Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy , Northwest A&F University , Yangling 712100 , China.
Xi'an Botanical Garden , Institute of Botany of Shaanxi Province , Xi'an 710061 , Shaanxi China.
ACS Chem Neurosci. 2018 Jul 18;9(7):1607-1615. doi: 10.1021/acschemneuro.7b00488. Epub 2018 Apr 27.
Sarcodonin G, one of the cyathane diterpenoids isolated from the mushroom Sarcodon scabrosus, possesses pronounced neurotrophic activity but ambiguous mechanical understanding. In this work, sarcodonin G was chosen as a lead compound to prepare a series of 19- O-benzoyl derivatives by semisynthesis and their neuritogenic activities were evaluated. 6 and 15 (10 μM) were investigated with opposite effects in PC12 cells. 6 exhibited a superior activity to sarcodonin G by promoting NGF-induced neurite outgrowth, while 15 showed an inhibitory effect. Supportingly, 6 and 15 (20 μM) significantly induced and suppressed neurite extension in primary cultured rat cortical neurons, respectively. In mechanism, the two derivatives were revealed to influence NGF-induced neurite outgrowth in PC12 cells through the regulation of PKC-dependent and -independent ERK/CREB signaling as well as the upstream TrkA receptor phosphorylation. Furthermore, a possible pattern of interaction among NGF, 6/15 and TrkA was presented using molecular simulations. It revealed that 6/15 may contribute to the stabilization of the NGF-TrkAd5 complex by establishing several hydrophobic and hydrogen-bond interactions with NGF and TrkA, respectively. Taken together, 6 and 15 modulate PKC-dependent and -independent ERK/CREB signaling pathways possibly by influencing the binding affinity of NGF to the receptor TrkA, and finally regulate neurite outgrowth in PC12 cells.
从蘑菇 Sarcodon scabrosus 中分离得到的一种杯烷二萜类化合物 sarcodonin G，具有明显的神经营养活性，但机械理解却不明确。在这项工作中，选择 sarcodonin G 作为先导化合物，通过半合成制备了一系列 19-O-苯甲酰基衍生物，并对其神经发生活性进行了评价。6 和 15（10 μM）在 PC12 细胞中表现出相反的作用。6 通过促进 NGF 诱导的神经突生长，表现出优于 sarcodonin G 的活性，而 15 则表现出抑制作用。支持这一结果，6 和 15（20 μM）分别在原代培养的大鼠皮质神经元中显著诱导和抑制神经突延伸。在机制上，这两种衍生物通过调节 PKC 依赖性和非依赖性 ERK/CREB 信号以及上游 TrkA 受体磷酸化，被揭示影响 PC12 细胞中 NGF 诱导的神经突生长。此外，还使用分子模拟呈现了 NGF、6/15 和 TrkA 之间相互作用的可能模式。结果表明，6/15 可能通过与 NGF 和 TrkA 分别建立几个疏水和氢键相互作用，有助于稳定 NGF-TrkAd5 复合物。综上所述，6 和 15 通过影响 NGF 与受体 TrkA 的结合亲和力，调节 PC12 细胞中的神经突生长，可能调节 PKC 依赖性和非依赖性 ERK/CREB 信号通路。
