Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues |
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| Authors: | Sicheng Shen Weiping Wang Zijun Chen Huihui Zhang Yuchun Yang Xiaoliang Wang Peng Fu Bingnan Han |
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| Institution: | 1.Department of Development Technology of Marine Resources, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China; (S.S.); (Z.C.); (H.Z.); (Y.Y.);2.Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (W.W.); (X.W.);3.Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China |
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| Abstract: | 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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| Keywords: | marine cyanobacterium debromoaplysiatoxin analogues absolute configuration Kv1 5 inhibitory activity brine shrimp toxicity |
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