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作为潜在的EGFR/HER2双抑制剂的新型thiazolyl-pyrazoline衍生物:设计,合成,抗癌活性评估和in-silico研究

Mariam M Fakhry¹, Amr A Mattar¹, Marwa Alsulaimany²

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, Egypt.

Molecules (Basel, Switzerland)

|November 14, 2023

概括

新的 thiazolyl-pyrazoline 衍生物通过抑制 EGFR 和 HER2 来表现出强大的抗癌活性. 化合物6a,6b,10a和10b有效地降低了乳腺癌细胞的扩散和诱导的亡.

科学领域:

药用化学医学化学
有机合成有机合成
癌症生物学癌症生物学

背景情况:

表皮生长因子受体 (EGFR) 和人类表皮生长因子受体2 (HER2) 是癌症治疗的关键点.
开发EGFR/HER2的新型双重抑制剂为克服耐药性和提高治疗疗效提供了一个有希望的策略.
提亚和皮拉基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 thiazolyl-pyrazoline衍生物作为EGFR和HER2的潜在双重抑制剂.
为了评估这些衍生物的体外抗癌活性与MCF-7乳腺癌细胞系相比.
调查作用机制,包括细胞循环停止和亡诱导,并执行分子建模和ADMET预测.

主要方法:

从pyrazoline carbothioamides中合成十八种 thiazolyl-pyrazoline衍生物.
在体外抗增殖试验中,使用MCF-7乳腺癌细胞系来确定IC50值.
酶性测试用于评估针对纯化的EGFR和HER2的抑制活性.
细胞周期分析和亡试验 (例如,Annexin V染色) 来阐明作用机制.
分子对接研究,以预测与EGFR和HER2活性部位的结合相互作用.
在 silico ADMET (吸收,分布,新陈代谢,分泌,毒性) 预测.

主要成果:

已经成功合成了18种新的 thiazolyl-pyrazoline 衍生物.
化合物6a,6b,10a和10b对MCF-7细胞表现出强烈的抗增殖活性,IC50值在3.37至5.64μM之间,性能优于lapatinib.
酶分析证实了6a和6b化合物对EGFR (IC50 = 0.0050.024μM) 和HER2 (IC50 = 0.0220.047μM) 的强有力的双抑制.
化合物6a和10a分别诱导了G1和G1/S阶段细胞周期停止,并在MCF-7细胞中促进了细胞亡.
分子建模支持了体外发现,显示了6a和10a与EGFR和HER2中关键氨基酸的有利结合相互作用.

结论:

合成的 thiazolyl-pyrazoline 衍生物代表了一种有前途的新型EGFR/HER2 双重抑制剂.
化合物6a,6b,10a和10b显示出作为乳腺癌治疗的抗癌剂的显著潜力.
这些化合物的进一步临床前开发是有必要的,因为它们具有强大的体外疗效,作用机制和有利的预测药物动力学特性.

关键词:

欧洲农业基金会 (EGFR) 是一个.在HER2中,HER2是HER2.这是一种抗癌药物.灭症 (apoptosis) 是一种死亡的过程.细胞循环中的细胞循环.这是一种 thiazolyl-pyrazoline.

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