Benzoxazinones as PPARγ Agonists. 2. SAR of the Amide Substituent and In Vivo Results in a Type 2 Diabetes Model

Rybczynski, Philip J.; Zeck, Roxanne E.; Dudash, Joseph; Combs, Donald W.; Burris, Thomas P.; Yang, Maria; Osborne, Melville C.; Chen, Xiaoli; Demarest, Keith T.

doi:10.1021/jm0301888

Cited by 48 publications

(20 citation statements)

References 32 publications

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“…The unnatural amino acid, tBuNle, was synthesized from pseudoephedrine glycinamide and 1-bromo-5,5-dimethylhexane (21,22) via the method of Myers et al (23) and incorporated into the ␤-hairpin peptide via standard solid-phase peptide synthesis to give the peptide WtBuNle (see Experimental Procedures). The side-chain-side-chain interaction was investigated by NMR and compared with WKMe3.…”

Section: Resultsmentioning

confidence: 99%

Recognition of trimethyllysine by a chromodomain is not driven by the hydrophobic effect

Hughes

Wiggins

Khorasanizadeh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

152

170

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However, whether the cationic component of the interaction is necessary for binding in the aromatic cage has not been addressed. In this article, the interaction of trimethyllysine with tryptophan is compared with that of its neutral analog, tert-butylnorleucine (2-amino-7,7-dimethyloctanoic acid), within the context of a ␤-hairpin peptide model system. These two side chains have near-identical size, shape, and polarizabilities but differ in their charges. Comparison of the two peptides reveals that the neutral side chain has no preference for interacting with tryptophan, unlike trimethyllysine, which interacts strongly in a defined geometry. In vitro binding studies of the histone 3A peptide containing trimethyllysine or tert-butylnorleucine to HP1 chromodomain indicate that the cationic moiety is critical for binding in the aromatic cage. This difference in binding affinities demonstrates the necessity of the cation-interaction to binding with the chromodomain and its role in providing specificity. This article presents an excellent example of synergy between model systems and in vitro studies that allows for the investigation of the key forces that control biomolecular recognition.cation-pi interactions ͉ histone code ͉ lysine methylation ͉ posttranslational modifications ͉ protein-protein interactions W ith rapid advancements in genomics, epigenetics has become the next major challenge in understanding how genetic information is controlled (1). It is becoming clear that posttranslational modifications of proteins are a key component in controlling gene expression. These modifications include a number of subtle structural changes, including Lys and Arg methylation, Lys acylation, and Ser/Thr/Tyr phosphorylation, which act as chemical switches to induce or repress proteinprotein interactions. Among all histone modifications, lysine methylation is especially important for chromatin function because of its stability and direct contribution to heritable patterns of gene expression (for review, see ref.2). To understand how such modest structural modifications can control biomolecular recognition events, it is critical to understand the underlying noncovalent interactions involved.Methylation of Lys induces a protein-protein interaction through the binding of methyl lysine (KMe n , n ϭ 1-3) in an aromatic cage. This interaction first was described for the binding of methylated histone 3 (H3) tail to the HP1 chromodomain ( Fig. 1) (3, 4). HP1 and methylated H3 interact specifically whether lysine 9 is mono-, di-, or trimethylated. However, the binding is most effective when lysine is trimethylated (5). In addition, more recent findings have shown that phosphorylation of serine 10 prevents interaction of HP1 with methylated H3 (for review, see ref. 6). Therefore, a binary switch mechanism has been proposed for the recognition of methyllysine-containing peptides by chromodomains. Interestingly, binding of a methylated lysine in an aromatic cage is not exclusive to chromodomains. Plant homeobox domain (PHD) fingers an...

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Section: Resultsmentioning

confidence: 99%

Recognition of trimethyllysine by a chromodomain is not driven by the hydrophobic effect

Hughes

Wiggins

Khorasanizadeh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

152

170

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“…The key intermediates 2 22 and benzyl 5-bromopentanoate 29 were synthesized following the reported procedures. Reactions were performed under a nitrogen atmosphere in dry glassware with magnetic stirring.…”

Section: Methodsmentioning

confidence: 99%

Suppression of Cocaine-Evoked Hyperactivity by Self-Adjuvanting and Multivalent Peptide Nanofiber Vaccines

Rudra

Ding

Neelakantan

et al. 2016

ACS Chem. Neurosci.

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The development of anti-cocaine vaccines that counteract the rewarding effects of the drug are currently being investigated as adjunct therapies for prevention of relapse in abstinent users. However, cocaine is weakly immunogenic and requires conjugation to carrier proteins and coadministration with strong adjuvants, which carry the risk of local reactogenicity and systemic toxicity. Here we report synthetic and multivalent self-assembling peptide nanofibers as adjuvant-free carriers for cocaine vaccines. A novel cocaine hapten modified at the P3 site was conjugated to the N-terminus of an amphipathic self-assembling domain KFE8. In aqueous buffers the cocaine-KFE8 conjugate assembled into β-sheet rich nanofibers, which raised anti-cocaine antibodies without the need for added adjuvants in mice. Vaccinated mice were treated with cocaine and a significant negative correlation was observed between antibody levels and cocaine-evoked hyperactivity. These totally synthetic and multivalent nanofibers with well-defined chemical composition represent the first generation of adjuvant-free cocaine vaccines.

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“…Benzoxazine and its derivatives have exhibited various biological activities, such as herbicides, fungicides, anti-diabetic, anxiolytic, cardiovascular and neuroprotective agents or antidepressants [1][2][3]. Moreover, they also act as useful intermeditates in the syntheses of compounds with therapeutic interest [4,5].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of 1-((2R,3S)-2,3-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenoxyethan-1-one, C₁₈H₁₉NO₃

Wang

Yang

et al. 2016

Zeitschrift Für Kristallographie - New Crystal Structures

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Benzoxazinones as PPARγ Agonists. 2. SAR of the Amide Substituent and In Vivo Results in a Type 2 Diabetes Model

Cited by 48 publications

References 32 publications

Recognition of trimethyllysine by a chromodomain is not driven by the hydrophobic effect

Recognition of trimethyllysine by a chromodomain is not driven by the hydrophobic effect

Suppression of Cocaine-Evoked Hyperactivity by Self-Adjuvanting and Multivalent Peptide Nanofiber Vaccines

Crystal structure of 1-((2R,3S)-2,3-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenoxyethan-1-one, C₁₈H₁₉NO₃

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Benzoxazinones as PPARγ Agonists. 2. SAR of the Amide Substituent and In Vivo Results in a Type 2 Diabetes Model

Cited by 48 publications

References 32 publications

Recognition of trimethyllysine by a chromodomain is not driven by the hydrophobic effect

Recognition of trimethyllysine by a chromodomain is not driven by the hydrophobic effect

Suppression of Cocaine-Evoked Hyperactivity by Self-Adjuvanting and Multivalent Peptide Nanofiber Vaccines

Crystal structure of 1-((2R,3S)-2,3-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenoxyethan-1-one, C18H19NO3

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Crystal structure of 1-((2R,3S)-2,3-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenoxyethan-1-one, C₁₈H₁₉NO₃