Department of Organic Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague, Czech Republic.
Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague, Czech Republic.
Org Biomol Chem. 2024 Jun 5;22(22):4536-4549. doi: 10.1039/d4ob00634h.
Cytochalasans are fungal metabolites that are known to inhibit actin polymerization. Despite their remarkable bioactivity, there are few studies on the structure-activity relationship (SAR) of the cytochalasan scaffold. The full potential of structural modifications remains largely unexplored. The substituent at position 10 of the cytochalasan scaffold is derived from an amino acid incorporated into the cytochalasan core, thus limiting the structural variability at this position in natural products. Additionally, modifications at this position have only been achieved through semisynthetic or mutasynthetic approaches using modified amino acids. This paper introduces a modular approach for late-stage modifications at position 10 of the cytochalasan scaffold. Iron-mediated cross-coupling reactions with corresponding Grignard reagents were used to introduce aryl or benzyl groups in position 10, resulting in the synthesis of six new cytochalasan analogues bearing non-natural aromatic residues. This methodology enables further exploration of modifications at this position and SAR studies among cytochalasan analogues.
细胞松弛素是一种真菌代谢产物，已知其能抑制肌动蛋白聚合。尽管它们具有显著的生物活性，但对细胞松弛素支架的结构-活性关系（SAR）的研究很少。结构修饰的全部潜力在很大程度上仍未得到探索。细胞松弛素支架 10 位的取代基来源于掺入细胞松弛素核心的氨基酸，因此限制了天然产物中该位置的结构可变性。此外，该位置的修饰仅通过使用修饰氨基酸的半合成或突变合成方法来实现。本文介绍了一种在细胞松弛素支架 10 位进行后期修饰的模块化方法。使用铁介导的交叉偶联反应与相应的格氏试剂，在 10 位引入芳基或苄基，从而合成了六个带有非天然芳基残基的新型细胞松弛素类似物。这种方法可以进一步探索该位置的修饰和细胞松弛素类似物之间的 SAR 研究。
