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Procaspase-3 activator design , synthesis and biological activity evaluation

Author: YangChunLing
Tutor: LiSong
School: Shenyang Pharmaceutical University
Course: Medicinal Chemistry
Keywords: Apoptosis procaspase-3 Activator
CLC: R91
Type: Master's thesis
Year: 2008
Downloads: 96
Quote: 1
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Abstract

Caspase-3 is a cell apoptosis may play important cutting enzymes eventually executed, it procaspase-3 in the form of a low activity zymogen synthesized. Can function only when procaspase-3 is activated, the transformation mechanism diseased cells may be destroyed, so procaspase-3 levels found in most cancer cells than in normal cells. procaspase-3 of the activator is likely to be anti-tumor drugs. Based on this theory, in August 2006, Hergenrother found by high-throughput screening of PAC-1 (procaspase-3 activating compound-1). PAC-1 is the first direct role in procaspase-3 small molecule drugs. PAC-1 on the piperazine ring at physiological pH values ??were positively charged and can be combined with the safety buckle of procaspase-3 - three aspartic, resulting in its automatic activation a IC ₅₀ value of 0.92μM. PAC-1 compounds have a significant inhibitory activity of a variety of tumor cells, is expected to become the low toxicity of anticancer drugs. The work of this dissertation is to transform the structure of the PAC-1, the design and synthesis of new compounds to activity comparable to or better than the PAC-1 compounds. In December of the same year, the the Hergenrother research team disclosed patent research, according to the results of the biological evaluation of patent, summed up some of the structure-activity relationships. According to preliminary structure-activity relationships, we have designed three major classes of compounds. Due to the original reported synthetic route to high yield, raw materials readily available, easy to operate, we will refer to the original route, the corresponding changes of the individual steps, synthesized into three categories, the 32 target compounds, the structure through ^{1 H-NMR, MS confirmatory structure. Determination of the target compounds of HL-60 tumor cells in vitro inhibitory activity. The results show that 30 compounds have significant inhibitory activity, IC ₅₀ value of the range was 0.25 to 3.63μM, most of the activity of the compounds is higher than the lead compound PAC-1 (IC _{50 = 1.92μM). Based on the inhibitory activity results, a preliminary discussion of the relationship between the structure of the compound with anti-tumor cell activity, and get a few new structure-activity relationship of great significance for further research work. Also determined the cytotoxic evaluation of the compounds of the normal cells, and results showed that there are some compounds of the normal cells IC ₅₀ value is higher than the PAC-1 on tumor cells, indicating that these compounds have better selectivity, activity and selectivity are higher than that of the PAC-1, these compounds have the potential for further development.}}

Procaspase-3 activator design , synthesis and biological activity evaluation

Abstract

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