Antiproliferative Study Of 1,2,3,4,6-Pentakis[-O-(3,4,5- Trihydroxybenzoyl)]-α,β-D-glucopyranose Analogues

Nowadays, cancer has already become a big health problem all over the world. The number of cancer patients continues to increase every year, the same as mortality rate. Therefore, the anticancer researches attract increasing attention. Finding a promising anticancer drug is an effective method to solve this problem. Tannin is a kind of polyphenols extracted in a large amount of plants. Tannin was found to have a lot of properties, such as antioxidant, antimicrobial and antitumor.1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose(PGG) is an important tannin. As the consequence, we take PGG and its analogues as our anticancer research objects.We synthesis 33 compounds in all including tannic acid, and divide them into 9 different groups according to their structure features. We primarily test these compounds anticancer activity on two colon cancer cells HCT116 and HT29, two lung cancer cells A549 and H1299. According to the primary screen of these compounds, we choose 2 groups and test their IC50 on these 4 different cancer cell lines taking doxorubicin as the positive control. The cytotoxicity studies indicate that the substitutions on aromatic ring has dominant effect on cytotoxicities of the analogues. The co-planner orientation of OH groups on the ring allowed the formation of highly stabilizing intramolecular (O)H...O interactions, which might play a role in the bioactivity via localized satiability effect. Hence, the number of OH groups and their orientation on aromatic ring had a drawstring effect on cytotoxicity. PVG has a strong cytotoxicity on these four cell lines based on the IC50, even stronger than the positive control on H1299 and HT29. As the result, we choose PVG as the represent compound to give a more detailed research on antiproliferative mechanism.At first, we test PVG’s cytotoxicities in different concentrations and at different times on the colon cancer cell HCT116 and lung cancer cell A549. We find that PVG can inhibit HCT116 and A549 in a dose-and time-dependent manner. On the other hand, we discuss if the anticancer activity of PVG has any relationship with ROS mediating cancer cells apoptosis. While the answer is not. In the next step, we test the mechanism of PVG on HCT116 and A549 cell lines by flow cytometry, and we find that PVG arrests colon cancer cell HCT116 and lung cancer cell A549 cell cycle both in G2/M phase in a dose-dependent manner. Then we detect the effect of PVG on the expression of proteins involved cell apoptosis on colon cancer cell line HCT116 and lung cancer cell line A549 by western blotting, including PARP and Hsp90. The result shows that PVG can increase the expression of cleaved PARP and inhibit the expression of Hsp90 dramatically in a dose-manner. Moreover PVG can reduce the expression of EGFR, upstream protein of apoptosis dramatically in a dose-manner. These results all indicate that PVG can induce the apoptosis on HCT116 and A549.In this paper, we take PGG and its analogues as our research object, and do some antiproliferative mechanism research on PVG, the representative compound. In conclusion, we have provided the certain basis and reference for the development of tannic acid and its analogues as antitumor drugs. We hope that our research could provide group designing and incredible thoughts of anti-tumor drug.