Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues

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 <i>Lyngbya</i> sp. Their planar structures were e...

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Autores principales:	Sicheng Shen, Weiping Wang, Zijun Chen, Huihui Zhang, Yuchun Yang, Xiaoliang Wang, Peng Fu, Bingnan Han
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	marine cyanobacterium debromoaplysiatoxin analogues absolute configuration Kv1.5 inhibitory activity brine shrimp toxicity Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7c31b6140be4450a9a86d853edfdb956
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spelling	oai:doaj.org-article:7c31b6140be4450a9a86d853edfdb9562021-11-25T18:12:56ZAbsolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues10.3390/md191106301660-3397https://doaj.org/article/7c31b6140be4450a9a86d853edfdb9562021-11-01T00:00:00Zhttps://www.mdpi.com/1660-3397/19/11/630https://doaj.org/toc/1660-3397Potassium 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 <i>Lyngbya</i> sp. Their planar structures were elucidated by HRESIMS, 1D and 2D NMR. The absolute configuration of oscillatoxin J (<b>1</b>) was determined by single-crystal X-ray diffraction, and the absolute configurations of oscillatoxin K (<b>2</b>), oscillatoxin L (<b>3</b>) and oscillatoxin M (<b>4</b>) 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 <b>1</b>, <b>2</b> and <b>4</b> exhibited blocking activities against Kv1.5 with IC<sub>50</sub> values of 2.61 ± 0.91 µM, 3.86 ± 1.03 µM and 3.79 ± 1.01 µM, respectively. However, compound <b>3</b> 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.Sicheng ShenWeiping WangZijun ChenHuihui ZhangYuchun YangXiaoliang WangPeng FuBingnan HanMDPI AGarticlemarine cyanobacteriumdebromoaplysiatoxin analoguesabsolute configurationKv1.5 inhibitory activitybrine shrimp toxicityBiology (General)QH301-705.5ENMarine Drugs, Vol 19, Iss 630, p 630 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	marine cyanobacterium debromoaplysiatoxin analogues absolute configuration Kv1.5 inhibitory activity brine shrimp toxicity Biology (General) QH301-705.5
spellingShingle	marine cyanobacterium debromoaplysiatoxin analogues absolute configuration Kv1.5 inhibitory activity brine shrimp toxicity Biology (General) QH301-705.5 Sicheng Shen Weiping Wang Zijun Chen Huihui Zhang Yuchun Yang Xiaoliang Wang Peng Fu Bingnan Han Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues
description	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 <i>Lyngbya</i> sp. Their planar structures were elucidated by HRESIMS, 1D and 2D NMR. The absolute configuration of oscillatoxin J (<b>1</b>) was determined by single-crystal X-ray diffraction, and the absolute configurations of oscillatoxin K (<b>2</b>), oscillatoxin L (<b>3</b>) and oscillatoxin M (<b>4</b>) 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 <b>1</b>, <b>2</b> and <b>4</b> exhibited blocking activities against Kv1.5 with IC<sub>50</sub> values of 2.61 ± 0.91 µM, 3.86 ± 1.03 µM and 3.79 ± 1.01 µM, respectively. However, compound <b>3</b> 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.
format	article
author	Sicheng Shen Weiping Wang Zijun Chen Huihui Zhang Yuchun Yang Xiaoliang Wang Peng Fu Bingnan Han
author_facet	Sicheng Shen Weiping Wang Zijun Chen Huihui Zhang Yuchun Yang Xiaoliang Wang Peng Fu Bingnan Han
author_sort	Sicheng Shen
title	Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues
title_short	Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues
title_full	Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues
title_fullStr	Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues
title_full_unstemmed	Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues
title_sort	absolute structure determination and kv1.5 ion channel inhibition activities of new debromoaplysiatoxin analogues
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7c31b6140be4450a9a86d853edfdb956
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Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues

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