On the basis of the Michael-addition mechanism of classical proteasome inhibitors, six dipeptide vinyl sulfonamide and dipeptide vinyl sulfonate derivatives were designed and synthesized. Moreover, an efficient method for the synthesis of g-amino vinyl sulfonamides, key intermediates to the target molecules, was developed via the Wittig-Horner reaction of peptide aldehyde with Wittig reagents derived from methanesulfonamides.
Compound YSY-01A, a recently synthesized proteasome inhibitor, has shown potent growth-inhibitory effect on tumor cells in previous researches. However, the mechanism of its inhibitory effects, especially on cell cycle, remains largely unclear. This study aims to evaluate the correlation between cell cycle arrest effect of YSY-01A and its anti-cancer effect, and to probe the possible molecular mechanisms for its effects on human colorectal adenocarcinoma cells HT-29. The results suggested that YSY-01A significantly （P0.05） inhibited cellular proliferation of HT-29 cells in a time and concentration-dependent manner. Furthermore, YSY-01A suppressed the G 2 /M transition of HT-29 cells, whereas the mitotic inhibitor paclitaxel induced M phase accumulation. Further investigation revealed that YSY-01A significantly （P0.05） up-regulated the expression levels of a series of cell cycle related protein, such as cyclin B1, Wee1, p-cdc2 （Tyr15）, p53, p21, and p27. The HT-29 cells only exhibited typical cytotoxic symptom when YSY-01A concentration reached 0.5 μM （P0.05）, which was above the dose we used in the mechanism research. In conclusion, YSY-01A showed remarkable anti-cancer activity on HT-29 cells, and its molecular mechanisms are related to G 2 /M cell cycle transition arrest.
