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显示对钾通道Kv1.5有抑制作用的海兔毒素衍生物的化学和生物学研究。

Chemical and biological study of aplysiatoxin derivatives showing inhibition of potassium channel Kv1.5.

作者信息

Tang Yang-Hua, Wu Jing, Fan Ting-Ting, Zhang Hui-Hui, Gong Xiao-Xia, Cao Zheng-Yu, Zhang Jian, Lin Hou-Wen, Han Bing-Nan

机构信息

Research Center of Marine Biology and Natural Products, College of Life Sciences and Medicine, Zhejiang Sci-Tech University Hangzhou 310018 China

Department of Pharmacy, Graduate School, Hunan University of Chinese Medicine Changsha 410208 People's Republic of China.

出版信息

RSC Adv. 2019 Mar 6;9(14):7594-7600. doi: 10.1039/c9ra00965e.

DOI:10.1039/c9ra00965e
PMID:35521179
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9061199/
Abstract

Three new aplysiatoxins, neo-debromoaplysiatoxin D (1), oscillatoxin E (2) and oscillatoxin F (3), accompanied by four known analogues (4-7), were identified from the marine cyanobacterium sp. Structural frames differ amongst these metabolites, and therefore we classified compounds 1 and 4-6 as aplysiatoxins as they possess 6/12/6 and 6/10/6 tricyclic ring systems featuring a macrolactone ring, and compounds 2, 3 and 7 as oscillatoxins that feature a hexane-tetrahydropyran in a spirobicyclic system. Bioactivity experiments showed that compounds 1 and 4-6 presented significant expression of phosphor-PKCδ whereas compounds 2, 5 and 7 showed the most potent blocking activity against potassium channel Kv1.5 with IC values of 0.79 ± 0.032 μM, 1.28 ± 0.080 μM and 1.47 ± 0.138 μM, respectively. Molecular docking analysis supplementing the binding interaction of oscillatoxin E (2) and oscillatoxin F (3) with Kv1.5 showed oscillatoxin E (2) with a strong binding affinity of -37.645 kcal mol and oscillatoxin F (3) with a weaker affinity of -32.217 kcal mol, further supporting the experimental data.

摘要

从海洋蓝藻中鉴定出三种新的海兔毒素，即新脱溴海兔毒素D（1）、振荡毒素E（2）和振荡毒素F（3），同时还伴有四种已知类似物（4 - 7）。这些代谢产物的结构框架各不相同，因此我们将化合物1以及4 - 6归类为海兔毒素，因为它们具有6/12/6和6/10/6三环系统并带有一个大环内酯环，而将化合物2、3和7归类为振荡毒素，其特征是在螺双环系统中含有一个己烷 - 四氢吡喃。生物活性实验表明，化合物1以及4 - 6呈现出显著的磷酸化PKCδ表达，而化合物2、5和7对钾通道Kv1.5表现出最强的阻断活性，IC值分别为0.79±0.032μM、1.28±0.080μM和1.47±0.138μM。补充振荡毒素E（2）和振荡毒素F（3）与Kv1.5结合相互作用的分子对接分析表明，振荡毒素E（2）具有-37.645千卡/摩尔的强结合亲和力，振荡毒素F（3）具有-32.217千卡/摩尔的较弱亲和力，这进一步支持了实验数据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/9c2c0b4cb6b6/c9ra00965e-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/3ff74f5e62c4/c9ra00965e-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/18546f66e25d/c9ra00965e-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/bdab96bef9d9/c9ra00965e-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/bbf78be2942b/c9ra00965e-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/aeaa6a95dbca/c9ra00965e-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/4147b10b1bb2/c9ra00965e-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/9c2c0b4cb6b6/c9ra00965e-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/3ff74f5e62c4/c9ra00965e-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/18546f66e25d/c9ra00965e-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/bdab96bef9d9/c9ra00965e-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/bbf78be2942b/c9ra00965e-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/aeaa6a95dbca/c9ra00965e-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/4147b10b1bb2/c9ra00965e-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1dd9/9061199/9c2c0b4cb6b6/c9ra00965e-f7.jpg

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