Synthesis of potential inhibitors targeting enzymes involved in methionine biochemistry

Abstract

Methionine is involved in numerous biological functions which range from its bioincorporation into proteins, its post-translational removal from proteins and its contribution to the cofactor S-adenosyl-L-methionine. The diverse metabolic pathways that utilize methionine and S-adenosyl-L-methionine are of great pharmacological interest. A series of compounds, which target some key enzymes involved in methionine biochemistry, have been prepared.

The design and synthesis of several sulfamoyl-containing nucleosides was accomplished which contained side chains consisting of methionine and trifluoromethionine. The synthesis was completed by peptide coupling of an activated amino acid and a sulfamoyl nucleoside.

Several multisubstrate analogue inhibitors of catechol-O-methyltransferase were prepared. The analogues were based on the skeleton of S-adenosyl-L-homocysteine in which the sulfur atom was substituted by a nitrogen atom. The synthesis of the phenethyl analogue, 5'-[N-(3S)-3-Amino-3-carboxypropyl]-N-(2-phenethyl)amino]-5'-deoxyadenosine, was accomplished through the alkylation of a phenethylatmino nucleoside analogue with an iodoalkyl amino acid. Protecting group manipulation was key to the completion of the synthesis as amino acid analogues which carried bulky protecting groups hindered the alkylation. The synthesis of an O-benzyl derivative was unsuccessful due to the inability to alkylate the nitrogen in this system.