基于雌激素的衍生物稳定了c-MYC和c-KIT的G-四重复DNA结构
Satendra Kumar1, Annyesha Biswas1, Sruthi Sudhakar1
1Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
ACS omega
|February 19, 2024
概括
新的雌激素衍生物稳定G-四重复合体 (G4s),显示出对癌症治疗的潜力. 基于雌激素的化合物如Est-3向特定的G4结构,影响基因表达和细胞生长.
科学领域:
- 药用化学 医学化学
- 分子生物学分子生物学
- 基因组学就是基因组学.
背景情况:
- 富G的序列形成G-四复合体 (G4s),是DNA复制,转录和翻译的关键调节者.
- 用小分子准G4结构提供了一个调节其生物功能的策略.
研究的目的:
- 合成和描述新的以雌激素为基础的衍生物作为G4稳定剂.
- 评估这些配体的G4结合和稳定偏好.
- 评估最有前途的配体的生物活性和作用机制.
主要方法:
- 合成具有非平面核心和阴离子侧链的雌激素衍生物 (Est-1,Est-2,Est-3).
- 循环二元化 (CD) 化试验和聚合酶停止试验以确定G4稳定性.
- 对癌细胞系和基因表达分析 (c-KIT) 的细胞毒性测定.
- 分子建模和动力学模拟以阐明配体-G4相互作用.
主要成果:
- 合成的雌激素衍生物有效地结合和稳定G4结构.
- 配体优先稳定并行c-MYC和c-KIT1 G4s,而不是其他G4s和双重DNA.
- Est-3在癌细胞系中表现出细胞毒性,并在HepG2细胞中降低了c-KIT基因表达的调节.
- 分子建模揭示了与G4 5'-四重奏的配体堆叠相互作用.
结论:
- 非平面支架可以成功地纳入G4连接体设计.
- 以雌激素为基础的衍生物代表了一类具有治疗潜力的有前途的G4稳定剂.
- Est-3显示了特定的G4向和抗癌活性,需要进一步调查.
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