Total Synthesis and Biological Evaluation of Alkaloid Natural Products (+)-7-Bromotrypargine and Phidianidines A & B and the Development of a Novel Class of Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1

Abstract

The first total synthesis of (+)-7-bromotrypargine, a β-carboline alkaloid from Ancornia sp. was completed in 9 steps, 8 steps longest linear sequence, and 40% overall yield. Biological characterization found that (+)-7-bromotrypargine is a histamine 3 receptor antagonist, and a selective inhibitor of the dopamine transporter and norepinephrine transporter, without inhibiting the serotonin transporter. Moreover, unlike electron rich congeners, (+)-7-bromotrypargine is not cytotoxic, and thus represents an attractive starting point for chemical optimization; therefore, we synthesized a number of unnatural analogs. The total synthesis of phidianidines A and B, the first 1,2,4-oxadiazole-containing alkaloids, from the marine opisthobranch mollusk Phidiana militaris was completed in seven steps in 39% (phidianidine A) and 20% (phidianidine B) overall yields. Biological characterization found that phidianidines A and B are selective inhibitors of dopamine transporter (versus the norepinephrine and serotonin transporters) and selective, potent ligands and partial agonists of the μ-opioid receptor (versus δ- and κ-opioid receptors). Moreover, neither phidianidines A nor B are cytotoxic, and thus represent an attractive starting point for chemical optimization; therefore, we prepared a diverse series of unnatural analogs. A parallel synthesis approach was utilized to probe the VU-48/71 and VU0405623 lead series toward the development of a novel, potent, and selective positive allosteric modulator for the human metabotropic glutamate receptor subtype 1 (hmGlu1 PAMs). After multiple rounds of parallel synthesis, calcium fluorescence assays revealed that new structure-activity-relationships engendering selectivity for hmGlu1 over other subtypes of the receptor were confirmed around the VU0405623 scaffold.