Date of Award

Winter 12-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Chemistry

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The G-protein coupled cell receptor signaling pathway is amongst the largest and most diverse class of cell-surface receptors in the body. Nearly 800 different genes encode for these cell membrane receptors which are responsible for mediating a variety of hormones, neurotransmitters, and sensory stimuli through the activation of intracellular G proteins. To date, roughly 34% of pharmaceuticals on the market target GPCR’s, but despite this fact, there are still many difficulties associated with targeting this family of receptors. The vast number of GPCR’s, disease states resulting from a dysregulation of multiple GPCR signaling pathways, and difficulties crystalizing and purifying the receptor—G-protein complex all pose significant challenges for targeting GPCR’s. Due to these challenges, in recent years there has been a growing interest in targeting the intracellular G protein as an alternative to the extracellular GPCR. For example, two known natural products YM-254890 and FR-900359, isolated from Chromobacterium sp. QS3666 and Ardisia Crenata respectively, potently and selectively inhibit signaling by Gq/11-class G-protein α subunits by trapping them in their inactive GDP-bound states. As part of an effort to better understand how these natural products operate and to develop chemical probes for the Gq signaling pathway we have developed a scalable solution phase synthesis of simplified analogs of YM/FR that retain important regions responsible for binding to Gαq.Through the use of this convergent synthesis with a longest linear sequence of eight steps with an overall yield of 11.6%. We have successfully synthesized multiple analogs used to probe the G-protein cell receptor signaling pathway. While the analogs synthesized to date are not as potent as YM or FR, they do selectively bind to Gαq. With these results in place, we are now probing the factors that are responsible for binding and potency of the analogs for Gq, along with factors that determine the selectivity of the molecules for Gαq.To this end, we have developed a new convergent synthesis, applying the lessons learned from our second-generation synthesis, that returns functionality found in the natural products. We believe the instillation of the “bottom bridge”, a dimer of an N-Me-O-Me-Thr and N-Ac-Thr, will provide conformational constraint and return activity lost in the first generation of analogs. Once more active analogs have been found, these molecules will be used as probes for understanding the biological function of the Gq signaling pathway and as potential lead compounds for the development of future therapeutics.

Language

English (en)

Chair and Committee

Kevin D. Moeller

Committee Members

Vladimir Birman, Timothy Wencewicz, Kendall J. Blumer, Jonathan Barnes,

Comments

Permanent URL: https://doi.org/10.7936/1mp6-0348

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