帕萨马普林A类同类与修改的二硫化键向素脱乙酶:合成和生物评估
Yukun Jiang1, Ya Tang1, Yuxuan Li1
1Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
European journal of medicinal chemistry
|June 8, 2024
概括
海洋代谢物psammaplin A与结合的类似物显示出增强的抗癌活性. 迪塞利尼德化合物P-503和P-116有效抑制HDAC6,诱导细胞亡,并导致细胞循环停止,提供新的治疗潜力.
科学领域:
- 海洋天然产品化学 海洋天然产品化学
- 药品化学 药品化学 是一个
- 癌症生物学 癌症生物学
背景情况:
- 萨玛普林A (PsA) 是一种海洋代谢物,可以抑制组织激素脱乙酶 (HDACs).
- 在PsA中的二硫化键对其生物活性至关重要.
- 探索具有修改二硫化键的类似物可以导致改进的治疗剂.
研究的目的:
- 设计和合成新的PsA类似物,通过用disenide或循环基因替换二硫化键.
- 评估这些类型的HDAC抑制,细胞生长抑制和亡诱导.
- 了解结构-活动关系和作用机制.
主要方法:
- 化学合成PsA类似物,其中包括迪塞化物,循环二硫化物,循环二硫化物和循环二硫化物键.
- 在体外测试以评估HDAC抑制 (特别是HDAC1,2,3和6).
- 基于细胞的测试来测量抗增殖活性,亡诱导和细胞周期进展.
主要成果:
- 与二硫化物类似物相比,合成二硫化物和循环二硫化物类似物显示出更高的抗增殖活性.
- 迪塞利尼德类似物P-503和P-116显著抑制了HDAC6,诱导了亡,并导致G2/M细胞循环停止.
- 循环烯硫化类似物P-111失去了HDAC抑制活性,这表明其抗增殖机制发生了转变.
结论:
- 在PsA类似物中用disenide键替换二硫化键可以增强抗癌性质.
- 特定的disenide类似物显示出强大的HDAC6抑制,并通过细胞亡和细胞循环停止诱导癌细胞死亡.
- 通过修改核心结构,可以改变抗增殖机制,如循环二硫化所见.
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