Synthesis and Preliminary Evaluation of trans-3,4-Conformationally-Restricted Glutamate and Pyroglutamate Analogues as Novel EAAT2 Inhibitors

Denton, Travis T.; Seib, Todd; Bridges, Richard J.; Thompson, Charles M.

doi:10.1016/s0960-894x(02)00520-6

Cited by 10 publications

(3 citation statements)

References 19 publications

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“…When the conformationally-restricted 1,3-dicarboxylic acid system is modified to a 2-carboxycyclohexylglycine as shown in (Fig. 4) [51], the compounds are inactive at VGLUT but active at EAAT3. Thus, it is possible to achieve inhibitory selectivity between the transporter types, and optimal spacing between the carboxylic acid groups may be important to bind VGLUT.…”

Section: Conformationally-restricted Amino Acid Analogsmentioning

confidence: 99%

Inhibitors of the Glutamate Vesicular Transporter (VGLUT)

Thompson¹,

Davis²,

Carrigan³

et al. 2005

CMC

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The vesicular glutamate transporter (VGLUT) is responsible for the uptake of the excitatory amino acid, L-glutamate, into synaptic vesicles. VGLUT activity is coupled to an electrochemical gradient driven by a vacuolar ATPase and stimulated by low Cl-. VGLUT has relatively low affinity (K(m) = 1-3 mM) for glutamate and is pharmacologically and structurally distinct from the Na+-dependent, excitatory amino acid transporters (EAATs) found on the plasma membrane. Because glutamatergic neurotransmission begins with vesicular release, compounds that block the uptake of glutamate into the vesicle may reduce excitotoxic events. Several classes of competitive VGLUT inhibitors have emerged including amino acids and amino acid analogs, fatty acids, azo dyes, quinolines and alkaloids. The potency with which these agents inhibit VGLUT varies from millimolar (amino acids) to nanomolar (azo dyes) concentrations. These inhibitors represent highly diverse structures and have collectively begun to reveal key pharmacophore elements that may elucidate the key interactions important to binding VGLUT. Using known inhibitor structures and preliminary molecular modeling, a VGLUT pharmacophore is presented that will aid in the design of new, highly potent and selective agents.

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Section: Conformationally-restricted Amino Acid Analogsmentioning

confidence: 99%

Inhibitors of the Glutamate Vesicular Transporter (VGLUT)

Thompson¹,

Davis²,

Carrigan³

et al. 2005

CMC

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“…[1] The catalytic asymmetric reactions of a,b-unsaturated carbonyl derivatives and cyclopentadiene have enabled a facile synthesis of these core structures. [2][3][4][5] It is important to note that cyclopentadiene not only acts as a 4p component, to give the bridged bicyclic compounds, [6] but can also behave as a dienophile to furnish the inverseelectron-demand hetero-Diels-Alder (HDA) [7][8][9] cycloadducts when it reacts with b,g-unsaturated a-ketoesters (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Diels–Alder and Inverse‐Electron‐Demand Hetero‐Diels–Alder Reactions of β,γ‐Unsaturated α‐Ketoesters with Cyclopentadiene Catalyzed by N,N′‐Dioxide Copper(II) Complex

Zhu

Chen

Xie

et al. 2010

Chemistry A European J

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Highly enantioselective Diels-Alder (DA) and inverse-electron-demand hetero-Diels-Alder (HDA) reactions of β,γ-unsaturated α-ketoesters with cyclopentadiene catalyzed by chiral N,N'-dioxide-Cu(OTf)(2) (Tf=triflate) complexes have been developed. Quantitative conversion of β,γ-unsaturated α-ketoesters and excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to >99% ee) were observed for a broad range of substrates. Both aromatic and aliphatic β,γ-unsaturated α-ketoesters were found to be suitable substrates for the reactions. Moreover, the chemoselectivity of the DA and HDA adducts were improved by regulating the reaction temperature. Good to high chemoselectivity (up to 94%) of the DA adducts were obtained at room temperature, and moderate chemoselectivity (up to 65%) of the HDA adducts were achieved at low temperature. The reaction also featured mild reaction conditions, a simple procedure, and remarkably low catalyst loading (0.1-1.5 mol%). A strong positive nonlinear effect was observed.

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“…Previous medicinal chemistry campaigns have led to SLC1A1 inhibitors based off two scaffolds. The first scaffold class maintains an aspartate-like backbone (35)(36)(37)(38)(39), which lacks specificity and pharmaceutical properties for systemic dosing. The second scaffold is derived from bicyclic imidazopyridine anilines (40), which maintains a steep Structure-Activity Relationship (SAR) profile requiring a furan ring for activity against SLC1A1, as represented by compound 3e (Cmpd 3e) (Supplementary Fig.…”

Section: Slc1a1 Activity Confers Actionable Metabolic Vulnerabilities...mentioning

confidence: 99%

TheSLC1A1/EAAT3 Dicarboxylic Amino Acid Transporter is an Epigenetically Dysregulated Nutrient Carrier that Sustains Oncogenic Metabolic Programs

Grubb,

Khatun,

Matar

et al. 2023

Preprint

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Inactivation of pVHL tumor suppressor in clear cell Renal Cell Carcinoma (ccRCC) increases the abundance of Histone H3 lysine 27 acetylation (H3K27ac). We hypothesized that H3K27ac, a marker of transcriptional activation, drives the expression of critical oncogenes in ccRCC. Using H3K27ac ChIP-Seq; RNA-Seq; an in vivo positive selection screen; cell-based functional studies; and clinical validations; here, we report the identification of the SLC1A1/EAAT3 aspartate (Asp) and glutamate (Glu) transporter as a ccRCC oncogene. pVHL loss promotes SLC1A1 expression in a HIF-independent manner. Importantly, SLC1A1 inactivation depletes Asp/Glu-derived metabolites, impedes ccRCC growth both in vitro and in vivo, and sensitizes ccRCCs to metabolic therapeutics (e.g., glutaminase blockers). Finally, in human ccRCC biospecimens, higher SLC1A1 expression is associated with metastatic disease and clusters with elevated expression of other solute carriers, but not HIF/Hypoxia pathways. Altogether, our studies identify a HIF-independent metabolic hub in ccRCC and credential SLC1A1 as an actionable ccRCC oncogene.

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Synthesis and Preliminary Evaluation of trans-3,4-Conformationally-Restricted Glutamate and Pyroglutamate Analogues as Novel EAAT2 Inhibitors

Cited by 10 publications

References 19 publications

Inhibitors of the Glutamate Vesicular Transporter (VGLUT)

Inhibitors of the Glutamate Vesicular Transporter (VGLUT)

Asymmetric Diels–Alder and Inverse‐Electron‐Demand Hetero‐Diels–Alder Reactions of β,γ‐Unsaturated α‐Ketoesters with Cyclopentadiene Catalyzed by N,N′‐Dioxide Copper(II) Complex

TheSLC1A1/EAAT3 Dicarboxylic Amino Acid Transporter is an Epigenetically Dysregulated Nutrient Carrier that Sustains Oncogenic Metabolic Programs

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