期刊
ACS CHEMICAL BIOLOGY
卷 9, 期 4, 页码 897-903出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb500009r
关键词
-
资金
- program NCET Foundation
- National Basic Research Program of China [2012CB822103]
- NSFC [81230090, 31270853, 81102377, 81102778]
- Global Research Network for Medicinal Plants (GRNMP)
- King Saud University
- Shanghai Leading Academic Discipline Project [B906]
- Key laboratory of drug research for special environments
- PLA
- Shanghai Engineering Research Center for the Preparation of Bioactive Natural Products [10DZ2251300]
- Scientific Foundation of Shanghai China [10DZ1971700, 12401900501]
- National Major Project of China [2011ZX09307-002-03, 2011ZX09102-006-02]
- National Key Technology R&D Program of China [2012BAI29B06]
- Shanghai Pujiang Program [12PJ1405000]
Dopamine, a biogenic amine with important biological functions, is produced from L-DOPA by DOPA decarboxylase (DDC). DDC is a potential target to modulate the production of dopamine in several pathological states. Known inhibitors of DDC have been used for treatment of Parkinson's disease but suffered low specificity and diverse side effects. In the present study, we identified and characterized a novel class of natural-product-based selective inhibitors for DDC from the extract of Euonymus glabra Roxb. by a newly developed high-throughput enzyme assay. The structures of these inhibitors are dimeric diarylpropane, a unique chemical structure containing a divalent dopamine motif. The most effective inhibitors 5 and 6 have an IC50 of 11.5 +/- 1.6 and 21.6 +/- 2.7 mu M in an in vitro purified enzyme assay, respectively, but did not inhibit other homologous enzymes. Compound 5 but not 6 dose-dependently suppressed the activity of hDDC and dopamine levels at low micromolar concentrations in cells. Furthermore, structure-activity relationship analyses revealed that p-benzoquinone might be a crucial moiety of these inhibitors for inhibiting hDDC. The natural-product-based selective inhibitors of hDDC could serve as a chemical lead for developing improved drugs for dopamine-related disease states.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据