Pyrrolo[2,1-c][1,4] benzodiazepine-3,11-diones protect SHSY-5Y cells from Cd-induced apoptosis involving suppression of endoplasmic reticulum stress.
Pyrrolo[2,1-c][1,4] benzodiazepine-3,11-diones protect SHSY-5Y cells from Cd-induced apoptosis involving suppression of endoplasmic reticulum stress.
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DOI：
10.1016/j.bmc.2018.09.011
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发表时间：
2018-10
影响因子：
3.5
通讯作者：
Chao Ma;Ke Du;Ying Zhao;Linkui Zhang;Baichun Hu;M. Cheng
中科院分区：
文献类型：
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作者：
Chao Ma;Ke Du;Ying Zhao;Linkui Zhang;Baichun Hu;M. Cheng
镉（Cd）是一种毒性很强的重金属，有研究表明Cd通过内质网应激途径诱导细胞凋亡。首次发现吡咯并[2，1-c][1，4]苯并二氮杂卓（PBD）-3，11-二酮类化合物对镉诱导的SH-SY 5 Y细胞毒性具有较强的神经保护作用。本研究合成了26个PBD-3，11-二酮衍生物，并通过CCK-8法评价了它们对镉毒性的神经保护活性。他们的初步SAR研究表明，苯环上的各种取代基是耐受的，并且PBD-3，11-二酮骨架的N10-位上的烷基杂环基团对于活性是重要的。其中化合物13 c的活性最好（细胞活力为68.6%，25 μM）。此外，我们通过Western blotting发现化合物13 c可以通过下调ER应激标志物GRP 78、CHOP、cleaved-caspase 12和cleaved-caspase 3来抑制镉诱导的细胞凋亡。计算机模拟ADME/T特性的结果表明，13 c具有中等的血脑屏障渗透水平和良好的毒性。这些结果证明了13 cas是一种很有前途的抗镉神经毒性的先导化合物。
Cadmium (Cd) is a potent toxic heavy metal, some studies showed that Cd-induced apoptosis is through ER stress pathway. Compounds of pyrrolo[2,1–c][1,4]benzodiazepine (PBD)-3,11-diones were discovered as potent neuroprotective agents against Cd-induced toxicity in SH-SY5Y cells for the first time. In this study, twenty-six PBD-3,11-dione derivatives were synthesized and evaluated for their neuroprotective activity against Cd-induced toxicity by CCK-8 assay. Their preliminary SARs studies indicated that various substituents were tolerated on the benzene ring, and alkyl heterocycles groups at the N10-position of the PBD-3,11-dione scaffold were important for the activities. Among them, compound13cexhibited the best activity (cell viability = 68.6%, 25 μM). Furthermore, we found that the compound13ccould inhibit cadmium-induced cell apoptosis with the downregulation of the ER stress markers GRP78, CHOP, cleaved-caspase12 and cleaved-caspase3 through western blotting. The results ofin silicoevaluation of ADME/T properties showed that13cexhibited medium BBB penetration level and promising toxicity profiles. These results proved the potential of13cas a promising lead compound against Cd-induced neurotoxicity.