544-77-4Relevant academic research and scientific papers
Lipid modifications of a ras peptide exhibit altered packing and mobility versus host membrane as detected by2H solid-state NMR
Vogel, Alexander,Katzka, Catherine P.,Waldmann, Herbert,Arnold, Klaus,Brown, Michael F.,Huster, Daniel
, p. 12263 - 12272 (2005)
The human N-ras protein binds to cellular membranes by insertion of two covalently bound posttranslational lipid modifications, which is crucial for its function in signal transduction and cell proliferation. Mutations in ras may lead to unregulated cell growth and eventually cancer, making it an important therapeutic target. Here we have investigated the molecular details of the membrane binding mechanism. A heptapeptide derived from the C-terminus of the human N-ras protein was synthesized including two hexadecyl modifications. Solid-state 2H NMR was used to determine the packing and molecular dynamics of the ras lipid chains as well as the phospholipid matrix. Separately labeling the chains of the peptide and the phospholipids with 2H enabled us to obtain atomically resolved parameters relevant to their structural dynamics. While the presence of ras only marginally affected the packing of DMPC membranes, dramatically lower order parameters (SCD) were observed for the ras acyl chains indicating modified packing properties. Essentially identical projected lengths of the 16:0 ras chains and the 14:0 DMPC chains were found, implying that the polypeptide backbone is located at the lipid-water interface. Dynamical properties of both the ras and phospholipid chains were determined from spin-lattice 2H relaxation (R 1Z) measurements. Plots of R1Z rates versus the corresponding squared segmental order parameters revealed striking differences. We propose the ras peptide is confined to microdomains containing DMPC chains which are in exchange with the bulk bilayer on the 2H NMR time scale (～10-5 s). Compared to the host DMPC matrix, the ras lipid modifications are extremely flexible and undergo relatively large amplitude motions. It is hypothesized that this flexibility is a requirement for the optimal anchoring of lipid-modified proteins to cellular membranes.
A hydroxylamine probe for profiling: S-acylated fatty acids on proteins
Schulte-Zweckel, Janine,Dwivedi, Mridula,Brockmeyer, Andreas,Janning, Petra,Winter, Roland,Triola, Gemma
supporting information, p. 11183 - 11186 (2019/09/30)
Reversible S-palmitoylation is a key regulatory mechanism of protein function and localization. There is increasing evidence that S-acylation is not restricted to palmitate but it includes shorter, longer, and unsaturated fatty acids. However, the diversity of this protein modification has not been fully explored. Herein, we report a chemical probe that combined with MS-based analysis allows the rapid detection and quantification of fatty acids linked to proteins. We have used this approach to profile the S-acylome and to show that the oncogene N-Ras is heterogeneously acylated with palmitate and palmitoleate. Studies on protein distribution in membrane subdomains with semisynthetic proteins revealed that unsaturated N-Ras presents an increased tendency toward clustering and higher insertion kinetic rate constants.
Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists
Schiano Moriello, Aniello,López Chinarro, Silvia,Novo Fernández, Olalla,Eras, Jordi,Amodeo, Pietro,Canela-Garayoa, Ramon,Vitale, Rosa Maria,Di Marzo, Vincenzo,De Petrocellis, Luciano
, p. 8255 - 8281 (2018/09/25)
The transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca2+ permeable channel member of the TRPV subfamily, still considered an orphan TRP channel due to the scarcity of available selective and potent pharmacological tools and endogenous modulators. Here we describe the discovery of novel synthetic long-chain capsaicin derivatives as potent TRPV2 antagonists in comparison to the totally inactive capsaicin, the role of their hydrophobic chain, and how the structure-activity relationships of such derivatives led, through a ligand-based approach, to the identification of endogenous long-chain fatty acid ethanolamides or primary amides acting as TRPV2 antagonists. Both synthetic and endogenous antagonists exhibited differential inhibition against known TRPV2 agonists characterized by distinct kinetic profiles. These findings represent the first example of both synthetic and naturally occurring TRPV2 modulators with efficacy in the submicromolar/low-micromolar range, which will be useful for clarifying the physiopathological roles of this receptor, its regulation, and its targeting in pathological conditions.
A mild and highly chemoselective iodination of alcohol using polymer supported DMAP
Das, Diparjun,H Anal, Jasha Momo,Rokhum, Lalthazuala
, p. 1695 - 1701 (2017/03/08)
The synthesis of organic compounds using polymer supported catalysts and reagents, where the required product is always in solution, has been of great interest in recent years, both in industries and academia especially in pharmaceutical research. Here, a simple and efficient method for conversion of alcohols into their iodides in high yield using polymer supported 4-(Dimethylamino)pyridine (DMAP) is described. Polymer supported DMAP is used in catalytic amount and is recovered and reused several times. Additionally, this method is highly chemoselective. [Figure not available: see fulltext.]
Vinyl Sulfonates: A Click Function for Coupling-and-Decoupling Chemistry and their Applications
Cruz, Carlos M.,Ortega-Mu?oz, Mariano,López-Jaramillo, F. Javier,Hernández-Mateo, Fernando,Blanco, Victor,Santoyo-González, Francisco
, p. 3394 - 3413 (2016/11/13)
The term coupling-and-decoupling (CAD) chemistry refers to applications in which efficient bond formation and subsequent cleavage between two moieties is required. Within this context, the scope of the vinyl sulfonate (VSO) group as an efficient tool for CAD chemistry is reported. The coupling step relies on the click features of the Michael-type addition of diverse nucleophiles to vinyl sulfonates as a valuable methodology. The feasibility of this strategy has been proved by the high yields obtained in mild conditions with model VSO derivatives. Cleavage of the resulting sulfonate adducts either through nucleophilic substitution with different nucleophiles (for alkyl VSO groups) or through hydrolysis (for both alkyl and aryl VSO) are successful strategies for the decoupling step, the former being the most promising, as the reaction proceeds under milder conditions with thiol nucleophiles. Moreover, the click VSO coupling chemistry proves to be orthogonal with the click CuAAC reaction, which enables the VSO-CAD methodology for the preparation of hetero-bifunctional clickable and cleavable linkers for double click modular strategies. The potential of the VSO-CAD chemistry is demonstrated in two biologically relevant examples: the decoupling of sulfonates with glutathione (GSH) under conditions compatible with those of living systems; and the synthesis of homo- and heterogeneous multivalent glycosylated systems from 1-thio and 1-azido or 1-azidoethyl sugar derivatives and bis-vinyl sulfonates (homo systems) or alkynyl-VSO bifunctional clickable-cleavable linkers (hetero systems). As proof of concept, the cleavable character of these multivalent systems was demonstrated by using one of them as a reversible linker for the non-covalent assembling and chemical decoupling of two model lectins. (Figure presented.).
One-pot transformation of simple furans into 4-Hydroxy-2-cyclopentenones in water
Kalaitzakis, Dimitris,Triantafyllakis, Myron,Alexopoulou, Ioanna,Sofiadis, Manolis,Vassilikogiannakis, Georgios
supporting information, p. 13201 - 13205 (2015/02/19)
A highly efficient one-pot transformation of readily accessible furans into 4-hydroxy-2-cyclopentenones in H2O, using singlet oxygen as oxidant, has been developed.
The fluid-mosaic model, homeoviscous adaptation, and ionic liquids: Dramatic lowering of the melting point by side-chain unsaturation
Murray, Samuel M.,O'Brien, Richard A.,Mattson, Kaila M.,Ceccarelli, Christopher,Sykora, Richard E.,West, Kevin N.,Davis Jr., James H.
body text, p. 2755 - 2758 (2010/07/06)
(Figure Presented) Defying conventional wisdom: Ionic liquids (ILs) with long, unsaturated alkyl appendages (see top structure) defy established trends that link long ion-bound alkyl groups to higher melting points. The new ILs are also less viscous than a saturated standard (see bottom structure) at the same temperature. These features parallel those that underpin homeoviscous adaptation in certain organisms and are indirectly supportive of a fluid-mosaiclike nanoscale character.
Applications of surfactant-modified clays to synthetic organic chemistry
Ghiaci,Sedaghat,Kalbasi,Abbaspur
, p. 5529 - 5534 (2007/10/03)
Two triphase catalysts (SLL) have been developed for organic phase-aqueous phase reactions catalyzed by suitable modified clay (solid phase). These triphase catalysts have been applied to nucleophilic displacement on activated (benzylic) as well as unactivated organic halides and provide a convenient and effective method of preparation of the corresponding products. Other useful transformations to, which these triphase catalysts have been successfully applied are the synthesis of 9,9-dichloro bicyclo[6.1.0]nonane, O-alkylation and C-alkylation of β-naphthol.
Synthesis and biological activities of 2- arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and its metabolically stable ether-linked analogues
Suhara, Yoshitomo,Takayama, Hiroaki,Nakane, Shinji,Miyashita, Tomoyuki,Waku, Keizo,Sugiura, Takayuki
, p. 903 - 907 (2007/10/03)
We synthesized 2-arachidonoylglycerol (1), an endogenous cannabinoid receptor ligand, and its metabolically stable ether- linked analogues. Compound 1 was synthesized from 1,3- benzylideneglycerol (6) and arachidonic acid in the presence of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine followed by treatment with boric acid and trimethyl borate. An ether-linked analogue of 2-arachidonoylglycerol (2) was synthesized from 6 and 5,8,11,14-eicosatetraenyl iodide (9). The ether-linked analogues of 2-palmitoylglycerol (4) and 2- oleoyglycerol (5) were synthesized from 6 and hexadecyl iodide (12) and 9-octadecenyl iodide (14), respectively. We confirmed that 1 stimulates NG108-15 cells to induce rapid transient elevation of the intracellular free Ca2+ concentrations through a CB1 receptor-dependent mechanism. Noticeably, 2 exhibited appreciable agonistic activity, although its activity was significantly lower than that of 1. Compound 2 would be a useful tool in exploring the physiological significance of 1, because this compound is resistant to hydrolyzing enzymes in contrast to 1. On the other hand, the ether-linked analogues of either 4 or 5 failed to act as a CB1 receptor agonist. Compounds 4 and 5 would also be valuable as control molecules in experiments where 2 is employed.
Synthesis of Optically Active Butenolides via Chromium Alkoxycarbene Complexes: Total Synthesis of (+)-Tetrahydrocerulenin and Two Butenolides from the Marine Sponge Plakortis lita
Miller, Michael,Hegedus, Louis S.
, p. 6779 - 6785 (2007/10/02)
Optically active butenolides were synthesized from the corresponding cyclobutanones, derived from the photolysis of chromium alkoxycarbene complexes and optically active ene-carbamates.The cyclobutanones were oxidized (Baeyer-Villiger) to the corresponding lactones, and subsequent base-induced elimination of the β-oxazolidinone ring provided optically active butenolides efficiently.The butenolides were utilized in the syntheses of (+)-tetrahydrocerulenin and two marine natural products.
