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Title page for ETD etd-07182013-112209

Type of Document Dissertation
Author Brogan, John Trevor
URN etd-07182013-112209
Title 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
Degree PhD
Department Chemical and Physical Biology
Advisory Committee
Advisor Name Title
Lawrence J. Marnett Committee Chair
Brian O. Bachmann Committee Member
Craig W. Lindsley Committee Member
Gary A. Sulikowski Committee Member
J. Scott Daniels Committee Member
  • opioid
  • H3
  • SERT
  • DAT
  • NET
  • natural product
  • alkaloid
  • mGlu1 PAM
Date of Defense 2013-05-08
Availability unrestricted
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.

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