Bioactivity-Guided Discovery of Human Carboxylesterase Inhibitors from the Roots of Paeonia lactiflora.,Journal of Natural Products

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Bioactivity-Guided Discovery of Human Carboxylesterase Inhibitors from the Roots of Paeonia lactiflora.
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-09-20 , DOI: 10.1021/acs.jnatprod.0c00464
Jing-Fang Zhang ₁ , Wan-Chao Zhong ₁ , Yan-Cheng Li ₁ , Yun-Qing Song ₂ , Gui-Yang Xia _{1,

3} , Gui-Hua Tian ₃ , Guang-Bo Ge ₂ , Sheng Lin _{1,

3}

Affiliation

In a continuing search for potential inhibitors against human carboxylesterases 1A1 and 2A1 (hCES1A1 and hCES2A1), an EtOAc extract of the roots of Paeonia lactiflora showed strong hCES inhibition activity. Bioassay-guided fractionation led to the isolation of 26 terpenoids including 12 new ones (1–5, 7–12, and 26). Among these, sesquiterpenoids 1 and 6, monoterpenoids 10, 11, and 13–15, and triterpenoids 18–20, 22, and 24–26 contributed to the hCES2A1 inhibition, in the IC₅₀ range of 1.9–14.5 μM, while the pentacyclic triterpenoids 18–26 were responsible for the potent inhibitory activity against hCES1A1, with IC₅₀ values less than 5.0 μM. The structures of all the compounds were elucidated using MS and 1D and 2D NMR data, and the absolute configurations of the new compounds were resolved via specific rotation, experimental and calculated ECD spectra, and single-crystal X-ray diffraction analysis. The structure–activity relationship analysis highlighted that the free HO-3 group in the pentacyclic triterpenoids is crucial for their potent inhibitory activity against hCES1A1.

中文翻译：

从芍药根中生物活性引导发现人羧酸酯酶抑制剂。

在继续寻找针对人羧酸酯酶 1A1 和 2A1（hCES1A1 和 hCES2A1）的潜在抑制剂的过程中，芍药根的 EtOAc 提取物显示出很强的 hCES 抑制活性。生物测定引导的分级分离导致26个萜类，包括12分新的（的隔离1 - 5，7 - 12，和26）。在这些之中，倍半萜化合物1和6，单萜类10，11，和13 - 15，和三萜类化合物18 - 20，22，和24 -26促成hCES2A1抑制，在IC ₅₀范围1.9-14.5μM，而五环三萜类化合物18 - 26负责针对hCES1A1的有效的抑制活性，以IC _50个值小于5.0μM。所有化合物的结构均使用 MS 和 1D 和 2D NMR 数据阐明，新化合物的绝对构型通过比旋光、实验和计算 ECD 光谱以及单晶 X 射线衍射分析进行解析。构效关系分析强调，五环三萜类化合物中的游离 HO-3 基团对其对 hCES1A1 的有效抑制活性至关重要。

更新日期：2020-10-26

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