Structure-Activity Relationships for the N-Me- Versus N-H-Amide Modification to Macrocyclic ent-Verticilide Antiarrhythmics.
Structure-Activity Relationships for the N-Me- Versus N-H-Amide Modification to Macrocyclic ent-Verticilide Antiarrhythmics.
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N-Me- 与 N-H-酰胺修饰对大环 ent-Verticilide 抗心律失常药的结构-活性关系。
DOI：
10.1021/acsmedchemlett.2c00377
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发表时间：
2022
影响因子：
4.2
通讯作者：
Johnston,JeffreyN
中科院分区：
文献类型：
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作者：
Smith,AbigailN;Thorpe,MadelaineP;Blackwell,DanielJ;Batiste,SuzanneM;Hopkins,CoreyR;Schley,NathanD;Knollmann,BjornC;Johnston,JeffreyN
本文描述了N-Me和N-H类似物的合成，使基于心脏兰尼定受体(RyR2)钙离子通道抑制的构效关系研究成为可能。通透性心肌细胞的使用使我们能够将N-甲基化的程度与活性联系起来，而不需要考虑这些修饰可能导致的被动膜通透性的变化。一个关键的假设是，最小的药效团可能在这个环状低聚八肽(一个24个成员的大环)中重复，从而打开了一种可能性，即单个N-Me→N-H修饰不一定会失去靶标结合。对相应的18元环低聚物(Et-verticilide B1)的影响也进行了考察。我们在此报告，高含量的N-甲基胺对对-轮内酯系列的活性是关键的，但对对-轮内酯B1系列的活性并不完全如此。
The synthesis of allN-Me andN-H analogues ofent-verticilide is described, enabling a structure–activity relationship study based on cardiac ryanodine receptor (RyR2) calcium ion channel inhibition. The use of permeabilized cardiomyocytes allowed us to correlate the degree ofN-methylation with activity without concern for changes in passive membrane permeability that these modifications can cause. A key hypothesis was that the minimal pharmacophore may be repeated in this cyclic oligomeric octadepsipeptide (a 24-membered macrocycle), opening the possibility that target engagement will not necessarily be lost with a singleN-Me →N-H modification. The effect in the corresponding 18-membered ring oligomer (ent-verticilide B1) was also investigated. We report here that a high degree ofN-methyl amide content is critical for activity in theent-verticilide series but not entirely so for theent-verticilide B1 series.