药物与水溶性聚合物共轭可提高它们的疗效。香兰素与聚烯丙基胺盐酸盐（NM10 和 NM15）共轭，萘二甲酰亚胺己胺（HEXNAP）与聚丙烯酸（N5 和 N10）共轭。评估了这些新型 PDC 的抗氧化和胆碱酯酶抑制活性，并将其与各自的起始材料进行了比较。此外，还进行了硅学分子建模研究，以探索这些共轭物潜在的胆碱酯酶抑制机制。与香兰素相比，NM15（未调整值和调整值）的体外抗氧化活性明显增强（p ≤ 0.0001）。N5 的调整值与 HEXNAP 相比，体外胆碱酯酶对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的抑制活性明显增强（p ≤ 0.0001）。动力学和分子模型研究表明，N5 是丁酰胆碱酯酶的竞争性抑制剂，并与人乙酰胆碱酯酶和人丁酰胆碱酯酶的活性位点相互作用。NM15 和 N5 分别因其更强的抗氧化性和胆碱酯酶抑制活性而被确定为先导 PDCs。总之，这项工作证明了 PDCs 作为神经退行性疾病治疗方案的潜在用途。

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Synthesis and Evaluation of Polymer-Drug Conjugates as Potential Antioxidants and Cholinesterase Inhibitors for Neurodegenerative Diseases

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Synthesis and Evaluation of Polymer-Drug Conjugates as Potential Antioxidants and Cholinesterase Inhibitors for Neurodegenerative Diseases

Polymer-drug conjugates (PDCs) may offer improved water-solubility and in vitro activity of potential antioxidant and cholinesterase (ChE) inhibitor drugs compared to the drugs alone. Conjugation of these potential drugs to water-soluble polymers could increase their therapeutic efficacy. Vanillin was conjugated to poly(allylamine hydrochloride) (NM10 and NM15) and naphthalimidohexylamine (HEXNAP) was conjugated to poly(acrylic acid) (N5 and N10). The antioxidant and cholinesterase inhibitory activities of these novel PDCs were evaluated and compared with those of their respective starting materials. Additionally, in silico molecular modeling studies were conducted to explore the potential cholinesterase inhibitory mechanisms of these conjugates. NM15 (unadjusted and adjusted value) showed significantly enhanced in vitro antioxidant activity (p ≤ 0.0001) compared to vanillin. The adjusted value of N5 compared to HEXNAP showed significantly enhanced in vitro cholinesterase inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) (p ≤ 0.0001). Kinetic and molecular modeling studies revealed that N5 was a competitive inhibitor of butyrylcholinesterase and interacted with the active sites of human acetylcholinesterase and human butyrylcholinesterase enzymes. NM15 and N5 were identified as lead PDCs based on their enhanced antioxidant and cholinesterase inhibitory activity, respectively. Overall, this work demonstrates the potential use of PDCs as treatment options for neurodegenerative diseases.

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来源期刊

ACS Applied Polymer Materials Multiple-

CiteScore

7.20

自引率

6.00%

发文量

810

期刊介绍： ACS Applied Polymer Materials is an interdisciplinary journal publishing original research covering all aspects of engineering, chemistry, physics, and biology relevant to applications of polymers. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrates fundamental knowledge in the areas of materials, engineering, physics, bioscience, polymer science and chemistry into important polymer applications. The journal is specifically interested in work that addresses relationships among structure, processing, morphology, chemistry, properties, and function as well as work that provide insights into mechanisms critical to the performance of the polymer for applications.