修改的三醇-基松支架的抗扩散潜力的探索:多目标方法
Alaa M Ali1, Mohamed A Khalaf1,2, Bhoomendra A Bhongade3
1Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Archiv der Pharmazie
|November 10, 2023
概括
新的三醇-化混合物显示出强大的抗癌活性. 化合物18通过向VEGFR-2和c-Met.等关键激酶,有效抑制癌细胞生长,特别是黑色素瘤和乳腺癌.
科学领域:
- 药用化学 医学化学
- 癌症生物学 癌症生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 抗增殖剂对于癌症治疗至关重要.
- 激酶抑制剂代表了一类重要的向性癌症药物.
- 开发新的混合分子为提高效率和选择性提供了机会.
研究的目的:
- 设计和合成新型的三醇-化混合物作为潜在的抗增殖剂.
- 评估这些化合物的疗效与人类癌症细胞系的小组对比.
- 阐明作用机制,重点关注激酶抑制和亡途径.
主要方法:
- 合成三醇-基松混合物.
- 通过国家癌症研究所 (NCI) 对60个癌症细胞系进行查.
- 在体外激酶抑制试验 (VEGFR-2,c-Met,B-Raf等) ),甲基绿色试验用于DNA结合,亡诱导试验,细胞周期分析,分子对接和物理化学性质的评估.
主要成果:
- 化合物16,17和18在白血病细胞系中显示出显著的生长抑制.
- 化合物18表现出广泛的抗增殖活性,对黑色素瘤和乳腺癌细胞系具有高强度,同时在正常细胞中显示出安全性.
- 化合物18强烈抑制了VEGFR-2和c-Met激酶 (IC50值分别为0.055和0.042μM),诱导了细胞亡,并导致G2/M细胞循环停止. 排除了DNA结合的可能性.
- 分子对接支持化合物18与c-Met和VEGFR-2活性位点的结合.
结论:
- 新型的三醇 - 化混合物,特别是18化合物,显示出有前途的广谱抗增殖活性.
- 化合物18通过强大的VEGFR-2和c-Met激酶的抑制作用,导致细胞亡和细胞循环停止.
- 化合物18具有有利的药物相似性特征,需要进一步研究作为潜在的抗癌疗法.
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