A New Class of Conformationally Rigid Analogues of 4-Amino-5-halopentanoic Acids, Potent Inactivators of γ-Aminobutyric Acid Aminotransferase

Abstract

Recently, we found (Qiu, J.; Pingsterhaus, J. M.; Silverman, R. B. J. Med. Chem. 1999, 42, 4725-4728) that conformationally rigid analogues of the GABA aminotransferase (GABA-AT) inactivator vigabatrin were not inactivators of GABA-AT. To determine if this is a general phenomenon of GABA-AT inactivators, several mono- and di-halogen-substituted conformationally rigid analogues (7-15) of other GABA-AT inactivators, 4-amino-5-halopentanoic acids, were synthesized as potential inactivators of GABA-AT. Four of them, (+)-7, (-)-9, (+)-10, and (+)-15, were inactivators, although not as potent as the corresponding open-chain analogues. The maximal inactivation rate constants, k(inact), for the fluoro- and bromo-substituted analogues were comparable, indicating that cleavage of the C-X bond is not rate determining. Consistent with that observation is the finding that [3-(2)H]-10 exhibits a deuterium isotope effect on inactivation of 3.3, suggesting that C-H bond cleavage is the rate-determining step. The rate of inactivation of GABA-AT by the fluorinated analogue 7 is 1/15 that of inactivation by the corresponding open-chain analogue, 4-amino-5-fluoropentanoic acid (3a). Whereas inactivation by 3a releases only one fluoride ion, inactivation by 7 releases 148 fluoride ions, accounting for the less efficient inactivation rate. Inactivation leads to covalent attachment of 2 equiv of inactivator after gel filtration; upon urea denaturation, 1 equiv of radioactivity remains bound to the enzyme. This suggests that, unlike the open-chain anlogue, the conformationally rigid analogue becomes, at least partially, attached to an active-site residue. It appears that the conformational constraint has a larger effect on inactivators that inactivate by a Michael addition mechanism than by an enamine mechanism.

Crystal structure of 2-(bromomethyl)-4-(4-chlorophenyl)-1-tosylpyrrolidine, C18H19BrClNO2S2

“…The bromine atom can easily be replaced by other functional groups to generate corresponding products [1][2][3][4][5][6][7]. They have been widely used as broad-spectrum anti-bacterial agents [8], these been reported in the utilize of anti-cancer research [9,10] and also arouse a signi cant pharmacological interest [11].…”

Synthesis of γ‐Aminobutyric Acid Analogs

“…Reaction of (558) with (diethylamino)sulfur trifluoride (DAST) and debromination yields the monofluoro compound (561), which can be deprotected and hydrolyzed to afford the monofluoro amino acid (562). Alternatively, debromination and oxidation of (558) to the ketone (559) and treatment with DAST affords the difluoro derivative (564) and the corresponding difluoro amino acid (564) [384]. Conversion of (559) to the iodo derivative (560) facilitates the synthesis of 3-fluoro-cyclopentene and 3-fluoroalkyl-cyclopentene amino acids (568a-c) [385].…”

“…Conversion of (559) to the iodo derivative (560) facilitates the synthesis of 3-fluoro-cyclopentene and 3-fluoroalkyl-cyclopentene amino acids (568a-c) [385]. Debromination and hydrolysis of (557) furnishes the 3-hydroxy derivative (565) which can be converted to the 3-bromo amino acid (566) [384]. Finally the ketone (559) can be converted to alkenes by reaction with fluoromethyl phenylsulfone to yield (567a) [386] or via Horner-Wadsworth-Emmons reactions to yield (567b and c) [387].…”

Catalytic Aminohalogenation of Alkenes and Alkynes

“…[1][2][3][4][5] Some vicinal amines of non-natural origin have also displayed significant bioactivity, for example, chlorambucil, a chemotherapeutic agent that acts by alkylating DNA (Figure 1). …”