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学科主题: 药学
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A new class of anti-thrombosis hexahydropyrazino-[1 ′,2 ′: 1,6]pyrido-[3,4-b]-indole-1,4-dions: Design, synthesis, log K determination, and QSAR analysis
作者: Liu, Jiawang1; Wu, Guofeng1; Cui, Guohui1; Wang, Wei-Xuan1; Zhao, Ming1; Wang, Chao1; Zhangc, Ziding1; Peng, Shiqi1
关键词: anti-thrombotic agent ; hexahydropyrazino[1 &prime ; ,2 &prime ; : 1,6]-pyrido[3,4-b]indole-1,4-dions ; intramolecular cyclization ; tetrahydro-beta-carboline-3-carboxylic acid
刊名: BIOORGANIC & MEDICINAL CHEMISTRY
发表日期: 2007-09-01
DOI: 10.1016/j.bmc.2007.06.012
卷: 15, 期:17, 页:5672-5693
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Chemistry, Medicinal ; Chemistry, Organic
研究领域[WOS]: Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
关键词[WOS]: PERFORMANCE LIQUID-CHROMATOGRAPHY ; PRO-ALA-LYS ; MYOCARDIAL-INFARCTION ; PLATELET ACTIVATION ; NITRONYL NITROXIDE ; COEFFICIENTS ; ANALOGS ; FUMITREMORGIN ; METABOLITES ; INHIBITION
英文摘要:

Based on the fact that the cyclization of N-[(3S)1-1,2,3,4-tetrahydro-beta-carboline-3-carboxyl]-L-lysine in both of acetic acid aqueous (5%) and rat plasma gave the same product and the hypothesis that the cyclization product is antithrombotic active, we report the synthesis, in vitro anti-aggregation, and in vivo anti-thrombosis activity of 20 hexahydropyrazino[1′,2′:1,6]pyrido[3,4-blindole-1,4-dions (5a-t) as potential anti-thrombosis agents in this study. Two intermediates (tetrahydro-beta-carboline-3-carboxy-L-amino acid benzylesters, 2-aminoacyltetrahydro-beta-carboline-3-carboxylic acid benzylesters) were prepared and used for the cyclization to form 5a-t. Coupling hydrochloric acid salt of tetrahydro-beta p-carboline-3-carboxylic acid esters and Boc-amino acids in the reported literature usually generates very low yield products accompanied by racernization. However, in our case, the free base of tetrahydro-beta-carboline-3-carboxylic acid benzylester produced the desired products in high yields and without racemization. The anti-thrombosis results from both in vitro and in vivo studies revealed that 5a-t may be a new class of anti-thrombosis agents with potent effective concentration at 0.5 mu mol/kg with oral administration. Moreover, a QSAR analysis was performed on these 20 compounds by using molecular descriptors generated by e-dragon server. Although the activities of these compounds are weakly correlated with the log P values, the current QSAR analysis revealed that the anti-thrombotic activity of these compounds can be explained by their steric and electrostatic effects. (c) 2007 Elsevier Ltd. All rights reserved.

语种: 英语
WOS记录号: WOS:000248779000003
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/50416
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Capital Med Univ, Coll Pharmaceut Sci, Beijing 100069, Peoples R China
2.Peking Univ, Coll Pharmaceut Sci, Beijing 100083, Peoples R China
3.China Agr Univ, Coll Biol Sci, Beijing 100094, Peoples R China

Recommended Citation:
Liu, Jiawang,Wu, Guofeng,Cui, Guohui,et al. A new class of anti-thrombosis hexahydropyrazino-[1 ′,2 ′: 1,6]pyrido-[3,4-b]-indole-1,4-dions: Design, synthesis, log K determination, and QSAR analysis[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2007,15(17):5672-5693.
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