作为 VEGFR-2/AKT 双重抑制剂、细胞凋亡和自噬诱导剂的新型噻吩并[2,3-d]嘧啶类似物的设计、合成和细胞毒性评价。
Design, synthesis and cytotoxic evaluation of new thieno[2,3-d]pyrimidine analogues as VEGFR-2/AKT dual inhibitors, apoptosis and autophagy inducers.
发表日期：2024 Jul 09
作者：
Heba K Abd El-Mawgoud, Asmaa M AboulMagd, Mohamed T M Nemr, Magdy M Hemdan, Aya I Hassaballah, Paula S Farag
来源：
BIOORGANIC CHEMISTRY
摘要：
设计、合成了新型噻吩并[2,3-d]嘧啶类似物，并评估了其对 HepG-2、PC-3 和 MCF-7 癌细胞系的抗增殖活性。此外，使用WI-38正常细胞系来探索所有测试化合物的安全性。化合物 2（IC50=4.29μM HePG-2、10.84μM MCF-7）、6（IC50=14.86μM HePG-2、8.04μM PC-3 和 12.90μM MCF-7）和 17（IC50=9.98μM HePG-2） 、33.66 μM PC-3 和 14.62 μM MCF-7) 是对测试的癌细胞最有希望的候选物，并且具有高选择性的毒性保留正常细胞。进一步的机制评估揭示了有希望的激酶抑制活性，其中化合物 2 分别以 IC50 = 0.161 和 1.06 μM 抑制 VEGFR-2 和 AKT，此外，衍生物 6 分别以 IC50 = 0.487 和 0.364 μM 抑制 VEGFR-2 和 AKT，而化合物 17 的 IC50 值分别为 0.164 和 0.452 μM。此外，化合物2、6导致G1期细胞周期停滞，而候选化合物17使细胞周期停滞在G2/M期。与细胞凋亡结果相似，化合物 17 在评估的衍生物中表现出最高的自噬诱导作用。最后，进行对接研究以评估这些活性衍生物的结合模式。结果表明，VEGFR-2 和 AKT-1（变构袋）晶体结构活性位点内的结合模式与参考配体相同。版权所有 © 2024 Elsevier Inc. 保留所有权利。
Novel thieno[2,3-d]pyrimidine analogues were designed, synthesized and evaluated for anti-proliferative activity against HepG-2, PC-3 and MCF-7 cancer cell lines. In addition, WI-38 normal cell line was used to explore the safety of all the tested compounds. Compounds 2 (IC50 = 4.29 µM HePG-2, 10.84 µM MCF-7), 6 (IC50 = 14.86 μM HePG-2, 8.04 μM PC-3 and 12.90 μM MCF-7) and 17 (IC50 = 9.98 μM HePG-2, 33.66 μM PC-3 and 14.62 μM MCF-7) were the most promising candidates on the tested cancer cells with high selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where compound 2 inhibited VEGFR-2 and AKT at IC50 = 0.161 and 1.06 μM, respectively, Furthermore, derivative 6 inhibited VEGFR-2 and AKT at IC50 = 0.487 and 0.364 μM, respectively, while compound 17 showed IC50 = 0.164 and 0.452 μM, respectively. Moreover, compounds 2, 6 resulted in G1 phase cell cycle arrest while candidate 17 arrest cell cycle at G2/M phase. Similar to the apoptosis results, compound 17 showed the highest autophagic induction among the evaluated derivatives. Finally, docking studies were conducted to assess the binding patterns of these active derivatives. The results showed that the binding patterns inside the active sites of both the VEGFR-2 and AKT-1 (allosteric pocket) crystal structures were identical to the reference ligands.Copyright © 2024 Elsevier Inc. All rights reserved.