Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues.
Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues.
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DOI：
10.3390/md19110630
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发表时间：
2021-11-11
期刊：
影响因子：
5.4
通讯作者：
Han B
中科院分区：
文献类型：
--
作者：
Shen S;Wang W;Chen Z;Zhang H;Yang Y;Wang X;Fu P;Han B
钾通道Kv1.5被认为是房性快速性心律失常新治疗的关键靶点，副作用少。从海洋蓝细菌Lyngbya sp.中分离得到4个新的6/6/12稠环脱溴类毒素类似物，用HRESIMS、1D和2D NMR确定了它们的平面结构。通过单晶X射线衍射确定了黄曲霉毒素J（1）的绝对构型，并根据GIAO NMR位移计算和DP 4分析确定了黄曲霉毒素K（2）、黄曲霉毒素L（3）和黄曲霉毒素M（4）的绝对构型。本研究确定了6/12/6三环体系的传统ATX的关键手性位置（7S、9 S、10 S、11 R、12 S、15 S、29 R和30 R）的绝对构型。化合物1、2和4显示出对Kv1.5的阻断活性，IC 50值分别为2.61 ± 0.91 μM、3.86 ± 1.03 μM和3.79 ± 1.01 μM。然而，化合物3在10 µM时对Kv1.5的影响最小。此外，所有这些新的脱溴黄曲霉毒素类似物在卤虫毒性试验中没有表现出明显的活性。
Potassium channel Kv1.5 has been considered a key target for new treatments of atrial tachyarrhythmias, with few side effects. Four new debromoaplysiatoxin analogues with a 6/6/12 fused ring system were isolated from marine cyanobacterium Lyngbya sp. Their planar structures were elucidated by HRESIMS, 1D and 2D NMR. The absolute configuration of oscillatoxin J (1) was determined by single-crystal X-ray diffraction, and the absolute configurations of oscillatoxin K (2), oscillatoxin L (3) and oscillatoxin M (4) were confirmed on the basis of GIAO NMR shift calculation followed by DP4 analysis. The current study confirmed the absolute configuration of the pivotal chiral positions (7S, 9S, 10S, 11R, 12S, 15S, 29R and 30R) at traditional ATXs with 6/12/6 tricyclic ring system. Compound 1, 2 and 4 exhibited blocking activities against Kv1.5 with IC50 values of 2.61 ± 0.91 µM, 3.86 ± 1.03 µM and 3.79 ± 1.01 µM, respectively. However, compound 3 exhibited a minimum effect on Kv1.5 at 10 µM. Furthermore, all of these new debromoaplysiatoxin analogs displayed no apparent activity in a brine shrimp toxicity assay.
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影响因子：
5.1
作者：
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影响因子：
11.1
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DOI：
10.1080/07391102.2016.1144528
发表时间：
2017-01-01
影响因子：
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作者：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
Tytgat J
DOI：
10.1126/stke.2003.188.re10
发表时间：
2003-06-24
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Armstrong, Clay M
通讯作者：
Armstrong, Clay M