We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.

中文翻译：

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唾液酸转移酶抑制剂抑制乳腺癌转移

我们报告了一系列的细胞渗透性和N-与O-选择性唾液酸转移酶抑制剂的合成和评估。抑制剂设计需要在C（3）和环戊烷环侧链上的石胆酸功能化。在该系列中，FCW34和FCW66与ST3GALIII基因敲除一样有效地抑制MDA-MB-231细胞迁移。在动物模型中，FCW34被证明可抑制肿瘤生长，减少血管生成并延缓癌细胞转移。此外，FCW34抑制了转基因斑马鱼模型中的血管发育并抑制了血管生成活性。我们的结果提供了明确的证据，表明FCW34诱导的唾液酸转移酶抑制作用通过降低N-聚糖唾液酸化作用来减少癌细胞转移，从而改变了塔林/整联蛋白/ FAK / paxillin和整联蛋白/NFκB信号通路的调节。