Total Synthesis and Biological Evaluation of Phidianidines A and B Uncovers Unique Pharmacological Profiles at CNS Targets
Total Synthesis and Biological Evaluation of Phidianidines A and B Uncovers Unique Pharmacological Profiles at CNS Targets
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DOI：
10.1021/cn300064r
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发表时间：
2012-09-01
影响因子：
5
通讯作者：
Lindsley, Craig W.
中科院分区：
文献类型：
--
作者：
Brogan, John T.;Stoops, Sydney L.;Lindsley, Craig W.
本文报道了从海洋后鳃软体动物北菲迪亚（Phidianamilitaris）中合成的第一个含1，2，4-恶二唑的生物碱--菲迪亚尼丁A和B。该合成从已知的吲哚乙酸以39.9%（phidianidine A）和21%（phidianidine B）的总收率从市售材料分六步进行。生物学特性鉴定发现，菲迪苯胺A和B是DAT的选择性抑制剂（相对于SEAT和NET），也是μ阿片受体的选择性、强效配体和部分激动剂（相对于δ-和κ-阿片受体）。此外，phidianidine A和B都不是细胞毒性的，因此代表了化学优化的有吸引力的起点;因此，我们试验了许多化学方法并制备了一系列不同的非天然类似物。
The synthesis of phidianidines A and B, the first 1,2,4-oxadiazole-containing alkaloid, from the marine opisthobranch mollusk Phidiana militaris is reported. The synthesis proceeds in six steps from known indole acetic acids in 39.9% (phidianidine A) and 21% (phidianidine B) overall yields from commercially available materials. Biological characterization found that phidianidines A and B are selective inhibitors of DAT (versus SEAT and NET) and a selective, potent ligand and partial agonist of the mu opioid receptor (versus delta- and kappa-opioid receptors). Moreover, neither phidianidines A and B are cytotoxic, and thus represent an attractive starting point for chemical optimization; therefore, we piloted a number of chemistries and prepared a diverse series of unnatural analogs.