甲基-/特洛克斯-胺基:合成,西格玛-1,HDAC-6和抗氧化活性
Rafael Flores1, Shoaib Iqbal1, Donald Sikazwe1
1Pharmaceutical Sciences Department, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, TX 78209, USA.
International journal of molecular sciences
|October 28, 2023
概括
研究人员开发了针对阿尔茨海默病 (AD) 的新型小分子,这些小分子针对sigma-1,HDAC-6和氧化应激. 化合物8显示承诺作为未来药物开发的领头羊.
科学领域:
- 药用化学 医学化学
- 神经科学是一个神经科学.
- 药物发现 药物发现 药物发现
背景情况:
- 阿尔茨海默氏症 (AD) 病原发生涉及复杂的机制,包括西格玛-1 (σ-1) 受体功能障碍,IIb类组胺脱乙酶-6 (HDAC-6) 活性和氧化应激 (OS).
- 当前的治疗策略往往针对单一的途径,突出显示了多机制方法的需要.
研究的目的:
- 合成能够同时准 σ-1,HDAC-6 和 OS 的新型单个小分子.
- 评估这些化合物作为阿尔茨海默病治疗的多机制剂的潜力.
主要方法:
- 合成20种胺基衍生物,包括基于酸盐和特洛克斯的化合物.
- 使用乙烯化物与氨基或通过HATU或CDI合剂与氨基进行酸凝结的化反应.
- 合成化合物对 σ-1 亲和力,HDAC-6 抑制和抗氧化能力的部分评估.
主要成果:
- 成功合成了20个胺化合物目标.
- 化合物8显示出显著的σ-1亲和力 (Ki=2.1μM),强大的HDAC-6抑制 (IC50=17nM) 和显著的抗氧化活性 (1.92个Trolox等效).
- 化合物8被确定为进一步结构-活性关系 (SAR) 研究的有希望的头.
结论:
- 开发的氨基酸代表了AD.的多机制小分子的新型类别.
- 化合物8显示了针对关键AD相关途径的理想配置,需要进一步调查和优化.
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