Diversity-oriented synthesis of diterpenoid alkaloids yields a potent anti-inflammatory agent,Phytomedicine

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Diversity-oriented synthesis of diterpenoid alkaloids yields a potent anti-inflammatory agent
Phytomedicine ( IF 6.7 ) Pub Date : 2023-05-29 , DOI: 10.1016/j.phymed.2023.154907
Xiaojie Li ₁ , Jifa Zhang ₂ , Qifeng Chen ₃ , Pan Tang ₂ , Ting Zhang ₁ , Qiyi Feng ₁ , Jiajun Chen ₃ , Yun Liu ₂ , Feng-Peng Wang ₃ , Cheng Peng ₄ , Yong Qin ₃ , Liang Ouyang ₂ , Kai Xiao ₁ , Xiao-Yu Liu ₃

Affiliation

Background

The diterpenoid alkaloids belong to a highly esteemed group of natural compounds, which display significant biological activities. It is a productive strategy to expand the chemical space of these intriguing natural compounds for drug discovery.

Methods

We prepared a series of new derivatives bearing diverse skeletons and functionalities from the diterpenoid alkaloids deltaline and talatisamine based on a diversity-oriented synthesis strategy. The anti-inflammatory activity of these derivatives was initially screened and evaluated by the release of nitric oxide (NO), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-activated RAW264.7 cells. Futhermore, the anti-inflammatory activity of the representative derivative 31a was validated in various inflammatory animal models, including phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mice ear edema, LPS-stimulated acute kidney injury, and collagen-induced arthritis (CIA).

Results

It was found that several derivatives were able to suppress the secretion of NO, TNF-α, and IL-6 in LPS-activated RAW264.7 cells. Compound 31a, one of the representative derivatives named as deltanaline, demonstrated the strongest anti-inflammatory effects in LPS-activated macrophages and three different animal models of inflammatory diseases by inhibiting nuclear factor kappa-B (NF-κB)/mitogen-activated protein kinase (MAPK) signaling and inducing autophagy.

Conclusion

Deltanaline is a new structural compound derived from natural diterpenoid alkaloids, which may serve as a new lead compound for the treatment of inflammatory diseases.

中文翻译：

二萜生物碱的多样性合成可产生有效的抗炎剂

背景

二萜生物碱属于一组备受推崇的天然化合物，具有显着的生物活性。扩大这些有趣的天然化合物的化学空间以进行药物发现是一种富有成效的策略。

方法

我们基于多样性导向的合成策略，从二萜类生物碱 deltaline 和 talatisamine 中制备了一系列具有不同骨架和功能的新衍生物。这些衍生物的抗炎活性最初是通过脂多糖（LPS）激活的RAW264中一氧化氮（NO）、肿瘤坏死因子（TNF-α）和白细胞介素6（IL-6）的释放来筛选和评估的。 7 个细胞。此外，代表性衍生物31a的抗炎活性在各种炎症动物模型中得到验证，包括佛波酯12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的小鼠耳水肿、LPS刺激的急性肾损伤和胶原蛋白诱发性关节炎（CIA）。

结果

研究发现，几种衍生物能够抑制 LPS 激活的 RAW264.7 细胞中 NO、TNF-α 和 IL-6 的分泌。化合物31a是Deltanaline的代表性衍生物之一，通过抑制核因子κ-B（NF-κB）/丝裂原激活蛋白激酶，在LPS激活的巨噬细胞和三种不同的炎症性疾病动物模型中表现出最强的抗炎作用(MAPK) 信号传导和诱导自噬。