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

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.