Structural Diversity and Anticancer Activity of Marine-Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer.
Structural Diversity and Anticancer Activity of Marine-Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer.
复制标题
DOI：
10.1002/cbic.201700627
复制
发表时间：
2018-04-16
期刊：
影响因子：
--
通讯作者：
Luesch H
中科院分区：
文献类型：
--
作者：
Al-Awadhi FH;Paul VJ;Luesch H
从一种海洋蓝藻中发现了三种新的含3-氨基-6-羟基-2-哌啶酮（Ahp）的环状缩酚酸肽，分别命名为loggerpeptin A-C（1-3）沿着糖蜜酰胺（4），扩展了蓝藻丝氨酸蛋白酶抑制剂的结构多样性。环核中含有2-氨基丁烯酸（Abu）单元的莫拉沙胺（4）是抗人中性粒细胞弹性蛋白酶（HNE）最有效和选择性的类似物。鉴于越来越多的证据支持HNE在乳腺癌进展和转移中的作用，我们评估了化合物3和4在靶向浸润性乳腺癌的背景下的细胞效应。这两种化合物在生物化学测定中抑制弹性蛋白酶底物CD 40的裂解;然而，只有4种化合物表现出显著的细胞活性。由于CD 40和其他受体蛋白水解过程在NF κ B活化中达到高潮，我们评估了对靶基因（包括ICAM-1）表达的影响。ICAM-1也是弹性蛋白酶的直接靶标，并且在我们的研究中，化合物4减弱弹性蛋白酶诱导的ICAM-1基因表达和弹性蛋白酶对ICAM-1的蛋白水解加工，揭示了通过调节基因表达和蛋白水解加工对迁移的潜在双重作用。莫拉沙胺（4）特异性抑制弹性蛋白酶介导的高度侵袭性三阴性乳腺癌细胞的迁移。对从佛罗里达Loggerhead Key采集的海洋蓝细菌进行化学探索，发现了三种新的弹性蛋白酶抑制剂，即loggerpeptin A-C（1-3）、沿着的糖蜜酰胺（4），它们可能对癌症有价值。最有效的类似物Molassamide（4）显示出抑制CD 40的切割、其下游靶ICAM-1的表达和切割、逆转HNE诱导的形态学变化以及弹性蛋白酶诱导的侵袭性乳腺癌细胞的迁移。
Three new 3-amino-6-hydroxy-2-piperidone (Ahp)-containing cyclic depsipeptides named loggerpeptins A–C (1–3) along with molassamide (4) were discovered from a marine cyanobacterium, extending the structural diversity of this prevalent scaffold of cyanobacterial serine protease inhibitors. Molassamide (4), containing the 2-amino-butenoic (Abu) unit in the cyclic core, was the most potent and selective analogue against human neutrophil elastase (HNE). Given the growing evidence supporting the role of HNE in breast cancer progression and metastasis, we assessed the cellular effects of compounds 3 and 4 in the context of targeting invasive breast cancer. Both compounds inhibited the cleavage of the elastase substrate CD40 in biochemical assays; however, only 4 exhibited significant cellular activity. Since CD40 and other receptor proteolytic processing culminates in NFKB activation, we assessed the effects on the expression of target genes, including ICAM-1. ICAM-1 is also a direct target of elastase, and in our studies compound 4 attenuated both elastase-induced ICAM-1 gene expression and ICAM-1 proteolytic processing by elastase, revealing a potential dual effect on migration through modulation of gene expression and proteolytic processing. Molassamide (4) specifically inhibited the elastase-mediated migration of highly invasive triple negative breast cancer cells. The chemical exploration of a marine cyanobacterium collected from Loggerhead Key, Florida led to the discovery of three new elastase inhibitors, loggerpeptins A–C (1–3), along with molassamide (4) that may have a value in the context of cancer. Molassamide (4), the most potent analogue, was shown to inhibit the cleavage of CD40, the expression and cleavage of its downstream target ICAM-1, reverse HNE-induced morphological changes as well as the elastase-induced migration of invasive breast cancer cells.
登录
查看更多内容
影响因子：
11.2
作者：
Mittendorf EA;Alatrash G;Qiao N;Wu Y;Sukhumalchandra P;St John LS;Philips AV;Xiao H;Zhang M;Ruisaard K;Clise-Dwyer K;Lu S;Molldrem JJ
通讯作者：
Molldrem JJ
咖啡酸苯乙酯与人中性粒细胞弹性蛋白酶之间的直接相互作用抑制 PANC-1 细胞的生长和迁移。
影响因子：
4.2
作者：
Duan, Jianhui;Xiaokaiti, Yilixiati;Li, Xuejun
通讯作者：
Li, Xuejun
影响因子：
3.2
作者：
Aikawa, Naoki;Ishizaka, Akitoshi;Kawasaki, Yasushi
通讯作者：
Kawasaki, Yasushi
影响因子：
5.4
作者：
Al-Awadhi FH;Salvador LA;Law BK;Paul VJ;Luesch H
通讯作者：
Luesch H
影响因子：
11.2
作者：
Aronchik, Ida;Bjeldanes, Leonard F.;Firestone, Gary L.
通讯作者：
Firestone, Gary L.