El Mansouri Az-Eddine, Oubella Ali, Maatallah Mohamed, AitItto Moulay Youssef, Zahouily Mohamed, Morjani Hamid, Lazrek Hassan B
Laboratoire de Materiaux, Catalyse & Valorisation des Ressources Naturelles, URAC 24, Faculte des Sciences et Techniques, Universite Hassan II, Casablanca, Morocco; Laboratory of Biomolecular and Medicinal Chemistry, Department of Chemistry, Faculty of Science Semlalia, BP 2390, Marrakech 40001, Morocco.
Laboratoire de Synthese Organique et de Physico-Chimie Moleculaire, Departement de Chimie, Faculté des Sciences, Semlalia BP 2390, Marrakech 40001, Morocco.
Bioorg Med Chem Lett. 2020 Oct 1;30(19):127438. doi: 10.1016/j.bmcl.2020.127438. Epub 2020 Jul 28.
A new series of uracil analogues-1,2,4-oxadiazole hybrid derivatives were synthesized by a new, simple, and efficient method using for the first time HAP-SOH as an heterogenous acid catalyst for the condensation and cyclization between amidoxime and aldehyde. The new derivatives were characterized by HRMS, FT-IR, H NMR, and C NMR spectroscopy techniques. The synthesized 1,2,4-oxadiazole hybrids were evaluated for their cytotoxic activity in five human cancer cell lines: melanoma (A-375), fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A-549). Data showed that compounds 22 and 23 were potent cytotoxic agents against HT-1080 and MFC-7 cells with IC inferior to 1 µM. The possible mechanism of apoptosis induction by the derivatives was investigated using Annexin V staining, caspase-3/7 activity, mitochondrial membrane potential measurement, and analysis cell cycle progression. The compound 22 induced apoptosis through caspase-3/7 activation and S-phase arrest in HT-1080 and A549 cells. The molecular docking showed that compound 22 activated the caspase-3 by forming a stable protein-ligand complex.
通过一种新的、简单且高效的方法，首次使用HAP-SOH作为非均相酸催化剂，用于促进偕胺肟与醛之间的缩合和环化反应，合成了一系列新的尿嘧啶类似物 - 1,2,4 - 恶二唑杂化衍生物。通过高分辨质谱（HRMS）、傅里叶变换红外光谱（FT-IR）、氢核磁共振（H NMR）和碳核磁共振（C NMR）光谱技术对新衍生物进行了表征。对合成的1,2,4 - 恶二唑杂化物在五种人类癌细胞系中进行了细胞毒性活性评估：黑色素瘤（A - 375）、纤维肉瘤（HT - 1080）、乳腺癌（MCF - 7和MDA - MB - 231）以及肺癌（A - 549）。数据表明，化合物22和23是针对HT - 1080和MFC - 7细胞的强效细胞毒性剂，其半数抑制浓度（IC）低于1 μM。使用膜联蛋白V染色、半胱天冬酶 - 3/7活性测定、线粒体膜电位测量以及细胞周期进程分析等方法，研究了这些衍生物诱导细胞凋亡的可能机制。化合物22通过激活半胱天冬酶 - 3/7并使HT - 1080和A549细胞停滞于S期来诱导细胞凋亡。分子对接显示，化合物22通过形成稳定的蛋白质 - 配体复合物激活了半胱天冬酶 - 3。
