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Synthetic Fluorinated L-Fucose Analogs Inhibit Proliferation of Cancer Cells and Primary Endothelial Cells.
ACS Chemical Biology ( IF 4 ) Pub Date : 2020-09-15 , DOI: 10.1021/acschembio.0c00228
Yuanwei Dai 1 , Ruth Hartke 2 , Chao Li 1 , Qiang Yang 1 , Jun O Liu 2 , Lai-Xi Wang 1
Affiliation  

Fucosylation is one of the most prevalent modifications on N- and O-glycans of glycoproteins, and it plays an important role in various cellular processes and diseases. Small molecule inhibitors of fucosylation have shown promise as therapeutic agents for sickle cell disease, arthritis, and cancer. We describe here the design and synthesis of a panel of fluorinated l-fucose analogs bearing fluorine atoms at the C2 and/or C6 positions of l-fucose as metabolic fucosylation inhibitors. Preliminary study of their effects on cell proliferation revealed that the 6,6-difluoro-l-fucose (3) and 6,6,6-trifluoro-l-fucose (6) showed significant inhibitory activity against proliferation of human colon cancer cells and human umbilical vein endothelial cells. In contrast, the previously reported 2-deoxy-2-fluoro-l-fucose (1) had no apparent effects on proliferations of all the cell lines tested. To understand the mechanism of cell proliferation inhibition by the fluorinated l-fucose analogs, we performed chemoenzymatic synthesis of the corresponding GDP-fluorinated l-fucose analogs and tested their inhibitory activities against the mammalian α1,6-fucosyltransferase (FUT8). Interestingly, the corresponding GDP derivatives of 6,6-difluoro-l-fucose (3) and 6,6,6-trifluoro-l-fucose (6), which are the stronger proliferation inhibitors, showed much weaker inhibitory activity against FUT8 than that of the 2-deoxy-2-fluoro-l-fucose (1). These results suggest that FUT8 is not the major target of the 6-fluorinated fucose analogs (3 and 6). Instead, other factors, such as the key enzymes involved in the de novo GDP-fucose biosynthetic pathway and/or other fucosyltransferases involved in the biosynthesis of tumor-associated glyco-epitopes are most likely the targets of the fluorinated l-fucose analogs to achieve cell proliferation inhibition. To our knowledge, this is the first comparative study of various fluorinated l-fucose analogs for suppressing the proliferation of human cancer and primary endothelial cells required for angiogenesis.

中文翻译:

合成的氟化L-岩藻糖类似物抑制癌细胞和原代内皮细胞的增殖。

岩藻糖基化是糖蛋白N和O聚糖最普遍的修饰之一,在各种细胞过程和疾病中起着重要作用。岩藻糖基化的小分子抑制剂已显示出有望作为镰状细胞疾病,关节炎和癌症的治疗剂。我们在这里描述了一组在代谢产物岩藻糖基化抑制剂中在1-岩藻糖的C2和/或C6位置带有氟原子的氟化1-岩藻糖类似物的设计和合成。对它们对细胞增殖的影响的初步研究表明,6,6-二氟-1-岩藻糖(3)和6,6,6-三氟-1-岩藻糖(6)显示出对人结肠癌细胞和人脐静脉内皮细胞增殖的显着抑制活性。相反,先前报道的2-脱氧-2-氟-1-岩藻糖(1)对所有测试的细胞系的增殖没有明显影响。为了了解氟化1-岩藻糖类似物抑制细胞增殖的机制,我们对相应的GDP氟化1-岩藻糖类似物进行了化学合成,并测试了它们对哺乳动物α1,6-岩藻糖基转移酶(FUT8)的抑制活性。有趣的是,6,6-二氟-1-岩藻糖(3)和6,6,6-三氟-1-岩藻糖(6)是更强的增殖抑制剂,对FUT8的抑制活性比2-脱氧-2-氟-1-岩藻糖的抑制活性弱得多(1)。这些结果表明,FUT8不是6-氟化岩藻糖类似物的主要靶标(36)。取而代之的是,其他的因素,例如所涉及的关键酶的从头GDP-岩藻糖生物合成途径和/或涉及肿瘤相关糖表位的生物合成其它fucosyltransferases是最有可能的氟化的目标岩藻糖类似物,以实现细胞增殖抑制。据我们所知,这是各种含氟的第一次比较研究-岩藻糖类似物可抑制人类癌症和血管生成所需的原代内皮细胞的增殖。
更新日期:2020-10-17
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