Novel liver-specific cholic acid-cytarabine conjugates with potent antitumor activities: Synthesis and biological characterization
文献类型：期刊论文
| 作者 | Chen, Dan-qi ; Wang, Xin; Chen, Lin; He, Jin-xue; Miao, Ze-hong; Shen, Jing-kang
|
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2011-05 |
| 卷号 | 32期号:5页码:664-672 |
| 关键词 | cytarabine cholic acid liver antitumor drug |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2011.7 |
| 文献子类 | Article |
| 英文摘要 | Aim: Cytarabine is an efficient anticancer agent for acute myelogenous leukemia, but with short plasma half-life and rapid deamination to its inactive metabolite. The aim of this study was to design and synthesize novel cholic acid-cytarabine conjugates to improve its pharmacokinetic parameters. Methods: The in vitro stability of novel cholic acid-cytarabine conjugates was investigated in simulated gastric and intestinal fluid, mouse blood and liver homogenate using HPLC. The portacaval samples of the conjugates were examined in male Sprague-Dawley rats using LC/MS, and in vivo distribution was examined in male Kunming mice using LC/MS. Antitumor activities were tested in HL60 cells using MTT assay. Results: Cholic acid-cytarabine compounds with four different linkers were designed and synthesized. All the four cholic acid-cytarabine conjugates could release cytarabine when incubated with the simulated gastric and intestinal fluid, mouse blood and liver homogenate. The conjugates 6, 12, and 16 were present in the portacaval samples, whereas the conjugate 7 was not detected. The conjugates 6 and 16 showed high specificity in targeting the liver (liver target index 34.9 and 16.3, respectively) and good absorption in vivo, as compared with cytarabine. In cytarabine-sensitive HL60 cells, the conjugates 6, 12, and 16 retained potent antitumor activities. Conclusion: Three novel cholic acid-cytarabine conjugates with good liver-targeting properties and absorption were obtained. Further optimization of the conjugates is needed in the future. |
| WOS关键词 | ORAL BIOAVAILABILITY ; PHARMACOKINETICS ; LEUKEMIA ; PRODRUG |
| 资助项目 | National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2009ZX09301-001] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000290276300015 |
| 出版者 | SHANGHAI INST MATERIA MEDICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278546]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Shen, Jing-kang |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Dan-qi,Wang, Xin,Chen, Lin,et al. Novel liver-specific cholic acid-cytarabine conjugates with potent antitumor activities: Synthesis and biological characterization[J]. ACTA PHARMACOLOGICA SINICA,2011,32(5):664-672. |
| APA | Chen, Dan-qi,Wang, Xin,Chen, Lin,He, Jin-xue,Miao, Ze-hong,&Shen, Jing-kang.(2011).Novel liver-specific cholic acid-cytarabine conjugates with potent antitumor activities: Synthesis and biological characterization.ACTA PHARMACOLOGICA SINICA,32(5),664-672. |
| MLA | Chen, Dan-qi,et al."Novel liver-specific cholic acid-cytarabine conjugates with potent antitumor activities: Synthesis and biological characterization".ACTA PHARMACOLOGICA SINICA 32.5(2011):664-672. |
入库方式： OAI收割
来源：上海药物研究所
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