Date of Award

8-8-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

John Chisholm

Keywords

Cancer;Enzyme Inhibitors;Esterification;Quinolines;Trichloroacetimidates

Subject Categories

Chemistry | Organic Chemistry | Physical Sciences and Mathematics

Abstract

SH2-constaining inositol 5’-phosphatase (SHIP) is an enzyme involved in the PI3K cellular signaling pathway. In response to external stressors, SHIP is recruited to the internal cell membrane of eukaryotic cells to selective hydrolyze the 5’ phosphate group of membrane-bound phosphatidylinositol-3,4,5-trisphosphate (P(3,4,5)P3) to generate phosphatidylinositol-3,4,- bisphosphate (PI(3,4)P2). This process, among others such as phosphorylation by PI3K and dephosphorylation by PTEN, is an intermediate in the transmission of signals from the cell membrane to the cell nucleus, effectively influencing cellular growth and development. Aberrations in these processes are known to influence abnormal cellular function and are observed in certain disease states such as cancer and insulin resistance. Modulation of the activity of SHIP has therefore been found to be a potential avenue for the treatment of such states. Indeed, the inhibition of SHIP by small molecules discovered by high-throughput screening of the NCI Diversity Set has been shown to induce apoptosis in cancer cells. This dissertation reports new milligram- to gram-scale synthetic routes for quinoline aminoalcohols NSC13480 and NSC30578 that were discovered to be active SHIP inhibitors. Additionally, analogues were made, and all molecules were assayed in vitro. Up to 46% inhibition was observed in the isoform SHIP1, while up to 66% inhibition was observed in SHIP2, suggesting that quinolines may be more selective SHIP2 inhibitors. Interestingly, the commercially available anti-malarial drug mefloquine was also shown to inhibit both SHIP1 and SHIP2 almost equally. Trichloroacetimidates (TCIs) are well-known and typically commercially available reagents in organic synthesis. They are often used for the installation of protecting groups for heteroatom functional groups such as alcohols, used in carbon-carbon forming reactions such as in Schmidt’s glycosylations in carbohydrate chemistry, or in Overman’s [3,3]-sigmatropic rearrangement of allylic trichloroacetimidates to trichloroacetamides for the stereoselective conversion of chiral alcohols to chiral amines. While these reactions are very typically acid- catalyzed, the reactions of trichloroacetimidates under mild conditions without any added catalysts or promoters is attractive, especially in cases where molecules may be sensitive to the acidic conditions introduced by the typically strong acids used such as BF3 or TMSOTf. This dissertation reports the development of the catalyst-free esterification reaction of a variety of carboxylic acids using 4-methoxybenzyl trichloroacetimidate. Most carboxylic acids were found to be reactive in dichloromethane at room temperature, including sterically hindered acids secondary- and tertiary- substituted carboxylic acids and Boc-protected amino acids. Additionally, a chiral acid such as Naproxen was successfully esterified without racemization, indicating the mild nature of the reaction conditions.

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