Organic and Bioorganic Chemistry, Faculty of Chemistry, Bielefeld University, D-33501 Bielefeld, Germany; Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City-Cairo 11884, Egypt.
Organic and Bioorganic Chemistry, Faculty of Chemistry, Bielefeld University, D-33501 Bielefeld, Germany.
Bioorg Chem. 2020 Apr;97:103678. doi: 10.1016/j.bioorg.2020.103678. Epub 2020 Feb 21.
In this study, a series of novel N-feruloyl dipeptides (10-17) have been synthesized through the coupling of N-feruloyl amino acids (6-9) with glycine/alanine methyl ester hydrochloride. Structures of the peptides were assigned using 1D and 2D NMR and HRESIMS. According to initial in vitro cytotoxic screening against the cervix carcinoma cell line KB-3-1, aromatic dipeptides (12, 13, 16, 17) were the most potent ones among all tested feruloyl dipeptides. Accordingly, these peptides were further intensively investigated as potential anticancer agents against a panel of ten cancer cell lines from different tissue origin. Based on that, compound 17 showed the strongest cytotoxic efficiency towards the whole panel of tested cell lines with IC values from 2.1 to 7.9 μM. By contrast, the dipeptides 12, 13 and 16 showed moderate to weak cytotoxicity (IC 16.1-28.3 or >30, 5.7-21.9 and 3.9-21.2 or ≥30 μM, respectively). Mechanistically, compound 17 induced a strong dissipation of the mitochondrial transmembrane potential and an early activation of caspase 3/7 in the triple-negative MDA-MB-231 breast cancer cell line. In an in vivo model, compound 17 inhibited growth, proliferation and induced apoptosis in MDA-MB-231 xenografted onto the chick chorioallantoic membrane. All the synthesized compounds were also tested against a set of pathogenic bacterial strains, displaying no potential activity.
在这项研究中，通过甘氨酸/丙氨酸甲酯盐酸盐与 N-阿魏酰氨基酸（6-9）的偶联，合成了一系列新型的 N-阿魏酰二肽（10-17）。利用 1D 和 2D NMR 和 HRESIMS 确定了肽的结构。根据对宫颈癌细胞系 KB-3-1 的初始体外细胞毒性筛选，芳香二肽（12、13、16、17）是所有测试的阿魏酰二肽中最有效的。因此，这些肽进一步作为潜在的抗癌剂进行了深入研究，针对来自不同组织来源的十种癌细胞系进行了测试。基于此，化合物 17 对整个测试细胞系表现出最强的细胞毒性效率，IC 值为 2.1 至 7.9 μM。相比之下，二肽 12、13 和 16 表现出中等至弱的细胞毒性（IC 16.1-28.3 或>30、5.7-21.9 和 3.9-21.2 或≥30 μM）。在机制上，化合物 17 可强烈破坏线粒体跨膜电位，并在三阴性 MDA-MB-231 乳腺癌细胞系中早期激活 caspase 3/7。在体内模型中，化合物 17 抑制 MDA-MB-231 异种移植到鸡胚绒毛尿囊膜上的生长、增殖并诱导细胞凋亡。所有合成的化合物也针对一组病原菌进行了测试，没有表现出潜在的活性。
