Drug resistance and cancer cells metastasis have been the leading causes of chemotherapy failure and cancer-associated death in breast cancer patients. In present, various active molecules either exhibiting novel mechanism of action such as inducing autophagy or inhibiting metastasis have been developed to address these problems. However, the compounds exhibiting such dual functions have rarely been described. Previous work in our group showed that TSA, as a synthetic analog of asperphenamate, induced autophagic cell death in breast cancer cells instead of apoptosis. Furthermore, the target enzyme of TSA was predicted to be cathepin L (Cat L) by natural product consensus pharmacophore strategy. Accumulated evidences have shown that cathepsins are closely associated with migration and invasion of breast cancer cells. It seemed likely that TSA-like molecules may possess the dual functions of inducing autophagy and inhibiting metastasis. Therefore, sixty optically active derivatives were firstly designed and synthesized by replacing the A-ring moiety of TSA with other substituted-phenyl sulfonyl groups. Further cathepsin inhibitory activity assay showed that (S, S) and (S, R) isomers displayed no activity against four kinds of cathepsins (L, S, K, B), while all derivatives tested were inactive toward K and B subtypes. Compound 6a with meta-bromo substituent displayed the greatest inhibitory activity, and its inhibitory capability against Cat L and S was 3.9 and 11.5-fold more potent than that of TSA, respectively. Molecular docking also exhibited that 6a formed more hydrogen bonds or π-π contacts with Cat L or S than TSA. In order to determine whether 6a could play dual roles, its anti-cancer mechanism was further investigated. On the one hand, MDC staining experiment and western blotting analysis validated that 6a can induce autophagy in MDA-MB-231 cells. On the other hand, its metastatic inhibitory ability was also confirmed by wound healing and transwell chamber experiment.

中文翻译：

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发现一种新型组织蛋白酶抑制剂，对乳腺癌细胞具有双重自噬和转移抑制作用。

耐药性和癌细胞转移已成为乳腺癌患者化疗失败和癌症相关死亡的主要原因。目前，已经开发出表现出新的作用机制如诱导自噬或抑制转移的各种活性分子以解决这些问题。但是，几乎没有描述显示出这种双重功能的化合物。我们小组以前的工作表明，TSA作为高苯甲酸酯的合成类似物，在乳腺癌细胞中诱导自噬细胞死亡，而不是凋亡。此外，通过天然产物共有药效团策略，TSA的靶酶被预测为cathepin L（Cat L）。越来越多的证据表明，组织蛋白酶与乳腺癌细胞的迁移和侵袭密切相关。TSA样分子似乎具有诱导自噬和抑制转移的双重功能。因此，首先通过用其他取代的苯基磺酰基取代TSA的A-环部分，首先设计和合成了六十种光学活性衍生物。进一步的组织蛋白酶抑制活性测定表明，（S，S）和（S，R）异构体对四种组织蛋白酶（L，S，K，B）没有显示活性，而所有测试的衍生物均对K和B亚型无活性。具有间溴取代基的化合物6a表现出最大的抑制活性，其对Cat L和S的抑制能力分别比TSA强3.9和11.5倍。分子对接还显示，与TSA相比，6a与Cat L或S形成更多的氢键或π-π接触。为了确定6a是否可以起双重作用，进一步研究了其抗癌机理。一方面，MDC染色实验和蛋白质印迹分析证实6a可以诱导MDA-MB-231细胞自噬。另一方面，它的转移抑制能力也通过伤口愈合和transwell室实验得到证实。