Synthetic Studies on Small Molecule Src Homology 2 Domain Containing Inositol 5’Phosphatase (SHIP) Modulators and Studies towards the Design and Synthesis of a SHIP PROTAC

The PI3K pathway is a biological pathway of great importance to the biomedical community. PI3K and mutations associated with it have often associated as the cause for various disease states due to its role in signaling other enzymes such as AKT. Targeting PI3K is one way to help regulate the PI3K pathway but there are other enzymes such as SHIP that also contribute to the delicate balance of the cell. It has been proposed that the modulation of SHIP could also provide some therapeutic benefit as its behavior opposes that of PI3K. Detailed in this work is the design and synthesis of aminosteroid inhibitors as well as agonist studies involving the optimization of an AQX-1125 analog synthetic route. These inhibitors and agonists may be used further to help analyze the role SHIP plays in certain disease states such as Alzheimer’s Disease. Proteolysis Targeting Chimeras or PROTACs have become a topic of discussion in the biomedical community in recent years. They provide an alternate route of modulating proteins by lowering protein levels in cells as opposed to inhibitor-based strategies. The potential for this strategy to be of therapeutic relevance is immense as it allows for the targeting of proteins and receptors, even ones that do not have enzymatic roles. A proper PROTAC can also incorporate a weak binding inhibitor and still be a potent and selective therapeutic which expands the library of possibilities for protein targets. With these studies, two proposed SHIP based PROTACs were synthesized and made. If proven to degrade SHIP, these molecules could provide valuable knowledge towards the role SHIP plays in disease. These molecules would also be useful in probing the scaffolding role of SHIP which has not been investigated in human disease

Esterifications with 2-(Trimethylsilyl)ethyl 2,2,2-Trichloroacetimidate

2-(Trimethylsilyl)ethyl 2,2,2-trichloroacetimidate is readily synthesized from 2-trimethylsilylethanol in high yield. This imidate is an effective reagent for the formation of 2-trimethylsilylethyl esters without the need for an exogenous promoter or catalyst, as the carboxylic acid substrate is acidic enough to promote ester formation without an additive. A deuterium labeling study indicated that a β-silyl carbocation intermediate is involved in the transformation

Esterifications with 2-(Trimethylsilyl)ethyl 2,2,2- Trichloroacetimidate

2-(Trimethylsilyl)ethyl 2,2,2-trichloroacetimidate is readily synthesized from 2-trimethylsilylethanol in high yield. This imidate is an effective reagent for the formation of 2-trimethylsilylethyl esters without the need for an exogenous promoter or catalyst, as the carboxylic acid substrate is acidic enough to promote ester formation without an additive. Deuterium labeling studies indicate that a β-silyl carbocation intermediate is involved in the transformation.</p

Synthetic Studies on the Indane SHIP1 Agonist AQX-1125.

A new synthetic route to the SHIP1 agonist AQX-1125 has been developed. This sequence utilizes a hydroxy-acid intermediate which allows for ready differentiation of the C6 and C7 positions. The role of the C17 alkene in the biological activity of the system is also investigated, and this functional group is not required for SHIP1 agonist activity

Relationships Between Game Attributes and Learning Outcomes: Review and Research Proposals

Games are an effective and cost-saving method in education and training. Although much is known about games and learning in general, little is known about what components of these games (i.e., game attributes) influence learning outcomes. The purpose of this article is threefold. First, we review the literature to understand the “state of play” in the literature in regards to learning outcomes and game attributes—what is being studied. Second, we seek out what specific game attributes have an impact on learning outcomes. Finally, where gaps in the research exist, we develop a number of theoretically based proposals to guide further research in this area