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

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 I25 (also named MY-943) not only showed the most effective inhibitory effects on three selected cancer cells MGC-803 (IC50 = 0.017 mu M), HCT-116 (IC50 = 0.044 mu M) and KYSE450 (IC50 = 0.030 mu M), but also exhibited low nanomolar IC50 values from 0.019 to 0.253 mu M 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 (MY943) could act on the colchicine binding site of p-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 SGC7901 cells. In addition, compound I-25 (MY-943) significantly modulated the expression of apoptosis- and cyclerelated 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.

Automated summary

In this study, N-benzylarylamide-dithiocarbamate based derivatives were synthesized and tested for their anticancer activities. Compound I-25 (also known as MY-943) showed potent inhibitory effects against multiple cancer cells, and induced cell cycle arrest, apoptosis, and inhibition of cell migration. The compound effectively inhibited tubulin polymerization and suppressed LSD1 activity. Molecular docking studies revealed the binding modes of compound I-25 with tubulin and LSD1. In vivo experiments demonstrated that compound I-25 effectively reduced the weight and volume of gastric cancer without noticeable toxicity. This study highlights the potential of N-benzylarylamide-dithiocarbamate derivatives as dual inhibitors targeting tubulin polymerization and LSD1 in gastric cancers.