新型吡啶并[2,3-d]嘧啶-4(3H)-酮衍生物的设计、合成及作为潜在的 EGFRWT 和 EGFRT790M 抑制剂和凋亡诱导剂的抗癌活性评价。

Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers.

机构信息

Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.

Pharmacognosy Department, National Research Centre, Dokki, Cairo, Egypt.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1053-1076. doi: 10.1080/14756366.2022.2062752.

A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 μM. The highest active derivatives ( and ) were selected for IC screening. Compounds and showed the highest cytotoxic activities and were further investigated for wild EGFR and mutant EGFR inhibitory activities. Compound showed the highest inhibitory activities against EGFR and EGFR with IC values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFR and EGFR.

设计并合成了一系列具有 EGFR 抑制剂基本药效团特征的新型吡啶并[2,3-d]嘧啶-4(3H)-酮衍生物。在 100μM 的剂量下，对这些化合物进行了针对 A-549、PC-3、HCT-116 和 MCF-7 细胞系的细胞活力筛选。选择最高活性的衍生物（和）进行 IC 筛选。化合物和表现出最高的细胞毒性活性，并进一步研究了其对野生型 EGFR 和突变型 EGFR 的抑制活性。化合物对 EGFR 和 EGFR 的抑制活性最高，IC 值分别为 0.099 和 0.123μM。此外，它将细胞周期阻滞在 G1 期前期，并在 PC-3 细胞中诱导显著的凋亡作用。此外，化合物在 PC-3 细胞中诱导 caspase-3 水平增加了 5.3 倍。最后，进行了对接研究，以检查合成化合物与 EGFR 和 EGFR 的结合模式。