Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh P.O. Box 84428, Saudi Arabia.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo P.O. Box 11795, Egypt.
Molecules. 2021 Dec 26;27(1):123. doi: 10.3390/molecules27010123.
This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds and resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound exhibited the highest inhibitory activity against FLT3.
这项工作描述了新设计的噻吩和噻吩并[2,3-d]嘧啶衍生物的合成及其对激酶酶的抗癌活性，以及它们在癌细胞中激活自噬和凋亡细胞死亡的潜力。设计的化合物被扫描其对激酶的亲和力。结果令人鼓舞，亲和力范围从 46.7%到 13.3%。进行了分子对接研究，然后筛选化合物的抗增殖作用。有趣的是，化合物 和 对 MCF-7 和 HepG-2 的细胞毒性作用高于参考标准。评估了这些化合物对 HT-29 和 HepG-2 细胞诱导凋亡和/或坏死的作用。与未经处理的对照 HT-29 细胞相比，三种化合物诱导了明显的早期凋亡，与未经处理的 HepG-2 细胞相比，四种衍生物更为显著。我们进一步用流式细胞术研究了四种化合物对 HT-29、HepG-2 和 MCF-7 细胞自噬过程的影响。与凋亡结果相似，化合物 在所有化合物中表现出最高的自噬诱导作用。评估了合成化合物对激酶的潜在抑制活性。筛选出的化合物表现出 41.4%至 83.5%的抑制活性。对记录到显著抑制作用的化合物进行了进一步研究，以确定其对特定的 FLT3 激酶的抑制活性。值得注意的是，化合物 对 FLT3 表现出最高的抑制活性。
