Shreekari Tadepalli
Advisor: Dr. William Malachowski

Department: Chemistry


O-hydroxylamines as IDO Inhibitors

 

Indoleamine 2,3-dioxygenase (IDO) is a naturally-occurring enzyme involved in immune suppression via the deletion of tryptophan. This enzyme is also expressed by cancer cells in a wide range of tumors, thereby suppressing immune response to malignant cells.  Recent data suggests that IDO inhibition is a viable pathway to treat cancer and enhance the antitumor activity of various chemotherapeutic agents.

Research has established O-hydroxylamines as a class of compounds that inhibit IDO, particularly those compounds with phenyl rings and electron withdrawing groups, such as bromine (Br) or trifluoromethyl (CF3). I will work to synthesize molecules within this category via the Mitsunobu reaction, which combines an alcohol and N-hydroxyphthalimide. Previous work in this lab has focused on deprotecting the resulting molecule, cleaving the phthalimide group with hydrazine monohydrate. I will investigate both protected and deprotected forms of these compounds, as well as substituents in different positions on the phenyl ring of the hydroxylamine. Their effectiveness as inhibitors will subsequently be tested on the IDO enzyme using the half maximal inhibitory concentration (IC50) by our collaborators at Lankenau Institute for Medical Research. Conclusions can then be drawn about which configurations of O-hydroxylamines are most potent.