Date of Award

August 2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

John D. Chisholm

Keywords

Agonist, Antagonist, AQX-1125, Drug, SHIP, Synthesis

Subject Categories

Physical Sciences and Mathematics

Abstract

Small molecule modulators of SH2-containing inositol 5’-phosphatase (SHIP) have recently become a hotly pursued area in medicinal chemistry. Pharmaceutical targeting of SHIP with small molecules has been identified as a new method to directly influence the phosphoinositide 3-kinase (PI3K) cell signaling pathway. Modulation of this pathway may be utilized in the development of interesting new therapeutics. A better understanding of the role that SHIP phosphatase activity plays in a number of disease states ranging from cancer to autoimmune disease to obesity may be ascertained by use of small molecule inhibitors. These investigations involved the synthesis of aminosteroid inhibitors and a variety of aminosteroid analogs to allow for further evaluation of structure-activity relationships in these systems for both potency and selectivity against both paralogs of SHIP, SHIP1 (primarily expressed in hematopoietic cells) and SHIP2 (expressed across all cell types).

SHIP1 has also been recognized to be an allosterically activated enzyme, with several small molecule agonists having been reported in the literature. These studies have culminated in the identification of AQX-1125, which is currently undergoing phase III clinical evaluation for interstitial cystitis / bladder pain syndrome. To facilitate our own studies on SHIP1 signaling, a new synthetic route to the SHIP1 agonist AQX-1125 has been developed. This route allows for more rapid access to AQX-1125 from dehydroepiandrosterone than the published synthetic pathway, saving time and resources. Key features of the new route include utilizing an allylic oxidation, ozonolysis, and lactonization for a more selective and controlled synthesis. In addition, this work has led to the synthesis of several new AQX-1125 analogs, providing information on structure activity relationships in this structural class of SHIP1 agonists.

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Open Access

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