Design and Synthesis a Water-soluble Group for Ether-linkage of 10-Hydroxycamptothecin Prodrug

• Main Authors: CHIU, PEI-FANG, 邱沛芳
• Other Authors: LEU, YU-LIN
• Format: Others
• Language: zh-TW
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/686w4t

碩士 === 嘉南藥理大學 === 藥學系 === 105 === Camptothecin has good anti-cancer activity, and current clinical use of two derivatives are Topotecan and Irinotecan which improve poor water solubility of Camptothecin by chemical modification. However, the lack of drugs specificity of tumor will cause severe side effects. Therefore, our laboratory designed and synthesized two glucuronide prodrugs of Camptothecin (9-ACG and 10-HCG) which will mainly be activated at tumor site expressing large number of β-glucuronidase. According to previous studies, 9-ACG and 10-HCG was 1800 and 20 times soluble than 10-HCG, respectively; 9-ACG and 10-HCG was 30-fold and 10-fold less toxic than the parent drug to cells, respectively; Enzyme kinetic studies showed that β-glucuronidase exhibited 520 times higher catalytic efficiency for 10-HCG than for 9-ACG, and molecular modeling studies predicted that 10-HCG would have a higher binding affinity to enzyme than 9-ACG. In this study, we design and synthesize the target compound 10-HCPG by creating N-methyl piperazine on the benzyl group of 10-HCG, expect for good water solubility, stable in blood, low cytotoxicity, good affinity with β-glucuronidase and specific to tumor cells.