Novel inhibitors of asparagine synthetase, that will lower circulating levels of blood asparagine, have considerable potential in developing new protocols for the treatment of acute lymphoblastic leukemia. We now report the indirect characterization of the aspartate binding site of Escherichia coli asparagine synthetase B (AS-B) using a number of stereochemically, and conformationally, defined aspartic acid analogs. Two compounds, prepared using novel reaction conditions for the stereospecific beta-functionalization of aspartic acid diesters, have been found to be competitive inhibitors with respect to aspartate in kinetic studies on AS-B. Chemical modification experiments employing [(fluorosulfonyl)benzoyl]adenosine (FSBA), an ATP analog, demonstrate that both inhibitors bind to the aspartate binding site of AS-B. Our results reveal that large steric alterations in the substrate are not tolerated by the enzyme, consistent with the failure of previous efforts to develop AS inhibitors using random screening approaches, and that all of the ionizable groups are placed in close proximity in the bound conformation of aspartate.
1,2-Asymmetric Induction in Dianionic FunctionalizationReactions of L-Aspartic Acid Diesters.-The functionalization of dianions derived from aspartic acid esters (I) with various electrophiles (II), (IX), and (XI) is studied. It is shown that the alkylation proceeds with moderate to high anti-selectivity in most cases which is probably due to the formation of a (Z)-lithium ester enolate intermediate. High levels in asymmetric induction are obtained when the alkylation is carried out at temperatures below -50 • C. The stereoselectivity can be reversed to syn-alkylation by increasing the steric bulk of the α-ester group [cf. compound (IVd)]. Reaction of triacid (V), derived from functionalization product (IIIa) by hydrolysis, with paraformaldehyde provides access to oxazolidone (VII), a key precursor of a potential peptidomimetic. -(PARR, IAN B.; DRIBBEN, ANTHONY B.; NORRIS, SIMON R.; HINDS, MARK G.; RICHARDS, NIGEL G.
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