Design and Synthesis of Hydroxylamine Derivatives as Indoleamine - 2,3 - Dioxygenase Inhibitors

<p>Current research describing therole of indoleamine 2,3-dioxygenase (IDO) and its mechanism of action suggests that the inhibition of IDO with small molecule inhibitors, especially in conjunction with chemotherapy, can provide an effective and novel cancer treatment strategy. This inspired our search for potent and biocompatible IDO inhibitors. A survey of commercially available, stable mimics of the indolenylper oxo intermediate led to our lead compound, <i>O</i>-benzylhydroxylamine, which exhibited sub-micromolar inhibition towards IDO. Structure-activity studies were conducted and focused on the design and synthesis of <i>O</i> benzylhydroxylamine analogues. The addition of a second aryl ring was discovered to be advantageous and resulted in a series of di-aryl analogues Derivatization around the aryl ring(s) with halogen atoms afforded the most potent analogues, displaying nanomolar level cell-based potency, with limited toxicity. The superior ceullar activity of these inhibitors makes them excellent candidates for further biological exploration as therapeutic agents.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Bryn Mawr only

Discipline thesis:degree_discipline

Chemistry

Year dc:date.available

2014

Author dc:creator

• Winters, Maria

Repository record dc:identifier

https://repository.brynmawr.edu/dissertations/105

OAI identifier oai:identifier

oai:repository.brynmawr.edu:dissertations-1105