Date of Award

1-24-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

John Chisholm

Keywords

Medicinal Chemistry;Synthesis

Subject Categories

Chemistry | Physical Sciences and Mathematics

Abstract

The PI3K pathway is a major cell signaling axis in eukaryotic cells. This pathway employs the second messenger, inositol phospholipid PI(3,4,5)P3, which is responsible for activating Akt and other kinases creating a cascade of signals. The enzyme, SH2-containing inositol-5’-phosphatase (SHIP), plays a key role in this pathway by maintaining the delicate balance of PI(3,4,5)P3. Modulation of SHIP activity through the use of small molecule inhibitors may be utilized for the treatment of certain types of cancer, Alzheimer’s disease, and diabetes. A high-throughput screen identified the small molecule SHIP1 inhibitor, NSC23922, a mixture of 3α- and 3β-aminocholestane. These diastereomers were synthesized and their inhibitory activity was evaluated. A structure activity relationship (SAR) was also undertaken to improve the potency, selectivity, and solubility. Various aminosteroid analogs were synthesized through modification of the C17, C3, and C2 positions. These synthetic studies and preliminary testing provided insight into the necessary fragments of the steroid structure. Additional studies have been performed involving the discovery and evaluation of hypoxia inducible factor (HIF) antagonists. HIFs are transcription factors responsible for regulating low cellular oxygen levels. The upregulation of HIF target genes modifies certain processes including angiogenesis, glycolysis, and erythropoiesis. The significant role of HIFs makes them potential therapeutic targets. Research has shown HIF-2α is responsible for promoting tumor growth and angiogenesis in renal cancer cells. The discovery of a selective HIF-2α antagonist, through docking studies and MTT screening, led us to synthesize analogs which were tethered to biotin and the BODIPY dye. These compounds were utilized for pull-down and fluorescence assays, respectively, which elucidated the binding between the antagonist and HIF-2α. The investigation of new rhodium carboxylate catalysts was also undertaken. Rhodium carboxylate catalysts are commonly utilized for challenging chemistry including aziridinations, cyclopropanations, and C-H functionalizations. This chemistry can be implemented towards the total synthesis of complex molecules that possess biomedical applications. A diverse collection of Rh catalysts are currently in use, such as Rh2(OAc)2, which provide both regio- and enantioselectivity. Another commercially available catalyst, Rh2(esp)2, developed by Du Bois, has been shown to participate in similar chemistry demonstrating high turnover and increased catalytic activity. Due to the incessant need for better performing catalysts, modifications were made to the Rh2(esp)2 structure, with the hope of improving activity and selectivity. This novel catalyst was investigated with aziridination and C-H activation reactions.

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