| Novel liver-specific cholic acid-cytarabine conjugates with potent antitumor activities: Synthesis and biological characterization. | |
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MedLine Citation:
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PMID: 21516131 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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.Acta Pharmacologica Sinica advance online publication, 25 Apr 2011; doi: 10.1038/aps.2011.7. |
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Authors:
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Dan-Qi Chen; Xin Wang; Lin Chen; Jin-Xue He; Ze-Hong Miao; Jing-Kang Shen |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-25 |
Journal Detail:
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Title: Acta pharmacologica Sinica Volume: - ISSN: 1745-7254 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100956087 Medline TA: Acta Pharmacol Sin Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. |
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