Prenylated Coumarins: Natural Phosphodiesterase-4 Inhibitors from Toddalia asiatica

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• 作者：Ting-Ting Lin ; Yi-You Huang ; Gui-Hua Tang ; Zhong-Bin Cheng ; Xin Liu ; Hai-Bin Luo ; Sheng Yin
• 刊名：Journal of Natural Products
• 出版年：2014
• 出版时间：April 25, 2014
• 年：2014
• 卷：77
• 期：4
• 页码：955-962
• 全文大小：402K
• 年卷期：v.77,no.4(April 25, 2014)
• ISSN：1520-6025

文摘

Bioassay-guided fractionation of the ethanolic extract of the roots of Toddalia asiatica led to the isolation of seven new prenylated coumarins (1鈥?b>7) and 14 known analogues (8鈥?b>21). The structures of 1鈥?b>7 were elucidated by spectroscopic analysis, and their absolute configurations were determined by combined chemical methods and chiral separation analysis. Compounds 1鈥?b>5, named toddalin A, 3鈥?O-demethyltoddalin A, and toddalins B鈥揇, represent an unusual group of phenylpropenoic acid-coupled prenylated coumarins. Compounds 1鈥?b>21 and four modified analogues, 10a, 11a, 13a, and 17a, were screened by using tritium-labeled adenosine 3鈥?5鈥?cyclic monophosphate ([³H]-cAMP) as substrate for their inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds 3, 8, 10, 10a, 11, 11a, 12, 13, 17, and 21 exhibited inhibition with IC₅₀ values less than 10 渭M. Toddacoumalone (8), the most active compound (IC₅₀ = 0.14 渭M), was more active than the positive control, rolipram (IC₅₀ = 0.59 渭M). In addition, the structure鈥揳ctivity relationship and possible inhibitory mechanism of the active compounds are also discussed.