Date of Award

Summer 8-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Chemistry

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

G Protein Coupled Receptors (GPCR’s) are responsible for a multitude of physiological, cellular, and disease processes. GPCR’s signal through non-receptor based heterotrimeric G proteins and since G proteins effectively mediate GPCR signal transduction they are attractive therapeutic targets. However, little is known about the signaling pathways associated with individual G proteins. For this reason, there is intense interest in the development of chemical probes that can help identify the downstream biochemistry of individual G proteins.

One small molecule natural product that shows promise along these lines is YM-254890 (YM). YM has been shown to specifically and potently inhibit the α subunit of the G protein Gq. Further studies of the natural product have been hampered because YM has yet to be synthesized due to its complex cyclic depsipeptide structure. By studying the X-ray crystal structure of YM bound to Gqα, the contact points between the molecule and the protein have been elucidated, and from this we targeted a simplified analog substructure. This analog structure preserves the protein contact points of YM while reducing the complexity of 22 member ring structure of YM. The heart of the project undertaken centers on the development of a convergent synthetic route to the analog’s core ring structure that is general enough to enable the synthesis of a variety of derivatives in the future.

To this effect we have synthesized two different YM analogs. The first, WU-07047, was completed with an overall yield of 6.4% and a longest linear reaction sequence of 10 steps. Initial biological testing of WU-07047 has shown that the simplified molecule is biologically active, albeit at a less potent level than YM. We currently have multiple collaborators testing the effectiveness of WU-07047 in different in-vivo studies. Before undertaking further biological studies in our labs, we wanted to increase the potency of the molecule.

To this end we reintroduced an intramolecular hydrogen bond in the molecule that had been lost in simplified WU-0747 molecule. The 2nd molecule synthesized, WU-09060, was completed using the same convergent synthetic approach developed for WU-07047 and yielded the target molecule with an overall yield of 1.8% and a longest linear reaction sequence of 10 steps. Initial biological testing has shown that the reintroduction of the intramolecular hydrogen bond has had little effect on the potency of the molecule and therefore is not worth the extra synthetic effort. During the synthesis of the WU-09060 molecule we were also able to probe the effects of the top bridging structure of the molecule on ease of overall molecule synthesis, which has larger implications on the synthesis of this class of molecule.

Language

English (en)

Chair and Committee

Kevin D. Moeller

Committee Members

John-Stephen Taylor, Vladimir Birman, Kendall J. Blumer, Garland Marshall

Comments

Permanent URL: https://doi.org/doi:10.7936/K7TM78HK

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