Electronic Theses and Dissertations

Date of Award

2013

Document Type

Dissertation

Degree Name

M.S. in Pharmaceutical Science

Department

Biomolecular Sciences

First Advisor

John M. Rimoldi

Second Advisor

Christopher R. Mccurdy

Third Advisor

Stephen J. Cutler

Relational Format

dissertation/thesis

Abstract

Marine sponges represent an excellent source of sphingolipids and their metabolites, especially sphingosine-1-phosphate (S1P). S1P plays an important role in cell differentiation, survival, proliferation and the immune response. The enzyme sphingosine kinase (SK) is critical for the phosphorylation of sphingosine to S1P and has been examined as a druggable target for the treatment of hyper-proliferative diseases, inflammation, cancer and other pathological conditions. Natural products that consist of an azetidine ring represents an interesting class of conformationally constrained scaffolds that may serve as effective lead compounds for SK inhibitor development. Hence, the goal of this thesis research was to synthesize natural-product based sphingosine analogs from easily accessible precursors. Our initial approach was to synthesize azetidine from the commercially available cinnamyl alcohol. The described synthetic methodology is proficient and scalable for the synthesis of fully substituted azetidines. We were successful at preparing two azetidine analogs, (±)-30 and (±) -31, via an intramolecular Mitsunobu reaction as a key step. Another crucial technique is the Grubbs' cross-metathesis reaction to the side-chain extension. This reaction provides an opportunity to develop various analogs through side-chain modification. Compound (±)-30 was synthesized in 11 steps and compound (±)-31 was synthesized in 10 steps with affordable overall yield. The described synthetic methodology represents a promising tool for the invention of various analogs of the natural products and the synthesized compounds will serve as lead compounds for the future optimizations.

Concentration/Emphasis

Emphasis: Medicinal Chemistry

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