Efficient synthesis of α-fluoromethylhistidine di-hydrochloride and demonstration of its efficacy as a glutathione S-transferase inhibitor

Abstract

Histidine decarboxylase (HDC) is an enzyme that converts histidine to histamine. Inhibition of HDC has several medical applications, and HDC inhibitors are of considerable interest for the study of histidine metabolism. (S)-α-Fluoromethylhistidine di-hydrochloride (α-FMH) is a potent HDC inhibitor that is commercially available at high cost in small amounts only. Here we report a novel, inexpensive, and efficient method for synthesis of α-FMH using methyl 2-aziridinyl-3-(N-triphenylmethyl-4-imidazolyl) propionate and HF/pyridine, with experimental yield of 57%. To identify novel targets for α-FMH, we developed a three step in silico work-flow for identifying physically plausible protein targets. The work-flow resulted in 21 protein target hits, including several enzymes involved in glutathione metabolism, and notably, two isozymes of the glutathione S-transferase (GST) superfamily, which plays a central role in drug metabolism. In view of this predictive data, the efficacy of α-FMH as a GST inhibitor was investigated in vitro. α-FMH was demonstrated to be an effective inhibitor of GST at micromolar concentration, suggesting that off-target effects of α-FMH may limit physiological drug metabolism and elimination by GST-dependent mechanisms. The present study therefore provides new avenues for obtaining α-FMH and for studying its biochemical effects, with potential implications for drug development.

Keywords: Glutathione S-transferase; Histidine decarboxylase; Reverse docking; α-Fluoromethylhistidine di-hydrochloride.