三乙烯衍生物的结构-活性关系及其作为抗癌和抗病毒剂的评估
Nermin S Ahmed1, Heba E El-Nakib1, Marian M Ramsis1
1Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, 11835 Cairo, Egypt.
ACS omega
|July 31, 2023
概括
新的塔莫西芬 (TAM) 类似物与副替代物显示出增强的雌激素活性和强大的抗增殖作用. 一种化合物表现出显著的抗埃博拉病毒活性,而另一种化合物表现出有利的药理动力学.
科学领域:
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
- 病毒学 病毒学
背景情况:
- 塔莫西芬 (TAM) 是一种选择性雌激素受体调节剂 (SERM),用于乳腺癌治疗,但具有子宫癌的风险.
- 理想的SERM将激活骨,心血管和中枢神经系统中的雌激素受体,同时在乳房和子宫中阻止它们.
研究的目的:
- 设计,合成和评估新的刚性和灵活的TAM类似物.
- 调查对甲替代剂对TAM功能活动的影响,并探索潜在的治疗应用,包括抗癌和抗病毒活动.
主要方法:
- 合成新的TAM类似物,包括在C环的Para位置引入替代物.
- 在石川细胞中使用酵母雌激素选试验和性酸酶刺激来评估雌激素活性.
- 对NCI 60细胞系和特定乳腺癌细胞系 (MCF-7,MDA-MB-231) 的抗增殖活性评估.
- 在卵巢切除的老鼠中评估子宫体重.
- 对埃博拉病毒 (EBOV) 的抗病毒活性测试和小鼠的药物动力学分析.
主要成果:
- 与TAM相比,Para-chloro替代剂显著增强了雌激素活性.
- 化合物2B对各种癌症细胞系表现出强烈的抗增殖活性,并且在小鼠中显示出雌激素作用而不增加子宫重量.
- 化合物2F显示出显著的抗EBOV活性,比法维皮拉维尔强200倍,这是首次报告使用雌激素三乙烯作为抗EBOV剂.
- 化合物3D在小鼠中显示出极好的口服药物动力学特性.
结论:
- 在TAM类化合物中阻断C环的对位置对于功能活性至关重要.
- 三乙烯支架的替代模式影响抗病毒活性,特定模式是有害的.
- 这些新型的TAM类似物对包括癌症治疗和抗病毒疗法在内的各种治疗应用具有前景.
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