Protein tyrosine phosphatase 1B (PTP1B) is an important therapeutic target for type II diabetes mellitus. Mollactones A–C (1–3), three naturally occurring highly functionalized 5,6-seco-grayanane diterpenoids bearing a unique 3-oxa-tricyclo[4,3,2,0^2,6]undecane motif, and their plausible biosynthetic precursor rhodojaponin III (4) were isolated from Rhododendron molle. The ¹³C NMR spectrum of 1 exhibited only 11 carbon signals, instead of 20 carbon signals, and this challenging structure was finally defined by single-crystal X-ray diffraction analysis. This abnormal NMR phenomenon was elucidated by quantum chemical calculation. Mollactones A–C (1–3) showed significant PTP1B inhibitory activity in a competitive inhibition mode, and their structure–activity-relationships were investigated. Based on the molecular docking studies, mollactone B 3-O-sulfate (9) was rationally designed and prepared, and exhibited significant PTP1B inhibitory activity with an IC₅₀ value of 0.22 ± 0.05 μM and a K_i value of 6.79 ± 1.28 μM. These results provide a basis to design novel competitive PTP1B inhibitors based on 5,6-seco-grayanane diterpenoids with 3-oxa-tricyclo[4,3,2,0^2,6]undecane and 5,5-dimethylcyclopent-2-en-1-one motifs.

中文翻译：

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发现功能强大的5,6-seco-grayanane二萜作为有效的竞争性PTP1B抑制剂

蛋白酪氨酸磷酸酶1B（PTP1B）是II型糖尿病的重要治疗靶标。Mollactones A-C（1-3），三个天然存在的高度官能化的5,6-开环-grayanane二萜类化合物带有独特3-氧杂-三环[4,3,2,0 ^2,6 ]十一烷基序，和它们的合理的生物合成前体杜鹃皂苷III（4）是从杜鹃花中分离出来的。的¹³ C NMR图谱1仅显示出11个碳的信号，而不是20点碳的信号，并且这个挑战结构最后用单晶X射线衍射分析确定。通过量子化学计算可以阐明这种异常的NMR现象。甲内酯A–C（1–3）在竞争性抑制模式下显示出显着的PTP1B抑制活性，并研究了它们的结构-活性关系。基于分子对接研究，合理地设计和制备了内酯B 3- O-硫酸盐（9），并显示出显着的PTP1B抑制活性，IC ₅₀值为0.22±0.05μM，K _i值为6.79±1.28μM。这些结果提供了一个基础基于5,6-设计新颖竞争性抑制剂PTP1B山高-grayanane二萜类化合物与3-氧杂-三环[4,3,2,0 ^2,6 ]十一烷和5,5-二甲基环戊-2-烯-1-一个主题。