Actin barbed end-binding macrolides have been shown to inhibit cancer cell motility and invasion of extracellular matrix (ECM), evoking their potential utility as therapies for metastatic cancers. Unfortunately, the direct use of these compounds in clinical settings is impeded by their limited natural abundance, challenging total synthesis, and detrimental effects on normal tissues. To develop potent analogues of these compounds that are simpler to synthesize and compatible with cell-specific targeting systems, such as antibodies, we designed over 20 analogues of the acyclic side chain (tail) of the macrolide Mycalolide B. These analogues probed the contributions of four distinct regions of the tail towards the inhibition of actin polymerization and ECM invasion by human lung cancer A549 cells. We observed that two of these regions tolerate considerable substituent variability, and we identified a specific combination of substituents that leads to the optimal inhibition of the ECM invasion activity of A549 cells.

中文翻译：

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迈向抑制癌细胞侵袭性的合成肌动蛋白靶向大环内酯类似物的模板


肌动蛋白倒钩末端结合大环内酯已被证明可抑制癌细胞运动和细胞外基质 （ECM） 的侵袭，从而激发其作为转移性癌症疗法的潜在效用。不幸的是，这些化合物在临床环境中的直接使用受到其有限的天然丰度、具有挑战性的总合成和对正常组织的有害影响的阻碍。为了开发这些化合物的强效类似物，这些类似物更易于合成并与细胞特异性靶向系统（如抗体）兼容，我们设计了 20 多种大环内酯麦卡内酯 B 的无环侧链（尾部）类似物。这些类似物探测了尾部的四个不同区域对人肺癌 A549 细胞抑制肌动蛋白聚合和 ECM 侵袭的贡献。我们观察到其中两个区域耐受相当大的取代基变异性，并且我们确定了一种特定的取代基组合，该组合导致对 A549 细胞的 ECM 侵袭活性的最佳抑制。