Discovery of 4-(3,5-dimethoxy-4-(((4-methoxyphenethyl)amino)methyl)phenoxy)-N-phenylaniline as a novel c-myc inhibitor against colorectal cancer in vitro and in vivo
- Eur J Med Chem. 2020 Jul 15:198:112336. doi: 10.1016/j.ejmech.2020.112336.
- 1. State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
- 2. College of Chemistry & Environment Protection Engineering, Southwest Minzu University, Chengdu, 610041, China.
- 3. State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
Proto-oncogene c-Myc plays an essential role in the development of colorectal Cancer (CRC), since downregulation of c-Myc inhibits intestinal polyposis, which is the most cardinal pathological change in the development of CRC. Herein, a series of novel phenoxy-N-phenylaniline derivatives were designed and synthesized. The cytotoxicity activities of all the derivatives were measured by MTT assay in different colon Cancer cells, 4-(3,5-dimethoxy-4-(((4-methoxyphenethyl)amino)methyl)phenoxy)-N-phenylaniline (42) was discovered, the lead compound 42 with excellent cytotoxicity activity of IC50 = 0.32 μM, IC50 = 0.51 μM, in HT29 and HCT 15 cells, respectively. Compound 42 had a good inhibitory activity of c-Myc/MAX dimerization and DNA binding. Besides, compound 42 could effectively induce Apoptosis and induced G2/M arrest in low concentration and G0/G1 arrest in high concentration to prevent the proliferation and differentiation in colon Cancer cells. Western blot analysis confirmed the 42 strongly down-regulated expression of c-Myc. Furthermore, during 30 days treatment 42 exhibited excellent efficacy in HT29 tumor xenograft model without causing significant weight loss and toxicity. Consequently, 42 could be a promising drug candidate for CRC therapy.