Despite its promising biological profile, the cellular targets of iriomoteolide-3a, a novel 15-membered macrolide isolated from Amphidinium sp., have remained unknown. A small library of non-natural iriomoteolide-3a analogues is presented here as a result of a novel, highly convergent, catalysis-based scaffold-diversification campaign, which revealed the suitable sites for chemical editing in the original core. We provide compelling experimental evidence for actin as one of iriomoteolides' primary cellular targets, establishing the ability of these secondary metabolites to inhibit cell migration, induce severe morphological changes in cells and cause a reversible cytoplasmic retraction and reduction of F-actin fibers in a time and dose dependent manner. These results are interpreted in light of the ability of iriomoteolides to stabilize F-actin filaments. Molecular dynamics simulations provide evidence for iriomoteolide-3a binding to the barbed end of G-actin. These results showcase iriomoteolides as novel and easily tunable chemical probes for the in vitro study of actin dynamics in the context of cell motility processes including cell invasion and division.

中文翻译：

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Iriomoteolides：研究肌动蛋白动力学的新型化学工具†

尽管 iriomoteolide-3a 具有良好的生物学特性，但它的细胞靶点是一种从Amphidinium中分离的新型 15 元大环内酯sp.，仍然未知。此处介绍了一个小型非天然 iriomoteolide-3a 类似物库，这是一项新颖的、高度收敛的、基于催化的支架多样化活动的结果，该活动揭示了原始核心中化学编辑的合适位点。我们为肌动蛋白作为 iriomoteolides 的主要细胞靶点之一提供了令人信服的实验证据，确定了这些次级代谢物抑制细胞迁移、诱导细胞严重形态变化并导致可逆的细胞质收缩和 F-肌动蛋白纤维减少的能力和剂量依赖的方式。这些结果是根据 iriomoteolides 稳定 F-肌动蛋白丝的能力来解释的。分子动力学模拟为 iriomoteolide-3a 与 G-肌动蛋白的带刺末端结合提供了证据。在包括细胞侵袭和分裂在内的细胞运动过程中肌动蛋白动力学的体外研究。