Department of Chemistry, The University of Sheffield, Sheffield, United Kingdom.
The Bateson Centre, The University of Sheffield, Sheffield, United Kingdom.
PLoS One. 2020 Oct 6;15(10):e0240231. doi: 10.1371/journal.pone.0240231. eCollection 2020.
During inflammation, dysregulated neutrophil behaviour can play a major role in a range of chronic inflammatory diseases, for many of which current treatments are generally ineffective. Recently, specific naturally occurring tanshinones have shown promising anti-inflammatory effects by targeting neutrophils in vivo, yet such tanshinones, and moreover, their isomeric isotanshinone counterparts, are still a largely underexplored class of compounds, both in terms of synthesis and biological effects. To explore the anti-inflammatory effects of isotanshinones, and the tanshinones more generally, a series of substituted tanshinone and isotanshinone analogues was synthesised, alongside other structurally similar molecules. Evaluation of these using a transgenic zebrafish model of neutrophilic inflammation revealed differential anti-inflammatory profiles in vivo, with a number of compounds exhibiting promising effects. Several compounds reduce initial neutrophil recruitment and/or promote resolution of neutrophilic inflammation, of which two also result in increased apoptosis of human neutrophils. In particular, the methoxy-substituted tanshinone 39 specifically accelerates resolution of inflammation without affecting the recruitment of neutrophils to inflammatory sites, making this a particularly attractive candidate for potential pro-resolution therapeutics, as well as a possible lead for future development of functionalised tanshinones as molecular tools and/or chemical probes. The structurally related β-lapachones promote neutrophil recruitment but do not affect resolution. We also observed notable differences in toxicity profiles between compound classes. Overall, we provide new insights into the in vivo anti-inflammatory activities of several novel tanshinones, isotanshinones, and structurally related compounds.
在炎症过程中，失调的中性粒细胞行为可能在一系列慢性炎症性疾病中发挥重要作用，其中许多疾病目前的治疗方法通常无效。最近，特定的天然丹参酮通过在体内靶向中性粒细胞显示出有希望的抗炎作用，但此类丹参酮，更确切地说，它们的异丹参酮对应物，在合成和生物学效应方面仍然是一个很大程度上未被探索的化合物类别。为了探索异丹参酮的抗炎作用，以及丹参酮更普遍的作用，我们合成了一系列取代的丹参酮和异丹参酮类似物，以及其他结构相似的分子。使用中性粒细胞炎症的转基因斑马鱼模型对这些进行评估，揭示了体内的差异抗炎谱，其中一些化合物表现出有希望的效果。几种化合物减少初始中性粒细胞募集和/或促进中性粒细胞炎症的消退，其中两种化合物还导致人中性粒细胞凋亡增加。特别是，甲氧基取代的丹参酮 39 特别加速炎症消退，而不影响中性粒细胞向炎症部位的募集，这使其成为潜在的促消退治疗的特别有吸引力的候选者，以及作为分子工具和/或化学探针的功能化丹参酮的未来发展的可能先导物。结构相关的β-拉帕醌促进中性粒细胞募集，但不影响消退。我们还观察到化合物类别之间在毒性谱方面存在显著差异。总体而言，我们提供了对几种新型丹参酮、异丹参酮和结构相关化合物体内抗炎活性的新见解。
