Department of Chemistry, Faculty of Science, Ain Shams University, Abbassiya 11566, Cairo, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt.
Bioorg Chem. 2024 Jan;142:106936. doi: 10.1016/j.bioorg.2023.106936. Epub 2023 Oct 24.
A novel series of ethylidenehydrazineylthiazol-4(5H)-ones were synthesized using various eco-friendly one-pot multicomponent synthetic techniques. The anticancer activity of compounds (4a-m) was tested against 11 cancer cell lines. While the IC of all compounds was evaluated against the most sensitive cell lines (MDA-MB-468 and FaDu). Our SAR study pinpointed that compound 4a, having a phenyl substituent, exhibited a significant growth inhibition % against all cancer cell lines. The frontier anticancer candidates against the MDA-MB-468 were also examined against the wild EGFR (EGFR-WT) and mutant EGFR (EGFR-T790M) receptors. Most of the synthesized compounds exhibited a higher inhibitory potential against EGFR-T790M than the wild type of EGFR. Remarkably, compound 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M with IC values (0.051 and 0.021 µM), respectively. The pro-apoptotic protein markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9) and the anti-apoptotic key marker (BCL-2) were also measured to propose a mechanism of action for the compound 4k as an apoptotic inducer for MDA-MB-468. Investigation of the cell cycle arrest potential of compound 4k was also conducted on MDA-MB-468 cancer cells. We also evaluated the inhibitory activities of compounds (4a-m) against both EGFR-WT and EGFR-T790M using two different molecular docking processes.
使用各种环保的一锅多组分合成技术，合成了一系列新型的亚乙基肼基噻唑-4(5H)-酮。对化合物（4a-m）进行了抗 11 种癌细胞系的抗癌活性测试。虽然所有化合物的 IC 都针对最敏感的细胞系（MDA-MB-468 和 FaDu）进行了评估。我们的 SAR 研究指出，具有苯基取代基的化合物 4a 对所有癌细胞系表现出显著的生长抑制%。还对针对 MDA-MB-468 的前线抗癌候选药物进行了针对野生型 EGFR（EGFR-WT）和突变型 EGFR（EGFR-T790M）受体的检查。大多数合成化合物对 EGFR-T790M 的抑制潜力均高于野生型 EGFR。值得注意的是，化合物 4k 对 EGFR-WT 和 EGFR-T790M 的抑制活性最高，IC 值分别为 0.051 和 0.021µM。还测量了促凋亡蛋白标志物（p53、BAX、caspase 3、caspase 6、caspase 8 和 caspase 9）和抗凋亡关键标志物（BCL-2），以提出化合物 4k 作为 MDA-MB-468 细胞凋亡诱导剂的作用机制。还对化合物 4k 在 MDA-MB-468 癌细胞中对细胞周期阻滞潜力进行了研究。我们还使用两种不同的分子对接过程评估了化合物（4a-m）对 EGFR-WT 和 EGFR-T790M 的抑制活性。
