新型quinazolin-2-yl 1,2,3-triazole混合物作为有前途的多目标抗癌剂:设计,合成和分子对接研究
Noura F M El Hamaky1, Abdelrahman Hamdi1, Waleed A Bayoumi1
1Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Bioorganic chemistry
|May 15, 2024
概括
新的quinazoline-1,2,3-triazole混合物显示出强大的抗癌活性. 这些多位抑制剂有效向EGFR,VEGFR-2和Topo II,在癌症研究中显示出前景.
科学领域:
- 药用化学 医学化学
- 分子生物学分子生物学
- 药理学 药理学 是一个学科.
背景情况:
- 癌症仍然是全球死亡的主要原因,需要新的治疗策略.
- 针对包括EGFR,VEGFR-2和Topo II在内的多个途径,提供了一种有希望的方法来克服耐药性并提高疗效.
- 基纳佐林和三醇支架因其多样化的生物活性而闻名,包括抗癌性质.
研究的目的:
- 设计和合成新型的quinazoline-1,2,3-triazole混合物作为多位抑制剂.
- 为了评估这些混合体在体外抗癌潜力,针对各种癌症细胞系.
- 调查对表皮生长因子受体 (EGFR),血管内皮生长因子受体2 (VEGFR-2) 和多酶II (Topo II) 的抑制活性.
主要方法:
- 合成基纳-1,2,3-二醇杂交物 (化合物14a-r).
- 使用MTT测定对HeLa,HePG-2,MCF-7和HCT-116癌细胞系和WI-38正常细胞进行抗癌活性评估.
- 对EGFR,VEGFR-2和Topo II的酶抑制测定.
- 细胞周期分析和亡诱导研究.
- 分子对接模拟. 分子对接模拟.
主要成果:
- 化合物14a,14d和14k在低微分子范围对癌细胞系表现出显著的细胞毒性,对正常细胞具有良好的选择性.
- 化合物14d显示出适度的EGFR抑制 (IC50 = 0.103μM),良好的VEGFR-2抑制 (IC50 = 0.069μM) 和强大的Topo II抑制 (IC50 = 19.74μM).
- 化合物14k和14a也表现出强烈的Topo II抑制活性.
- 化合物14d诱导了HeLa细胞中的G2/M细胞周期停止 (17.53%) 和细胞亡 (44.08%).
- 分子对接研究证实了与目标酶的有利结合相互作用.
结论:
- 合成的quinazoline-1,2,3-triazole混合物代表了一类有前途的多向抗癌药物.
- 化合物14d是一种强大的Topo II抑制剂,通过细胞循环停止和亡诱导表现出显著的抗癌作用.
- 这些杂交物需要进一步研究,作为癌症治疗的潜在治疗候选者.
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