Synthesis and Biological Evaluation of Norcantharidin Analogues as Protein Phosphatase Inhibitiors

• Main Authors: Shin-Syuan Fu, 傅士軒
• Other Authors: Jin-Yi Wu
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/79186882335859690416

碩士 === 國立嘉義大學 === 生物藥學研究所 === 97 === Norcantharidin (4,10-Dioxa-tricyclo[5.2.1.02,6]decane-3,5-dione, NCTD), for the improved Cantharidin the human body resulting from urinary tract toxicity, is a kind of chemical synthesis of clinical anti-cancer drugs, for many human cell lines have potential capacity to kill, Including liver cancer, leukemia, bladder cancer, colorectal cancer, prostate cancer, etc. NCTD may be through with the Protein Phosphotase-1, 2A (PP1, PP2A) binding site combination to achieve the inhibition of protein dephosphory lation, in turn rest the cell cycle, and finally led to the effects of apoptosis. In the previous literature that, NCTD A ring C-1', 5' position of functional groups and the B ring access to its activity. Therefore, in this study, we modified by NCTD, synthesis of two series of derivatives: the first series for the B ring for the oxygen atoms, B ring opening, A ring C-1', 5' position in different functional groups to replace; the second series for the B ring nitrogen atom, B ring opening, A ring C-1', 5' position in different functional groups to replace. In these compounds, we found the first series A ring will not receive functional groups, C-5' position then functional group with the second series of B ring opening inhibition PP1, 2A with good choice of specificity. Compounds O1, O6, N8, N12, N13 for PP1 inhibitory concentration IC50 = 1.9, 9.3, 6.8, 6.9, 4.1 μM, respectively, for PP2A inhibitory concentration IC50 = 0.8, 0.7, 2.1, 6.6, 3.7 μM, respectively, has a strong inhibitory effect. Compounds O3, N12 for PP2B inhibitory concentration IC50 = 9.1, 11.5 μM, with good inhibitory effect, it is worth further study and discussion. In this study, we selected compounds O1, O6, and N13 on human hepatoma cell line HepG2 (IC50 = 42.6, 61.6, 76.1 μM), human bladder cancer cell line BFTC905 (IC50 = 25.9, 36.6, 56.2 μM) for toxicity strong drug, N13 has the potential of which can be used as anti-cancer drugs in the future development of the new anti-cancer drug.