用于治疗神经退行性疾病的4-氨基吡啶肽衍生物的合成和生物学研究。

IF 1.8 4区 医学 Q3 CLINICAL NEUROLOGY
Lyubomir T Vezenkov, Daniela S Tsekova, Ivanka Kostadinova, Rositsa Mihaylova, Valentin Lozanov, Nikolay G Vassilev, Nikolai Danchev, Ivanka Tsakovska, Ilza Pajeva
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引用次数: 0

摘要

背景:阿尔茨海默病(AD)和多发性硬化症(MS)导致神经退行性过程对全世界数百万人产生负面影响。他们的治疗仍然很困难,而且实际上是不完整的。治疗这些神经退行性疾病最常用的药物之一是4-氨基吡啶。但由于其毒性大,限制了其使用。目的:制备毒性较4-氨基吡啶低的4-氨基吡啶肽衍生物。方法:采用连续缩合法在溶液中合成。用熔点、核磁共振和质谱对新衍生物进行了表征。使用ACD/Percepta v.2020.2.0软件在计算机上研究了重要的ADME(吸收、分布、代谢和排泄)特性。根据标准方案测定小鼠急性毒性。所有新衍生物通过标准的mtt比色法在体外对人(HEP-G2, BV-173)和小鼠(NEURO 2A)肿瘤细胞系进行细胞毒活性测试。采用荧光法测定β-分泌酶抑制活性。结果:获得了含有β-分泌酶抑制肽(Boc-Val-Asn-Leu-Ala-OH)类似物的4-氨基吡啶衍生物。试验化合物的体内毒性高达1500毫克/公斤。对不同来源肿瘤细胞系的细胞毒性筛选显示,所有研究的4-氨基吡啶类似物的生长抑制作用可以忽略不计。结论:合成了新的4-氨基吡啶肽衍生物。急性毒性研究表明,与4-氨基吡啶相比,新化合物的毒性低约150倍,这可能归因于它们的肽片段。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Synthesis and Biological Study of 4-Aminopyridine-Peptide Derivatives Designed for the Treatment of Neurodegenerative Disorders.

Background: Alzheimer's disease (AD) and Multiple sclerosis (MS) lead to neurodegenerative processes negatively affecting millions of people worldwide. Their treatment is still difficult and practically incomplete. One of the most commonly used drugs against these neurodegenerative diseases is 4-aminopyridine. However, its use is confined by the high toxicity.

Objectives: The aim of this work is to obtain new peptide derivatives of 4-aminopyridine with decreased toxicity compared to 4-aminopyridine.

Methods: Synthesis was conducted in solution using a consecutive condensation approach. The new derivatives were characterized by melting points, NMR, and Mass spectra. Important ADME (absorption, distribution, metabolism, and excretion) properties have been studied in silico using ACD/Percepta v.2020.2.0 software. Acute toxicity was determined in mice according to a Standard protocol. All new derivatives were tested in vitro for cytotoxic activity in a panel of human (HEP-G2, BV-173) and murine (NEURO 2A) tumor cell lines via a standard MTT-based colorimetric method. β-secretase inhibitory activity was determined by applying the fluorescent method.

Results: New derivatives of 4-aminopyridine containing analogues of the β-secretase inhibitory peptide (Boc-Val-Asn-Leu-Ala-OH) were obtained. The in vivo toxicity of the tested compounds was found to be as high as 1500 mg/kg. Cell toxicity screening against tumor cell lines of different origins showed negligible growth-inhibitory effects of all investigated 4-aminopyridine analogues.

Conclusion: Synthesis of new peptide derivatives of 4-aminopyridine is reported. Acute toxicity studies revealed a ca. 150 times lower toxicity of the new compounds as compared to 4-aminopyridine that may be ascribed to their peptide fragment.

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来源期刊
Current Alzheimer research
Current Alzheimer research 医学-神经科学
CiteScore
4.00
自引率
4.80%
发文量
64
审稿时长
4-8 weeks
期刊介绍: Current Alzheimer Research publishes peer-reviewed frontier review, research, drug clinical trial studies and letter articles on all areas of Alzheimer’s disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer’s disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer’s disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer''s disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer’s disease. Current Alzheimer Research provides a comprehensive ''bird''s-eye view'' of the current state of Alzheimer''s research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.
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