Macrocephatriolides A and B: Two Guaianolide Trimers from Ainsliaea macrocephala as PTP1B Inhibitors and Insulin Sensitizers,The Journal of Organic Chemistry

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Macrocephatriolides A and B: Two Guaianolide Trimers from Ainsliaea macrocephala as PTP1B Inhibitors and Insulin Sensitizers
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2021-12-01 , DOI: 10.1021/acs.joc.1c01996
Yong-Mei Ren _{1,

2,

3} , Rui Zhang ₁ , Zheling Feng ₄ , Chang-Qiang Ke ₁ , Sheng Yao ₁ , Chunping Tang ₁ , Ligen Lin ₄ , Yang Ye _{1,

2,

3}

Affiliation

Macrocephatriolides A and B (1 and 2), two novel guaiane-type sesquiterpene lactone trimers possessing unique linkage patterns, were identified from the whole plant of Ainsliaea macrocephala. The trimeric architecture of 1 features a cyclohexene linkage and a methylene bridge, which were presumably constructed from three constitutive monomers via a Diels–Alder cycloaddition and a Michael addition, respectively. The three monomers of 2 were tethered by a 1,2-ethanediyl and a methylene linkage at the same time. Their complex structures were established by extensive analysis of spectroscopic data inclusive of band-selective CT-HSQC and CT-HMBC and time-dependent density functional theory (TDDFT) ECD calculations. Compound 2 showed potent inhibition against protein tyrosine phosphatase 1B (PTP1B) with an IC₅₀ value of 26.26 ± 0.88 μM but not compound 1. In the kinetic study, compound 2 was disclosed as a competitive inhibitor of PTP1B with a K_i value of 16.34 ± 4.72 μM. In insulin-stimulated C2C12 myotubes, compound 2 dose-dependently enhanced glucose uptake by activating the insulin signaling pathway. Compound 2 might represent a new scaffold of insulin sensitizers.

中文翻译：

Macrocephatriolides A 和 B：来自 Ainsliaea macrocephala 的两种 Guaianolide 三聚体作为 PTP1B 抑制剂和胰岛素增敏剂

Macrocephatriolides A 和 B ( 1和2 ) 是两种具有独特连接模式的新型愈创木脂型倍半萜内酯三聚体。1的三聚体结构具有环己烯键和亚甲基桥，它们可能分别由三个组成单体通过 Diels-Alder 环加成和迈克尔加成构建而成。2的三个单体同时由1,2-乙二基和亚甲基键连接。它们的复杂结构是通过对光谱数据的广泛分析建立的，包括波段选择性 CT-HSQC 和 CT-HMBC 以及时间相关密度泛函理论 (TDDFT) ECD 计算。化合物2对蛋白酪氨酸磷酸酶 1B (PTP1B) 显示出有效的抑制作用，IC ₅₀值为 26.26 ± 0.88 μM，但化合物1没有。在动力学研究中，化合物2被公开为 PTP1B 的竞争性抑制剂，K _i值为 16.34 ± 4.72 μM。在胰岛素刺激的 C2C12 肌管中，化合物2通过激活胰岛素信号通路，剂量依赖性地增强葡萄糖摄取。化合物2可能代表一种新的胰岛素增敏剂支架。

更新日期：2021-12-17

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