Synthesis of a phosphinic acid containing inhibitor of trypanothione synthetase

Gould, Alex, Kevin Smalley, Samual Reiter, Justin Schupbach, and David Bartley

Several parasitic species including Trypanosoma and Leishmania utilize N1, N8-(bisglutathionyl)spermidine (trypanothione, TSH) as part of their defense mechanism against oxidative and chemical stress and to regulate polyamine levels.  Their mammalian hosts on the other hand use glutathione for this purpose.  Since these parasites utilize TSH instead of glutathione, the TSH biosynthetic pathway is a logical target for inhibition in order to avoid harm to the host and is a potential target for drug design.

The enzyme responsible for TSH biosynthesis in these parasites is trypanothione synthetase.  TSH synthetase is an ATP-dependent ligase which catalyzes the synthesis of TSH from glutathionylspermidine and glutathione.  The design and progress toward the synthesis of a phosphinic acid containing inhibitor of TSH synthetase will be presented.