Synthesis of saxitoxin derivatives bearing guanidine and urea groups at C13 and evaluation of their inhibitory activity on voltage-gated sodium channels
Synthesis of saxitoxin derivatives bearing guanidine and urea groups at C13 and evaluation of their inhibitory activity on voltage-gated sodium channels
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DOI：
10.1039/c3ob41398e
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发表时间：
2013-10-14
影响因子：
3.2
通讯作者：
Nagasawa, Kazuo
中科院分区：
文献类型：
--
作者：
Akimoto, Takafumi;Masuda, Asako;Nagasawa, Kazuo
在此，我们描述了通过完全保护的石房蛤毒素酚衍生物8分别合成带有胍、脲基和乙酰胺的第一C13-N-取代的STX衍生物4、5和6。这些化合物是令人感兴趣的，因为先前的石房蛤毒素（STX）与电压门控钠通道（Na（v）Ch）的对接研究表明，STX的C13氨基甲酰基与Na（v）Ch的孔区域中的残基E403相互作用。4和5的Na（v）Ch-抑制活性比十氨甲酰基-STX（3）弱20- 50倍以上，十氨甲酰基-STX（3）的效力比STX低10倍。另一方面，6比3的效力低1000倍。使用EON计算的STX及其类似物4-6中的C13的静电分析表明，这些衍生物的Na（v）CH-抑制活性受到C13处取代基的亲水性和电荷平衡的影响。
Here, we describe the synthesis of the first C13-N-substituted STX derivatives 4,5, and 6 bearing a guanidine, a urea group, and an acetamide, respectively, via the fully protected saxitoxinol derivative 8. These compounds are of interest because a previous docking study of saxitoxin (STX) with voltage-gated sodium channels (Na(v)Ch) suggested that the C13 carbamoyl group of STX interacts with residue E403 in the pore region of Na(v)Ch. In a cell-based assay with Neuro-2a cells, the Na(v)Ch-inhibitory activities of 4 and 5 were more than 20- to 50-fold weaker than that of decarbamoyl-STX (3), which is 10-fold less potent than STX. On the other hand, 6 was 1000 times less potent than 3. The electrostatic analysis of C13 in STX and its analogs 4-6 using EON calculations suggested that the Na(v)Ch-inhibitory activity of these derivatives is influenced by both the hydrophilicity and the charge balance of the substituent at C13.