Reactivity Of L1 Research Articles

Mechanistic approaches for chemically modifying the coordination sphere of copper–amyloid-β complexes

Neurotoxic implications of the interactions between Cu(I/II) and amyloid-β (Aβ) indicate a connection between amyloid cascade hypothesis and metal ion hypothesis with respect to the neurodegeneration associated with Alzheimer's disease (AD). Herein, we report a mechanistic strategy for modifying the first coordination sphere of Cu(II) bound to Aβ utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)-Aβ was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)-Aβ was able to disrupt binding of Cu(II) to Aβ and result in chemically modified Aβ with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)-Aβ could stem from the molecule's ability to 1) interact with Cu(II)-Aβ and 2) foster copper-O2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)-Aβ at a metal-binding amino acid residue and consequently alter Aβ's coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.

Structure, vibrational analysis, electronic properties and chemical reactivity of two benzoxazole derivatives: Functional density theory study

In the present work we calculate structural parameters, vibrational spectra (IR, 1H NMR and UV–Visible Absorption) and corresponding mode of vibrational assignments of two ligands derived from benzoxazole; L1: 2-(5-(trifluoromethylpyridin-2-yl)-benzoxazole and L2: 2-(5-methylpyridin-2-yl)-benzoxazole at B3LYP/6-311++G** level, in the gas phase. The HOMO and LUMO study is used to determine the charge transfer within the molecules. Reactivity descriptors such as ionization energy, electronic affinity, global hardness, global softness, electrophilicity, nucleophilicity and condensed Fukui functions using NBO population analysis are also determined to predict the reactivity of L1 and L2. The calculated geometrical parameters are in good agreement with those of similar benzoxazole derivatives. Theoretical frequencies assignments confirmed the experimental ones of these benzoxazole derivatives.

LINE-1 silencing by retinoblastoma proteins is effected through the nucleosomal and remodeling deacetylase multiprotein complex.

BackgroundLong Interspersed Nuclear Element-1 (L1) is an oncogenic mammalian retroelement silenced early in development via tightly controlled epigenetic mechanisms. We have previously shown that the regulatory region of human and murine L1s interact with retinoblastoma (RB) proteins to effect retroelement silencing. The present studies were conducted to identify the corepressor complex responsible for RB-mediated silencing of L1.MethodsChromatin immunoprecipitation and silencing RNA technology were used to identify the repressor complex that silences L1 in human and murine cells.ResultsComponents of the Nucleosomal and Remodeling Deacetylase (NuRD) multiprotein complex specifically enriched the L1 5′-untranslated DNA sequence in human and murine cells. Genetic ablation of RB proteins in murine cells destabilized interactions within the NuRD macromolecular complex and mediated nuclear rearrangement of Mi2-β, an ATP-dependent helicase subunit with nucleosome remodeling activity. Depletion of Mi2-β, RbAP46 and HDAC2 reduced the repressor activity of the NuRD complex and reactivated a synthetic L1 reporter in human cells. Epigenetic reactivation of L1 in RB-null cells by DNA damage was markedly enhanced compared to wild type cells.ConclusionsRB proteins stabilize interactions of the NuRD corepressor complex within the L1 promoter to effect L1 silencing. L1 retroelements may serve as a scaffold on which RB builds heterochromatic regions that regulate chromatin function.

Imine-tautomers of aminothiazole derivatives: intriguing aspects of chemical reactivities

Intriguing reactivities of positional isomers 1-(5-methylthiazol-2-yl)-3-(4-nitrophenyl)thiourea (L1) and 1-(4-methylthiazol-2-yl)-3-(4-nitrophenyl)thiourea (L2) towards environment polluting ions such as mercuric, fluoride, bromide and solvents provide scope to study various self-assemblies formed under different conditions and allied applications. The solid state structures of L1 and L2 revealed that both adopt the imine form. However, the number of symmetry independent molecules in asymmetric units as well as the packing patterns of these two compounds have distinguishable features. The asymmetric unit of L1 has three symmetry non-equivalent molecules. The packing patterns of these two positional isomers differ as L1 has two arrays of dimeric self-assemblies in contrast to the single array found in the packing of L2. The reactivity of L1 and L2 with solvents was explored through crystal structure elucidation. The compound L1 forms solvates with N,N′-dimethylacetamide or dimethylsulphoxide. The structural analysis of solvates of L1 provided avenues to study conformational adjustments. An unusual example of a metastable solvate of L1 with N,N′-dimethylacetamide was isolated. A ring-opening reaction of 1,8-diazabicyclo [5.4.0] undec-7-ene with L1 has been observed. The compound L2 underwent hydrolysis cum bromination with hydrobromic acid in dimethylsulphoxide. The reactivities of L1 and L2 towards mercuric and fluoride ions contributed to chemodosimetric signal transductions. The study establishes the impact of subtle changes in structure, reaction and crystallization conditions, which can influence pre-designed crystal engineering.

Reactivation of L1 retrotransposon by benzo(a)pyrene involves complex genetic and epigenetic regulation

Benzo(a)pyrene (BaP), is an environmental pollutant present in tobacco smoke and a byproduct of fossil fuel combustion which likely contributes to the tumorigenic processes in human cancers including lung and esophageal. Long Interspersed Nuclear Element-1 (LINE-1) or L1 is a mobile element within the mammalian genome that propagates via a “copy-and-paste” mechanism using reverse transcriptase and RNA intermediates. L1 is strongly expressed during early embryogenesis and then silenced as cells initiate differentiation programming. Although the complex transcriptional control mechanisms of L1 are not well understood, L1 reactivation has been described in several human cancers and following exposure of mouse or human cells to BaP. In this study we investigated the molecular mechanisms and epigenetic events that regulate L1 reactivation following BaP exposure. We show that challenge of HeLa cells with BaP induces early enrichment of the transcriptionally-active chromatin markers histone H3 trimethylated at lysine 4 (H3K4Me3) and histone H3 acetylated at lysine 9 (H3K9Ac), and reduces association of DNA methyltransferase-1 (DNMT1) with the L1 promoter. These changes are followed by proteasome-dependent decreases in cellular DNMT1 expression and sustained reduction of cytosine methylation within the L1 promoter CpG island. Pharmacological inhibition of the proteasome signaling pathway with the inhibitor MG132 blocks degradation of DNMT1 and alters BaP-mediated histone epigenetic modifications. We conclude that genetic reactivation of L1 by BaP involves an ordered cascade of epigenetic events that begin with nucleosomal histone modifications and is completed with alterations in DNMT1 recruitment to the L1 promoter and reduced DNA methylation of CpG islands.

Synthesis and Structure of Pd and Pt Complexes with Doubly Stabilized Phosphorus Ylides

AbstractThe doubly stabilized P‐ylide ligands Ph3P=C(CO2Me)C(=S)N(H)Ph (L1), Ph3P=C(CN)C(=S)N(H)Ph (L2), and Ph3P=C(CN)–[(E)‐C(CO2Me)=CH(CO2Me)] (L3) have been prepared and fully characterized. The X‐ray structures of L1 and L2 are reported. The reactivity of L1, L2, and L3 towards cationic PdII and PtII precursors with two vacant coordination sites has been studied. Adducts of general formula [M(CX)(Ln)]ClO4, [M(CX)(Ln)2]ClO4, and [M(μ‐Ln)(CX)]2(ClO4)2 (CX = ancillary ligands) were obtained. The ylides Ln coordinate to the metal center through their heteroatoms (O, N, S), while the C bonding of Ln has not been observed in any of the cases studied. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Palladium Complexes of a Phosphorus Ylide with Two Stabilizing Groups: Synthesis, Structure, and DFT Study of the Bonding Modes

The phosphorus ylide ligand [Ph3P=C(CO2Me)C(=NPh)CO2Me] (L1) has been prepared and fully characterized by spectroscopic, crystallographic, and density functional theory (DFT) methods (B3LYP level). The reactivity of L1 toward several cationic Pd(II) and Pt(II) precursors, with two vacant coordination sites, has been studied. The reaction of [M(C/\X)(THF)2]ClO4 with L1 (1:1 molar ratio) gives [M(C/\X)(L1)]ClO4 [M = Pd, C/\X = C6H4CH2NMe2 (1), S-C6H4C(H)MeNMe2 (2), CH2-8-C9H6N (3), C6H4-2-NC5H4 (4), o-CH2C6H4P(o-tol)2 (6), eta3-C3H5 (7); M = Pt, C/\X = o-CH2C6H4P(o-tol)2 (5); M(C/\X) = Pd(C6F5)(SC4H8) (8), PdCl2 (9)]. In complexes 1-9, the ligand L1 bonds systematically to the metal center through the iminic N and the carbonyl O of the stabilizing CO2Me group, as is evident from the NMR data and from the X-ray structure of 3. Ligand L1 can also be orthopalladated by reaction with Pd(OAc)2 and LiCl, giving the dinuclear derivative [Pd(mu-Cl)(C6H4-2-PPh2=C(CO2Me)C(CO2Me)=NPh)]2 (10). The X-ray crystal structure of 10 is also reported. In none of the prepared complexes 1-10 was the C(alpha) atom found to be bonded to the metal center. DFT calculations and Bader analysis were performed on ylide L1 and complex 9 and its congeners in order to assess the preference of the six-membered N,O metallacycle over the four-membered C,N and five-membered C,O rings. The presence of two stabilizing groups at the ylidic C causes a reduction of its bonding capabilities. The increasing strength of the Pd-C, Pd-O, and Pd-N bonds along with other subtle effects are responsible for the relative stabilities of the different bonding modes.