Nicholas R. Natale

System xc⁻ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS.

System xc‐ is an amino acid antiporter that typically mediates the exchange of extracellular l‐cystine and intracellular l‐glutamate across the cellular plasma membrane. Studied in a variety of cell types, the import of l‐cystine through this transporter is critical to glutathione production and oxidative protection. The exchange‐mediated export of l‐glutamate takes on added significance within the CNS, as it represents a non‐vesicular route of release through which this excitatory neurotransmitter can participate in either neuronal signalling or excitotoxic pathology. When both the import of l‐cystine and the export of l‐glutamate are taken into consideration, system xc‐ has now been linked to a wide range of CNS functions, including oxidative protection, the operation of the blood–brain barrier, neurotransmitter release, synaptic organization, viral pathology, drug addiction, chemosensitivity and chemoresistance, and brain tumour growth. The ability to selectively manipulate system xc‐, delineate its function, probe its structure and evaluate it as a therapeutic target is closely linked to understanding its pharmacology and the subsequent development of selective inhibitors and substrates. Towards that goal, this review will examine the current status of our understanding of system xc‐ pharmacology and the structure–activity relationships that have guided the development of an initial pharmacophore model, including the presence of lipophilic domains adjacent to the substrate binding site. A special emphasis is placed on the roles of system xc‐ within the CNS, as it is these actions that are among the most exciting as potential long‐range therapeutic targets.

Selective reduction of isoxazoles with samarium diiodide

Abstract Samarium diiodide is an efficient reagent for the reductive cleavage of the ON bond of isoxazoles. Olefins, esters, and acetals are stable to the reaction conditions, benzylic halides and aldehydes are not.

THE DIRECT SYNTHESIS OF 2-OXAZOLINES FROM CARBOXYLIC ESTERS USING LANTHANIDE CHLORIDE AS CATALYST

Abstract Using catalytic amounts of lanthanide III (Ln = La, Sm) chlorides and amino alkoxides as reagents, an one-pot direct synthesis for 2-oxazolines, in good yield, from carboxylic esters has been developed.

Chiral 1,4-dihydropyridines. Synthesis and absolute configuration.

Abstract Addition of organometallics to chiral 3-pyridyl oxazolines gave high diastereoselectivity at the 4-position of the pyridine nucleus. Absolute configuration was determined by x-ray analysis.

The coordination chemistry of isoxazoles

Isoxazole-metal complexes are often postulated as intermediates in reactions of considerable synthetic utility, for example the reductive ring opening of isoxazoles. Several isoxazole-metal complexes have been reported and well characterized. However, an updated review of this chemistry is needed. Because the behaviour of isoxazoles as their metal complexes is of interest to the long-term goals of several of our own projects, it seemed expedient to conduct and report such a review at this time

Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates

The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinrebs amide formation technique, using SmCl(3) as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institutes (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.

The isoxazole as a linchpin for molecules that target folded DNA conformations: selective lateral lithiation and palladation

Abstract 3-(10′-Halo-9′-anthracenyl)-5-methyl-4-isoxazolecarboxylic acid ethyl esters served as a useful scaffold for highly efficient lateral metalation at the C(5), and Suzuki–Fu palladium catalyzed cross coupling at the C(10′).

Neutral Dichromate Oxidation. Preparation and Utility of Isoxazole Aldehydes

Abstract Isoxazole alcohols 1 can be oxidized by potassium dichromate in neutral organic media to give the corresponding aldehydes, 2 without destruction of the isoxazole ring. Isoxazole aldehydes 2 are of utility as starting materials for 4-(4′-isoxazyl)-1, 4-dihydropyridines 3.

An improved procedure for the lateral lithiation of ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate

Abstract Ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate was smoothly lithiated at the 5-methyl position, when the 4-acetyl group was protected with a 5,5-dimethyl-1,3-dioxanyl group. The lithio anion was quenched with a variety of electrophiles such as alkyl halides, aldehydes, TMSCl, and Me3SnCl in good to excellent yields. The lithiation of the unprotected compound and the 4-acetyl group protected as 1,3-dioxolanyl both failed. The effects of different bases have been investigated and the addition of LiCl significantly increased yields. Based on variable temperature NMR studies the 5,5-dimethyl-1,3-dioxanyl group appears to occupy a single chair conformation which may facilitate lateral metalation. This represents a facile entry into 5-functionalized 3-isoxazolyl carboxylic acid derivatives as prodrugs for the AMPA glutamate neurotransmitters of the central nervous system.

A new direct synthesis of ACPA and novel AMPA analogues

Abstract A novel synthesis of the potent glutamate neurotransmitter agonist (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl) propionic acid (ACPA) provides access to numerous analogues as drug candidates for neurological disorders. The one-pot synthesis of an alpha amino phosphonate from aldehyde 4 was successful using ErCl3 as a catalyst. Molecular modeling of the new amino phosphonic acid with the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA) receptor crystal structure suggests this should be an effective receptor binder.