V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, 02094 Kiev, Ukraine.
Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gandhinagar 382055, India.
Molecules. 2022 Jul 20;27(14):4637. doi: 10.3390/molecules27144637.
Despite extensive studies and the great variety of existing anticancer agents, cancer treatment remains an aggravating and challenging problem. Therefore, the development of novel anticancer drugs with a better therapeutic profile and fewer side effects to combat this persistent disease is still necessary. In this study, we report a novel series of benzothiazole and chromone derivatives that were synthesized and evaluated for their anticancer activity as an inhibitor of ATR kinase, a master regulator of the DDR pathway. The cell viability of a set of 25 compounds was performed using MTT assay in HCT116 and HeLa cell lines, involving 72 h incubation of the compounds at a final concentration of 10 µM. Cells incubated with compounds , and were found to show viability ≤50%, and were taken forward for dose-response studies. Among the tested compounds, three of them (, and ) showed higher potency, with compound exhibiting the best IC values in both the cell lines. Compounds and were found to be equally cytotoxic towards both the cell lines, namely, HCT116 and HeLa, while compound showed better cytotoxicity towards HeLa cell line. For these three compounds, an immunoblot assay was carried out in order to analyze the inhibition of phosphorylation of Chk1 at Ser 317 in HeLa and HCT116 cells. Compound showed inhibition of pChk1 at Ser 317 in HeLa cells at a concentration of 3.995 µM. Further analysis for Chk1 and pChk1 expression was carried out in Hela cells by treatment against all the three compounds at a range of concentrations of 2, 5 and 10 µM, wherein compound showed Chk1 inhibition at 2 and 5 µM, while pChk1 expression was observed for compound at a concentration of 5 µM. To support the results, the binding interactions of the compounds with the ATR kinase domain was studied through molecular docking, wherein compounds , and showed binding interactions similar to those of Torin2, a known mTOR/ATR inhibitor. Further studies on this set of molecules is in progress for their specificity towards the ATR pathway.
尽管进行了广泛的研究和存在大量现有的抗癌药物，癌症治疗仍然是一个加剧和具有挑战性的问题。因此，开发具有更好治疗谱和更少副作用的新型抗癌药物来对抗这种持续存在的疾病仍然是必要的。在这项研究中，我们报告了一系列新的苯并噻唑和色酮衍生物，这些衍生物被合成并作为 ATR 激酶的抑制剂进行评估，ATR 激酶是 DDR 途径的主要调节剂。使用 MTT 测定法在 HCT116 和 HeLa 细胞系中进行了一组 25 种化合物的细胞活力测定，其中将化合物在最终浓度为 10 μM 下孵育 72 小时。发现用化合物 、 和 孵育的细胞的活力≤50%，并进行了剂量反应研究。在所测试的化合物中，其中三种（ 、 和 ）表现出更高的效力，化合物 在两种细胞系中均表现出最佳的 IC 值。发现化合物 和 对两种细胞系（即 HCT116 和 HeLa）同样具有细胞毒性，而化合物 对 HeLa 细胞系表现出更好的细胞毒性。对于这三种化合物，进行了免疫印迹分析，以分析 HeLa 和 HCT116 细胞中 Chk1 在 Ser 317 处磷酸化的抑制。化合物 在 HeLa 细胞中以 3.995 μM 的浓度显示出对 pChk1 的抑制。在 HeLa 细胞中通过用三种化合物在 2、5 和 10 μM 的一系列浓度处理进一步分析 Chk1 和 pChk1 的表达，其中化合物 在 2 和 5 μM 时显示出 Chk1 抑制，而在 5 μM 时观察到化合物 的 pChk1 表达。为了支持这些结果，通过分子对接研究了化合物与 ATR 激酶结构域的结合相互作用，其中化合物 、 和 表现出与已知的 mTOR/ATR 抑制剂 Torin2 相似的结合相互作用。正在对这组分子进行进一步的研究，以了解它们对 ATR 途径的特异性。
