Discovery of dehydroabietic acid sulfonamide based derivatives as selective matrix metalloproteinases inactivators that inhibit cell migration and proliferation
Discovery of dehydroabietic acid sulfonamide based derivatives as selective matrix metalloproteinases inactivators that inhibit cell migration and proliferation
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发现脱氢松香酸磺酰胺基衍生物作为选择性基质金属蛋白酶灭活剂，抑制细胞迁移和增殖
DOI：
10.1016/j.ejmech.2017.07.020
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发表时间：
2017-09-29
影响因子：
6.7
通讯作者：
Wang, Heng-Shan
中科院分区：
文献类型：
--
作者：
Huang, Ri-Zhen;Liang, Gui-Bin;Wang, Heng-Shan
设计、合成了一系列含有磺胺部分的脱氢枞酸（DHAA）二肽衍生物，并对其抑制MMPs和体外细胞迁移的作用进行了评价。这些化合物对MMPs具有较好的抑制活性，IC50值在低微摩尔范围内。对最具活性的化合物8k的对接研究揭示了8k与MMP-3之间的关键相互作用，其中磺胺部分和二肽组对提高活性很重要。值得注意的是，进一步的抗肿瘤活性筛选显示，一些化合物表现出比商业抗癌药物5-FU更好的抑制活性。特别是，化合物8k似乎是对HepG2细胞系最有效的化合物，至少部分是通过抑制MMP-3的活性和诱导凋亡。通过伤口愈合实验，化合物8k对HepG2细胞的处理抑制了细胞的体外迁移，阻滞了细胞周期的Cl期。此外，8k诱导的HepG2细胞凋亡明显加快。因此，我们得出结论，含有磺胺部分的DHAA二肽衍生物可能是具有抑制细胞迁移能力的潜在MMPs抑制剂。(C) 2017 Elsevier Masson SAS。版权所有。
A series of dehydroabietic acid (DHAA) dipeptide derivatives containing the sulfonamide moiety were designed, synthesized and evaluated for inhibition of MMPs as well as the effects of in vitro cell migration. These compounds exhibited relatively good inhibition activity against MMPs with IC50 values in low micromolar range. A docking study of the most active compound 8k revealed key interactions between 8k and MMP-3 in which the sulfonamide moiety and the dipeptide group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU. In particular, compound 8k appeared to be the most potent compound against the HepG2 cell line, at least partly, by inhibition of the activity of MMP-3 and apoptosis induction. The treatment of HepG2 cells with compound 8k resulted in inhibition of in vitro cell migration through wound healing assay and Cl phase of cell cycle arrested. In addition, 8k-induced apoptosis was significantly facilitated in HepG2 cells. Thus, we conclude that DHAA dipeptide derivatives containing the sulfonamide moiety may be the potential MMPs inhibitors with the ability to suppress cells migration. (C) 2017 Elsevier Masson SAS. All rights reserved.