Novel anticancer hybrids from diazen-1-ium-1,2-diolate nitric oxide donor and ROS inducer plumbagin: Design, synthesis and biological evaluations
Novel anticancer hybrids from diazen-1-ium-1,2-diolate nitric oxide donor and ROS inducer plumbagin: Design, synthesis and biological evaluations
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DOI：
10.1016/j.ejmech.2018.04.047
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发表时间：
2018-06-25
影响因子：
6.7
通讯作者：
Chen, Li
中科院分区：
文献类型：
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作者：
Bao, Na;Ou, Jinfeng;Chen, Li
高水平的一氧化氮（NO）和活性氧（ROS）可作为癌细胞的促凋亡信号。在这项研究中，我们共轭diazeniumdiolates（NONOates），一个重要的一类NO供体，与天然存在的白花丹素（PL），这主要是一个很好的ROS诱导剂。本文中，总共合成了12种新的白花丹苷/NONOate杂合体，并评价了它们对一组人癌细胞系（MDA-MB-231、A549、HepG 2和HCT-116细胞）和两种正常人细胞（HK-2和WRL-68细胞）的抑制作用。其中，化合物10 a和10 b对上述癌细胞系表现出比其母体化合物更好的上级效力（IC 50值为3.48-6.68 μ M），但对正常细胞的抑制作用较弱。与它们的选择性细胞毒性一致，10a和10 b在癌细胞中比正常细胞释放更高水平的NO。此外，有效化合物10a以浓度依赖的方式诱导A549细胞凋亡，并导致更多的ROS产生与母体化合物白花丹素相比。(C)2018年Elsevier Masson SAS。All rights reserved.
High levels of both nitric oxide (NO) and reactive oxygen species (ROS) could act as pro-apoptotic signals in cancerous cells. In this study, we conjugated diazeniumdiolates (NONOates), an important class of NO donors, with a natural occurring plumbagin (PL) which is primarily an excellent ROS inducer. Herein, a total of 12 novel plumbagin/NONOate hybrids have been synthesized and evaluated for their inhibitory effects on a panel of human cancer cell lines (MDA-MB-231, A549, HepG2 and HCT-116 cells) and two normal human cells (HK-2 and WRL-68 cells). Among them, compounds 10a and 10b demonstrated superior potencies compared to their parent compound (IC50 values of 3.48-6.68 mu M) against the above cancer cell lines but weak inhibitory effects on normal cells. In concordance with their selective cytotoxicities, 10a and 10b released higher level of NO in cancer cells than normal cells. Besides, the potent compound 10a induced apoptosis of A549 cells in a concentration-dependent manner and resulted in more ROS generation compared with the parent compound plumbagin. (C) 2018 Elsevier Masson SAS. All rights reserved.