Eri Arai and Shorouk Badir

Professor William P. Malachowski

Abstract for Indoleamine 2,3-dioxygenase (IDO) Synthesis

The indoleamine 2,3-dioxygenase (IDO) enzyme inhibitors have demonstrated substantial therapeutic potential towards cancer.  An IDO inhibitor is a small, drug-like molecule that hinders IDO, an enzyme known for driving immune escape, from inappropriately switching on in the presence of developing tumors.  To date, the Malachowski lab has synthesized, optimized, and explored the properties of three structural classes of IDO: dithiocarbamates, the naphthoquinones, and the phenyl-imidazoles.  Currently, the lab is exploring a new structural class of IDO inhibitors called O-alkylhydroxylamine hydrochlorides. Our focus this summer is to synthesize four different highly potent hydroxylamine compounds with 3-chlorobenzyl alcohol, 4-iodo benzyl alcohol, 2,4-dichloro-α-phenyl benzene methanol, and 3,5-dichloro-α-phenyl benzene methanol using the Mitsunobu reaction. These compounds will be sent to the Lankenau Institute of Medical Research for further investigation on their effect on mice tumors. A second important extension of the project will be creating an enantiomerically selective synthesis of the O-(2,4-Dichloro)-α-phenyl benzyl hydroxylamine hydrochloride and the O-(3,5-Dichloro)-α-phenyl benzyl hydroxylamine hydrochloride inhibitor molecules by an asymmetric addition process. Since both compounds are enantiomers, it is likely that one enantiomer is more potent than the other. To date, only racemic mixtures have been tested, so selective generation of each enantiomer should identify the one most potent derivative leading to an even more potent IDO inhibitor.