Procaspase-3 Activator Of The Design, Synthesis And Biological Activity Evaluation

Caspase-3 of caspase family plays the executant's role in the PCD. Caspase-3 is biologically synthesized as procaspase-3 that is inactivated. Only procaspase-3 is activated and converted to caspase-3, it can work. But the transformation may be destroyed in the abnormal cells, so in most of cancer cells, the level of procaspase-3 is higher than the normal cells'. We can conclude that the activator of procaspase-3 is hoping to become the antitumor drug. Base on this theory, Hergenrother find the PAC-1 (procaspase-3 activating compound-1) by high-flux screen in August 2006. PAC-1 is the first small molecular known to directly activate procaspase-3 to caspase-3. It is possible that the piperazine nitrogens in PAC-1 are positively charged at physiological pH, and may directly interact with the triaspartic acid safety catch, thereby inducing the autoactivation of procaspase-3. This compound has distinguished inhibit activity to many cancer cells in vitro. It is possible to be a low-toxic and high-performance antitumor drug.Our work is to modify the structure of PAC-1, design and synthesis the new compounds, and wish to get compound that has better or the same activity as PAC-1. Hergenrother's group made the interrelated patent public in December 2006. Base on the structure-activity relationship in the patent, we designed three types of compounds. Consulting with the synthesis rout of original reference, we synthesized 32 compounds, the structure were evaluated by NMR and MS.Pharmacological studies shows that these 32 compounds have distinguished inhibit activity to HL-60 cells in vitro, and the range of IC₅₀ value is from 0.25 to 3.63μM. Almost compounds' activity is better than PAC-l(IC5o=1.92μM). Base on the result of inhibit activity, we discuss the structure-activity relationship of the compounds, and conclude some new structure-activity relationships that are significance to make the further study. We tested the cytotoxicity of the new compounds to the normal cells. The result shows that some compounds have selectivity to the tumor cells. These compounds have potential to be antitumor drugs.