Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell-cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition.

中文翻译：

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一种新型的高尔基甘露糖苷酶抑制剂：分子设计，合成，酶抑制和球体形成的抑制。

由于阻止了抗癌药物到达肿瘤中心的渗透率的限制，因此对实体癌的有效化学疗法具有挑战性，因此无法限制癌细胞的生长。为了解决这个问题，我们计划先通过折叠外部结构将药物直接应用于中心。为此，我们专注于肿瘤细胞表面N-聚糖和蛋白质之间的细胞间通讯（CCC）。成熟的N-聚糖建立CCC；但是，当细胞表面存在大量未成熟的N-聚糖时，CCC受阻。高尔基甘露糖苷酶（GMs）的抑制导致未成熟的N-聚糖转运到细胞表面。这可以用来破坏CCC。在这里，我们描述了从化合物库中筛选的具有非糖模拟支架的改良GM抑制剂的分子设计和合成。使用基于细胞的方法测试合成的化合物的酶抑制能力和球体形成的抑制。设计和合成的大多数化合物在细胞水平上均表现出GM抑制作用。其中，AR524的抑制活性高于已知的GM抑制剂kifunensine。此外，基于GM抑制作用对CCC的破坏，AR524在低浓度（10 µM）时抑制人恶性细胞的球状形成。