Synthesis of potential inhibitors targeting enzymes involved in methionine biochemistry

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 phenethylamino 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.;The design and synthesis of several sterol-based potential inhibitors of the enzyme sterol-Delta24-methyltransferase was accomplished. Reductive amination of a side-chain aldehyde of a protected sterol with several amino acids and a nucleoside analogue resulted in compounds which carry a C-25 amino group, which may serve to mimic the C-25 carbocation intermediate of an AdoMet-dependant methylation of a sterol.;The synthesis of organophosphorus analogues of methionine were prepared and utilized in a collaborative study to deduce the catalytic mechanism of the Escherichia coli methionine aminopeptidase.;Organophosphorus analogues of both S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) were prepared. Compounds were prepared in which the alpha-carboxyl moiety was replaced with an isosteric phosphonic acid functionality. The synthesis was accomplished by coupling an adenosine analogue containing a nucleophilic sulfur in the 5'-position with an alpha-aminophosphonate carrying a side-chain halogen suitable for displacement. The halogen-containing alpha-aminophosphonate analogue was prepared through alkylation of a Schiff-base intermediate. Intriguing chemistry was developed for the expedient preparation of the alpha-aminophosphonate Schiff-base synthon through DDQ-mediated imine formation. This oxidative method of imine formation was investigated further as a mild method for deprotection of diphenylmethylamines. A similar approach was attempted to prepare alpha-aminophosphinic acid analogues of both AdoHcy and AdoMet. Thus far, a protected AdoHcy derivative has been prepared using this methodology.