| Summary: | 碩士 === 中國文化大學 === 應用化學研究所 === 98 === Abstract
Combretastatin A-4 (CA-4), a naturally occurring stilbene, was isolated from Combretum caffrum (African bush willow). CA-4 strongly inhibited the polymerization of tubulin by binding to the colchicine site and showed potent cytotoxicity against a variety of human cancer cell lines including multiple drug resistant cancer cell lines. CA-4 also showed strong anti-vascular activity.
In the previously comparative studies of the combretastatins it appears that the cis orientation of the two aromatic rings plays an important role of cytotoxicity. Therefore, a number of cis-restricted analogues of CA-4 were prepared using 1,2-substituted five memberd heterocycles to avoid decreasing cytotoxic activity.
In this study, we utilized isoxazole ring and pyrazole ring to mimic the cis double bond in CA-4. A series of halogen substituted 4,5-diarylisoxazoles and 4,5-diarylpyrazoles (TYC526, TYC516, TYC506, TYC517, TYC507, TYC518, TYC508, TYC519, TYC509) were prepared and their cytotoxic activity were also evaluated against human cancer cell lines including human cervical epitheloid carcinoma (HeLa), human hepatocellular carcinoma (HepG2), human ovarian adenocarcinoma (OVCAR-3), and human colon carcinoma (HT29). Among the synthesized compounds, TYC526 was the most potent compound in this series with an IC50 value of 3.64–3.96 nM.
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