Synthesis of Endothelin‐1 Analogues, Endothelin‐3, and Sarafotoxin S6b: Structure‐Activity Relationships
Synthesis of Endothelin‐1 Analogues, Endothelin‐3, and Sarafotoxin S6b: Structure‐Activity Relationships
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内皮素-1 类似物、内皮素-3 和 Sarafotoxin S6b 的合成：结构-活性关系
DOI：
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发表时间：
1989
影响因子：
3
通讯作者：
S. Sakakibara
中科院分区：
文献类型：
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作者：
K. Nakajima;S. Kumagaye;H. Nishio;H. Kuroda;Takushi X. Watanabe;Yuji Kobayashi;H. Tamaoki;Terutoshi Kimura;S. Sakakibara
合成了内皮素-3（ET-3;以前称为大鼠ET）、sarafotoxin S6 B和apamin的两种二硫键类似物（A型和B型），以确定其二硫键结构，如内皮素-1（ET-1;以前称为人和猪ET）的情况。ET-3和sarafotoxin S6 B b的二硫键结构与ET-1（A型）相同，但与apamin（B型）不同。ET-3和Sarafotoxin S6 b的缩血管活性分别约为ET-1的1/60和1/3。内皮素和sarafotoxin S6 b之间的这种不同的生物学效力可能在很大程度上归因于N-末端部分的序列异质性。ET-1类似物也被合成，以阐明构效关系。ET-1分子中任何二硫键的打开都极大地降低了活性，而Met残基的氧化并没有改变它。末端COOH基团的酰胺化和Lys-Arg序列向N-末端的延伸分别导致活性降低16倍和540倍。C-末端色氨酸残基的去除导致活性完全丧失。ET-1的其它二硫键类似物（B和C型）的活性明显低于母体分子（A型）。这些结果表明具有适当双环结构的整个分子对决定其活性构象的重要性。
Summary Two disulfide analogues (types A and B) of endothelin-3 (ET-3; formerly, rat ET), sarafotoxin S6b, and apamin, were synthesized to determine their disulfide structures as in the case of endothelin-1 (ET-1; formerly human and porcine ET). The disulfide structures of ET-3 and sarafotoxin S6b were found to be identical with that of ET-1 (type A) but distinct from that of apamin (type B). The vasoconstricting activities of ET-3 and sarafotoxin S6b were about one-60th and one-third that of ET-1, respectively. Such different biological potencies between endothelins and sarafotoxin S6b could be largely attributed to the sequence heterogeneity at the N-terminal portion. ET-1 analogues were also synthesized to clarify the structure-activity relationships. The opening of any disulfide bond in the ET-1 molecule extremely decreased the activity, while oxidation of the Met residue did not alter it. Amidation of the terminal COOH group and extension of the Lys-Arg sequence to the N-terminus led to 16-and 540-fold decreases in activity, respectively. Removal of the C-terminal Trp residue resulted in complete loss of the activity. The other disulfide analogues (type B and C) of ET-1 showed markedly lower activity than the parent molecule (type A). These results indicated the importance of the whole molecule with the proper double cyclic structure for determining its active conformation.