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Total Synthesis and Biological Evaluation of Phidianidines A and B Uncovers Unique Pharmacological Profiles at CNS Targets
journal contribution
posted on 2012-09-19, 00:00 authored by John T. Brogan, Sydney L. Stoops, Craig W. LindsleyThe 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
SERT and NET) and a selective, potent ligand and partial agonist of
the μ opioid receptor (versus δ- and κ-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.