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Total synthesis and biological evaluation of phidianidines A and B uncovers unique pharmacological profiles at CNS targets.

ABSTRACT: 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 SERT and NET) and a selective, potent ligand and partial agonist of the ? opioid receptor (versus ?- and ?-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.

SUBMITTER: Brogan JT

PROVIDER: S-EPMC3447392 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Total synthesis and biological evaluation of phidianidines A and B uncovers unique pharmacological profiles at CNS targets.

Brogan John T JT Stoops Sydney L SL Lindsley Craig W CW

ACS chemical neuroscience 20120627 9

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 SERT and NET) and a selective, potent ligand and partial agonist of t ...[more]

PMID: 23019492

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