El-Sayed Ebead Eman, Aboelnaga Asmaa, Nassar Ekhlass, Naguib Mohamed M, Ismail Mahmoud F
Chemistry Department, Faculty of Women for Arts, Science and Education, Ain Shams University Heliopolis Egypt.
Department of Biochemistry, Faculty of Science, Ain Shams University 11566 Abbassia Cairo Egypt.
RSC Adv. 2023 Oct 10;13(42):29749-29767. doi: 10.1039/d3ra05799b. eCollection 2023 Oct 4.
A series of arylidenes derivatives was synthesized under ultrasonic methodology Knoevenagel condensation reaction of cyanoacetohydrazide derivative with the appropriate aldehydes and/or ketone. The anticancer properties of the newly synthesized compounds were tested against four different human cancer cell lines (HEPG-2, MCF-7, HCT-116, and PC-3); compounds 5d and 6 demonstrated the greatest anticancer activity against all cancer cell lines. The MLR technique was used to create the QSAR model using five molecular descriptors (AATS6p, AATS7p, AATS8p, AATS0i, and SpMax4_Bhv). The examination of the constructed QSAR model equations revealed that the selected descriptors influence the tested compound's anti-proliferative activity. The descriptors identified in this work by QSAR models can be utilized to predict the anticancer activity levels of novel arylidenes derivatives. This will allow for significant cost savings in the drug development process and synthesis at pharmaceutical chemistry laboratories. According to the physicochemical properties, the results revealed that all of these compounds comply with Lipinski's Rule of Five, indicating that they may have high permeability across biological membranes and reveal drug-relevant properties. The Swiss Target Prediction webtool was used to assess the probable cellular mechanism for the promising candidate compounds (5d and 6), and the results revealed that adenosine A1 receptor (ADORA1) was a common target for both compounds. ADORA1 is involved in the regulation of cell metabolism and gene transcription. ADORA1 overexpression has been linked to a variety of cancers, including colon cancer, breast cancer, leukemia, and melanoma. The docking study of tested compounds 5d and 6 revealed that their binding scores to ADORA1 are more favorable than those of its co-crystalized ligand (DU172, selective ADORA1 antagonist) and adenosine (ADORA1 endogenous agonist), implying that they may hold great promise as an anti-cancer therapy. Density functional theory (DFT) with a (B3LYP)/6-31G (d,p) basis set was used to calculate the physicochemical parameters of these compounds. The theoretical data from the DFT computation was found to be in good agreement with the experimental values.
在超声方法下，通过氰基乙酰肼衍生物与适当的醛和/或酮的Knoevenagel缩合反应合成了一系列亚芳基衍生物。对新合成的化合物针对四种不同的人类癌细胞系（HEPG - 2、MCF - 7、HCT - 116和PC - 3）进行了抗癌性能测试；化合物5d和6对所有癌细胞系表现出最大的抗癌活性。使用MLR技术，利用五个分子描述符（AATS6p、AATS7p、AATS8p、AATS0i和SpMax4_Bhv）创建了QSAR模型。对构建的QSAR模型方程的检验表明，所选描述符影响测试化合物的抗增殖活性。通过QSAR模型在这项工作中确定的描述符可用于预测新型亚芳基衍生物的抗癌活性水平。这将在药物开发过程和药物化学实验室的合成中显著节省成本。根据物理化学性质，结果表明所有这些化合物均符合Lipinski的五规则，表明它们可能具有高跨生物膜渗透性并显示出与药物相关的性质。使用瑞士靶标预测网络工具评估有前景的候选化合物（5d和6）的可能细胞机制，并结果表明腺苷A1受体（ADORA1）是这两种化合物的共同靶标。ADORA1参与细胞代谢和基因转录的调节。ADORA1过表达与多种癌症有关，包括结肠癌、乳腺癌、白血病和黑色素瘤。对测试化合物5d和6的对接研究表明，它们与ADORA1的结合分数比其共结晶配体（DU172，选择性ADORA1拮抗剂）和腺苷（ADORA1内源性激动剂）更有利，这意味着它们作为抗癌疗法可能具有很大的前景。使用具有（B3LYP）/6 - 31G（d,p）基组的密度泛函理论（DFT）来计算这些化合物的物理化学参数。发现DFT计算的理论数据与实验值吻合良好。
