Shaalan Mai M, Osman Essam Eldin A, Attia Yasmeen M, Hammam Olfat A, George Riham F, Naguib Bassem H
Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo-Suez Desert Road, Cairo 11837, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
ACS Omega. 2024 Aug 19;9(35):37310-37329. doi: 10.1021/acsomega.4c05250. eCollection 2024 Sep 3.
A series of novel 3,6-disubstituted pyridazine derivatives were designed, synthesized, and biologically evaluated as preclinical anticancer candidates. Compound exhibited the highest growth inhibition against most of the NCI-60 cancer cell lines. The anticancer activity of was subsequently investigated at two dose levels using the Ehrlich ascites carcinoma solid tumor animal model, where a reduction in the mean tumor volume allied with necrosis induction was reported without any signs of toxicity in the treated groups. Interestingly, compound was capable of downregulating c-jun N-terminal kinase-1 (JNK1) gene expression and curbing the protein levels of its phosphorylated form, in parallel with a reduction in its downstream targets, namely, c-Jun and c-Fos in tumors, along with restoring p53 activity. Furthermore, molecular docking and dynamics simulations were carried out to predict the binding mode of and prove its stability in the JNK1 binding pocket.
设计、合成了一系列新型的3,6-二取代哒嗪衍生物，并作为临床前抗癌候选药物进行了生物学评估。化合物对大多数NCI-60癌细胞系表现出最高的生长抑制作用。随后，使用艾氏腹水癌实体瘤动物模型在两个剂量水平上研究了该化合物的抗癌活性，结果显示治疗组的平均肿瘤体积减小且伴有坏死诱导，且无任何毒性迹象。有趣的是，该化合物能够下调c-jun氨基末端激酶-1（JNK1）基因表达并抑制其磷酸化形式的蛋白质水平，同时降低其下游靶点，即肿瘤中的c-Jun和c-Fos水平，并恢复p53活性。此外，进行了分子对接和动力学模拟以预测该化合物的结合模式并证明其在JNK1结合口袋中的稳定性。
