Antitumor evaluation of novel phenothiazine derivatives that inhibit migration and tubulin polymerization against gastric cancer MGC-803 cells.

Two novel series of 1,2,3-triazole-phenothiazine hybrids and dithiocarbamate-phenothiazine hybrids were designed and synthesized by molecular hybridization strategy. Their antiproliferative activity against three gastric cancer cell lines (MKN28, MGC-803 and MKN45) were evaluated. Among them, hybrid 13h displayed the most potent inhibitory activity against gastric cancer MGC-803 cells with an IC50 value of 1.2 μM. Hybrid 13h could inhibit migration by regulating the expression level of N-cadherin, E-cadherin, Vimentin, and actived-MMP2. Furthermore, it could regulate wnt/β-catenin signaling pathway on MGC-803 cells in a concentration-dependent manner by decreasing the expression level of Wnt5α, β-catenin and TCF4. From the tubulin polymerization assay results in vitro, hybrid 13h was a novel tubulin polymerization inhibitor. By oral administration assay, compound 13h could effectively inhibit MGC-803 xenograft tumor growth in vivo without obvious side effects. In summary, compound 13h might be an orally active antitumor agent with clinical applications to the treatment of gastric cancer. Graphical abstract Antitumor mechanisms of novel phenothiazine derivative.