Design and Synthesis of 1,4-Dimethylcarbazole and Ellipticine Analogues Containing Benzenesulfonamide Moiety as Potential Anti-cancer Agents

• Main Authors: Hsueh-Yun Lee, 李學耘
• Other Authors: 陳基旺
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/52140611308061909449

博士 === 臺灣大學 === 藥學研究所 === 98 === Abstract An attempt to develop potent agents to arrest cell cycle, E7010 (6) was chosen as the lead compound. Based on conformational restriction approach, to constrain the secondary amine linkage between pyridine and benzene in E7010 was proposed. Accordingly, 1,4-dimethylcarbazole motif was considered to be an essential scaffold. In the result, 18a demonstrated activities against several cancer cell lines, especially for HeLa, HT-29 and Hep3B cancer cell lines with GI50 in the range of 0.02 to 0.07 µM. Besides, carbazolyl sulfonamide 26b also exhibited potent cytotoxic activities. It inhibited A549 cell with GI50 at 0.08 µM. Compounds containing methyl (22a) and ethyl (23a) on sulfonamide nitrogen lead to not only enhance the potency but also to provide better activities against AGS and PC-3 cell lines. Since ellipticine has a common skeleton of 1,4-dimethylcarbazole, to promote the activities of 18a, the 1,4-dimethylcarbazole of 18a was replaced with ellipticine. Therefore, ellipticine derivatives within benzenesulfonamide are developed. According to the initial biological assays, the attachment of benzenesulfonamide to ellipticine reduced the activities. Although ellipticine sulfonamide (30) didn’t demonstrate promising results, the research focus on the C-7 of ellipticine is still interesting. To explore the substituents on this position may provide opportunity to search potent anticancer agents. To improve the total synthesis of ellipticine based on Saxton’s approach, the one-pot synthesis of secondary amine 47 is considered to shorten the reaction time and improve the reaction yield compared to original approach. The long-lasting problematic low yield in the D-ring cyclization of ellipticine (27) by Saxton’s approach was dramatically improved through N-(1,4-dimethylcarbazol-3-ylmethyl)-N-tosylaminoacetaldehyde diethyl acetal (56) with microwave irradiation. The yield of D-ring cyclization of ellipticine was improved to 75%. The overall yield of ellipticne starting from indole was significantly increased by 25-folds. Microwave was also used in the synthesis of 9-bromoellipticine and 9-nitroellipticine. Hence, this new approach is superior to reported methods in yields, reaction time, and it provides efficient access to a broad spectrum of ellipticine derivatives.