Discovery of novel microtubule inhibitors through screening of natural products and rationale design

• Main Authors: Hsieh, Cheng-Chih, 謝政智
• Other Authors: Chang, Jang-Yang
• Format: Others
• Language: en_US
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/36289022624515747555

博士 === 國防醫學院 === 醫學科學研究所 === 100 === Microtubule is a popular target for anti-cancer drugs. A novel antitubulin compound chamaecypanone C was isolated from the heartwood of Chamaecyparis obtusa var. Formosan. In addition, a series of 4-aroyl- 6,7,8-trimethoxyquinolines antitubulin compounds were synthesized and evaluated for anticancer activity. Chamaecypanone C induces mitotic arrest through binding to the colchicine-binding site of tubulin, thus preventing tubulin polymerization. Cytotoxic activity of Chamaecypanone C in a variety of human tumor cell lines has been ascertained, with IC50 values in nanomolar ranges. Flow cytometric analysis revealed that chamaecypanone C treated human KB cancer cells were arrested in G2-M phases in a time-dependent manner before cell death occurred. Additional studies indicated that the effect of Chamaecypanone C on cell cycle arrest was associated with an increase in cyclin B1 levels and a mobility shift of Cdc2/Cdc25C. The changes in Cdc2 and Cdc25C coincided with the appearance of phosphoepitopes recognized by a marker of mitosis, MPM-2. Interestingly, this compound induced apoptotic cell death through caspase8-Fas/FasL dependent pathway, instead of mitochondria/caspase9 dependent pathway. Notably, several KB-derived multidrug- resistant cancer cell lines overexpressing P-gp170/MDR and MRP were sensitive to Chamaecypanone C. A series of 2-aroyl, 2-aryl-5,6,7-trimethoxyquinolines and 4-aroyl- 6,7,8-trimethoxyquinolines based on CA 4 chemical structure were also synthesized to discover novel microtubule inhibitor in this study, and the lead compound 4-aroylquinoline 11 inhibited the growth of the human cancer cells lines KB, HT-29, and MKN45, as well as three human-resistant cancer cell lines of KB-vin10, KB-S15, and KB-7D, with an IC50 of 217, 327, 239, 246, 213, and 252 nM, respectively. In conclusion, our findings indicate that Chamaecypanone C and 4-aroylquinoline 11 are promising anticancer compounds that have potential for management of various malignancies, particularly for patients with drug resistance. The antitubulin profiles of these two compounds make them interesting compounds for further development.