Design, synthesis and antitumor activity of novel 4-oxobutanamide derivatives

• Published in: Bioorganic & medicinal chemistry letters 2024-11, Vol.113, p.129978, Article 129978
• Main Authors: Wu, Caiju, He, Jingliang, Li, Hanxue, Zhang, Siyi, Wang, Siqi, Dong, Xue, Yan, Lili, Wang, Ruiying, Chen, Jiayin, Liu, Zhiyu, Zhang, Luyao, Jiang, Zirui, Wang, Xiaoshuo, Gu, Yifei, Ji, Jing
• Format: Article
• Language: English
• Subjects: 4-oxobutanamide derivatives; Antiproliferative ability; Antitumor drugs
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129978

[Display omitted] •Novel 4-oxobutanamide derivatives were designed by molecular hybridization strategy and synthesized.•Compound DN4 displayed potent inhibition of A498 cells, with an IC50 value of 1.94 µM.•Compound DN4 inhibited the cloning, invasion and adhesion of A498 cells.•Compound DN4 showed efficient anti-tumor effects in the xenograft model of A498 cells.•Compound DN4 exhibited the physicochemical properties and toxic properties of candidate drugs. To find highly effective and low-toxicity antitumor drugs to overcome the challenge of cancer, we designed and synthesized a series of novel 4-oxobutanamide derivatives using the principle of molecular hybridization and tested the antiproliferative ability of the title compounds against human cervical carcinoma cells (HeLa), human breast carcinoma cells (MDA-MB-231) and human kidney carcinoma cells (A498). Among them, N1-(4-methoxybenzyl)-N4-(4-methoxyphenyl)-N1-(3,4,5-trimethoxyphenyl) succinimide DN4 (IC50 = 1.94 µM) showed the best proliferation activity on A498, superior to the positive control paclitaxel (IC50 = 8.81 µM) and colchicine (IC50 = 7.17 µM). Compound DN4 not only inhibited the proliferation, adhesion and invasion of A498, but also inhibited angiogenesis and tumor growth in a dose-dependent manner in the xenograft model of A498 cells. In addition, we also predicted the physicochemical properties and toxicity (ADMET) of these derivatives, and the results suggested that these derivatives may have the absorption, distribution, metabolism, excretion, and toxicity properties of drug candidates. Thus, compound DN4 may be a promising drug candidate for the treatment of cancer.