Discovery of novel N-benzylarylamide-dithiocarbamate based derivatives as dual inhibitors of tubulin polymerization and LSD1 that inhibit gastric cancers

• Published in: European journal of medicinal chemistry 2023-04, Vol.252, p.115281-115281, Article 115281
• Main Authors: Yuan, Xin-Ying, Song, Chun-Hong, Liu, Xiu-Juan, Wang, Xiao, Jia, Mei-Qi, Wang, Wang, Liu, Wen-Bo, Fu, Xiang-Jing, Jin, Cheng-Yun, Song, Jian, Zhang, Sai-Yang
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activities; Cell Line, Tumor; Cell Proliferation; Dithiocarbamate; Drug Screening Assays, Antitumor; Dual inhibitor; Histone Demethylases - metabolism; Humans; LSD1; Molecular Docking Simulation; N-benzylarylamide; Polymerization; Stomach Neoplasms - drug therapy; Structure-Activity Relationship; Tubulin; Tubulin - metabolism; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115281

In this work, N-benzylarylamide-dithiocarbamate based derivatives were designed, synthesized, and their biological activities as anticancer agents were explored. Some of the 33 target compounds displayed significant antiproliferative activities with IC50 values at the double-digit nanomolar level. The representative compound I-25 (also named MY-943) not only showed the most effective inhibitory effects on three selected cancer cells MGC-803 (IC50 = 0.017 μM), HCT-116 (IC50 = 0.044 μM) and KYSE450 (IC50 = 0.030 μM), but also exhibited low nanomolar IC50 values from 0.019 to 0.253 μM against the other 11 cancer cells. Compound I-25 (MY-943) effectively inhibited tubulin polymerization and suppressed LSD1 at the enzymatic levels. Compound I-25 (MY-943) could act on the colchicine binding site of β-tubulin, thus disrupting the construction of cell microtubule network and affecting the mitosis. In addition, compound I-25 (MY-943) could dose-dependently induce the accumulation of H3K4me1/2 (MGC-803 and SGC-7091 cells) and H3K9me2 (SGC-7091 cells). Compound I-25 (MY-943) could induce G2/M phase arrest and cell apoptosis, and suppress migration in MGC-803 and SGC-7901 cells. In addition, compound I-25 (MY-943) significantly modulated the expression of apoptosis- and cycle-related proteins. Furthermore, the binding modes of compound I-25 (MY-943) with tubulin and LSD1 were explored by molecular docking. The results of in vivo anti-gastric cancer assays using in situ tumor models showed that compound I-25 (MY-943) effectively reduced the weight and volume of gastric cancer in vivo without obvious toxicity. All these findings suggested that the N-benzylarylamide-dithiocarbamate based derivative I-25 (MY-943) was an effective dual inhibitor of tubulin polymerization and LSD1 that inhibited gastric cancers. [Display omitted] •Compound MY-943 showed low nanomolar IC50 values of 0.017–0.253 μM against 14 cancer cells.•Compound MY-943 inhibited tubulin polymerization by binding to the colchicine site.•Compound MY-943 suppressed LSD1, and induced the accumulation of H3K4me1/2 and H3K9me2.•Compound MY-943 induced G2/M phase arrest and apoptosis, and suppress migration.•Compound MY-943 effectively reduced the weight and volume of gastric cancer in vivo without obvious toxicity.