Synthesis and anticancer properties of celastrol derivatives involved in the inhibition of VEGF

In this study, fourteen celastrol derivatives (1–14) were synthesised by esterification of celastrol at the 29th position. The in vitro anticancer activity of them was determined by the MTT assay. All the synthetic compounds showed significant antiproliferative activity against six cancer cells, with IC50 of the submicron molar level. The most promising compound (2) blocked the cell cycle in the G2 phase and inhibited the expression of VEGF and MMP-9 in gastric cancer cell line MGC-803. In flow cytometry analysis, compound 2 induced cancer cell apoptosis in a dose-dependent manner. In the mouse tumour xenograft model, compound 2 showed significant anti-tumour activity in vivo at the dosage of 2.5 mg/kg and 1 mg/kg, with a higher inhibition rate than 5-FU (10 mg/kg). What's more, the anticancer mechanism involved in the inhibition of VEGF and the toxicity evaluation of compound 2 were also investigated.