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.

中文翻译：

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肌钙蛋白G衍生物通过调节PC12细胞中的NGF信号表现出对神经突生长的显着影响。

Sarcodonin G，从蘑菇中分离的二萜cyathane之一Sarcodon scabrosus，具有显着的神经营养活性，但不明确的机械理解。在这项工作中，选择了肌钙蛋白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，并评估了它们的神经生成活性。研究了在PC12细胞中具有相反作用的6和15（10μM）。6个通过促进NGF诱导的神经突向外生长，表现出比sarcodonin G更高的活性，而15个则表现出抑制作用。支持性地，分别为6和15（20μM）分别显着诱导和抑制了原代培养的大鼠皮质神经元的神经突延伸。在机理上，揭示了这两种衍生物通过调节PKC依赖性和非依赖性ERK / CREB信号传导以及上游TrkA受体磷酸化来影响PC12细胞中NGF诱导的神经突增生。此外，使用分子模拟显示了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来促进NGF-TrkAd5复合物的稳定。合计为6和15 可能通过影响NGF对受体TrkA的结合亲和力来调节PKC依赖性和非依赖性ERK / CREB信号通路，并最终调节PC12细胞中的神经突生长。