Synthesis and inhibitory properties of α(chlorofluoromethyl)-α-amino acids, a novel class of irreversible inactivators of decarboxylases

Abstract

The synthesis of a-(chlorofluoromethyl) -0rnithine 7, -metatyrosine 8 and -glutamic acid 14 is described. Separation of diastereoisomers and relative configuration assignment by X-ray analysis are reported. Assignment of absolute configuration of the four enantiomers of a-(chlorofluoromethyl)ornithine 7 is also described. The inhibitory properties against ornithine decarboxylase, aromatic amino acid decarboxylase and glutamate decarboxylase are reported in terms of diastereoselectivity (8 and 1 4 ) or enantioselectivity (7).* Available from Fluorochem. Ltd., Peakdale Road, Glossop, Derbyshire, SK13 9XE, England. Freon 21 was condensed at -20 "C in a graduated cylinder.

Design and Synthesis of [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)- ethyl]phosphonic Acid (EAA-090), a Potent N-Methyl-d-aspartate Antagonist, via the Use of 3-Cyclobutene-1,2-dione as an Achiral α-Amino Acid Bioisostere

“…Although the two-carbon side chain length requirement had been optimum for NMDA affinity in the acyclic series, it was deemed necessary to confirm this expectation in the cyclic series. The propenyl side chain (24) was chosen because it would be intermediate in length between the ethyl (15) and propyl (16) side chains. Compound 24 would also possess additional structural constraints, which proved productive in the propenyl derivative of 4 (CPP-ene).…”

“…By having only one of the four mentioned attributes of an amino acid, the 3,4-diamino-3-cyclobutene-1,2-dione group has potential to be more selective in its effects at NMDA versus other receptors, limiting the potential for deleterious side effects. For example, amino acid substrates bind to decarboxylase enzymes by the nucleophilic nitrogen reacting with pyridoxal phosphate to form an imine; a 3,4-diamino-3-cyclobutene-1,2-dione-containing substrate probably would not bind to such a receptor because of its lack of a nucleophilic nitrogen. The discovery of 3 was an exciting finding in the NMDA antagonist area; however, 3 lacks the potency of earlier NMDA antagonists such as 4-(3-phosphonopropyl)-2- piperazinecarboxylic acid ( 4 , CPP) and cis -4-(phosphonomethyl)-2-piperidinecarboxylic acid ( 5 )…”

Phthalimides: Supramolecular Interactions in Crystals, Hypersensitive Solution 1H-NMR Dynamics and Energy Transfer to Europium(III) and Terbium(III) States

“…While factors governing the magnetic susceptibility dynamics that are responsible for the spectacular 1 H-NMR line profiles are still obscure, the potential of such profiles to provide insights into supramolecular interactions [ 1 ], in which the phthalimide moiety so readily engages [ 1 , 2 , 3 , 5 , 6 , 7 , 8 , 9 ], is of great interest. For these reasons, preparation and detailed structural characterization of new examples of phthalimides with potential to exhibit solid state n-π interactions that are accompanied by hypersensitive solution 1 H-NMR spectral profiles were undertaken.…”

Theoretical analysis of fluoroglycine conformers

“…9 Incorporation of fluorinated amino acids into peptides gives analogues of ground-state and transition-state enzyme inhibitors, which have been shown to be useful chemotherapeutic agents. 10 Also, unnatural amino acids that have electronegative substituents in the α position, such as trifluoroalanine (H 2 NCH(CF 3 )CO 2 H), are now routinely incorporated into proteins to induce specific protein activities.…”