Synthesis of Thiohydantoin Tryptophan Derivatives as Indoleamine-2, 3-Dioxygenase Inhibitors

Posted May 26th, 2010 at 3:12 pm.

Ronke Imbeah-Ampiah

Mentor: Dr. William Malachowski

Recent studies have shown that tumor cells express the enzyme indoleamine-2, 3-dioxygenase (IDO). The catalytic activity of this enzyme protects the tumor from attack by T cells thus encouraging the growth and multiplication of the tumor cells.

Thiohydantoin derivatives of tryptophan have been identified as moderate inhibitors of the enzyme IDO. One synthetic pathway of these enzyme inhibitors begins with the synthesis of glycine thiohydantoin derivatives from glycine methyl ester and isothiocyanate. The glycine thiohydantoin derivative is then reacted with indole-3-carboxaldehyde derivatives to form a dehydro product which is reduced to form the desired thiohydantoin derivative and potential inhibitor.

An alternative synthetic pathway involves the reaction between an alpha-amino ester and methyl isothiocyanate. To produce an alpha-amino ester, an indole carboxyaldehyde derivative is first protected with a t-butoxycarbonyl protecting group (BOC-group) in the presence of DMAP and dichloromethane. The BOC indole is then reacted with a glycine phosphonate trimethyl ester derivative in 1,1,3,3-tetramethyl guanidine and THF to form a didehydro tryptophan derivative. The reduction and deprotection of the didehydro tryptophan derivative results in the alpha-amino ester which reacts with an isothiocyanate derivative in triethyl amine and dichloromethane to form a thiohydantoin derivative. Importantly, the reduction process can be performed stereoselectively to form one particular enantiomer.

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