6094-36-6Relevant articles and documents
Discovery of novel chemical scaffolds as RhoA inhibitors using virtual screening, synthesis, and bioactivity evaluation
Zhang, Chao,Wang, Hui-Jie,Bao, Qi-Chao,Bian, Jin-Lei,Yang, Ying-Rui,You, Qi-Dong,Xu, Xiao-Li
, p. 56738 - 56746 (2016/07/06)
RhoA has been implicated in diverse cellular functions and is a potential cancer therapeutic target. Through virtual screening, we have identified a RhoA inhibitor, DDO-5701. DDO-5701 has an affinity to RhoA at the micromolar level in vitro. By structural modifications, considering the binding activity and synthesis ease of DDO-5701, 17 compounds were designed and synthesized accordingly. Among these compounds, 4 compounds (DDO-5713, DDO-5714, DDO-5715, DDO-5716) exhibited higher RhoA inhibition activities than DDO-5701, while DDO-5716 can effectively reverse the functions of breast cancer cells regulated by RhoA. Thus, the rationally designed small molecule inhibitor of RhoA (DDO-5716) is useful for studying the physiological and pathological roles of Rho GTPase. However, DDO-5701 is an approved drug-proglumide, which makes it and its derived compound DDO-5716 more likely to be well tolerated in humans and could quickly lead to further clinical development.
Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors
Garella, Davide,Atlante, Sandra,Borretto, Emily,Cocco, Mattia,Giorgis, Marta,Costale, Annalisa,Stevanato, Livio,Miglio, Gianluca,Cencioni, Chiara,Fernández-de Gortari, Eli,Medina-Franco, José L.,Spallotta, Francesco,Gaetano, Carlo,Bertinaria, Massimo
, p. 664 - 676 (2016/10/25)
The inhibition of human DNA Methyl Transferases (DNMT) is a novel promising approach to address the epigenetic dysregulation of gene expression in different diseases. Inspired by the validated virtual screening hit NSC137546, a series of N-benzoyl amino acid analogues was synthesized and obtained compounds were assessed for their ability to inhibit DNMT-dependent DNA methylation in vitro. The biological screening allowed the definition of a set of preliminary structure–activity relationships and the identification of compounds promising for further development. Among the synthesized compounds, L-glutamic acid derivatives 22, 23, and 24 showed the highest ability to prevent DNA methylation in a total cell lysate. Compound 22 inhibited DNMT1 and DNMT3A activity in a concentration-dependent manner in the micromolar range. In addition, compound 22 proved to be stable in human serum and it was thus selected as a starting point for further biological studies.
Isotope-labeled differential profiling of metabolites using N-benzoyloxysuccinimide derivatization coupled to liquid chromatography/high-resolution tandem mass spectrometry
Wagner, Michel,Ohlund, Leanne B.,Shiao, Tze Chieh,Vézina, Amélie,Annabi, Borhane,Roy, René,Sleno, Lekha
, p. 1632 - 1640 (2015/11/16)
Rationale An isotopic labeling strategy based on derivatizing amine-containing metabolites has been developed using light (12C6) and heavy (13C6) N-benzoyloxysuccinimide reagents for semi-targeted metabolomic applications. Methods Differentially labeled samples were combined and analyzed simultaneously by liquid chromatography/high-resolution tandem mass spectrometry (LC/HR-MS/MS) to compare relative amounts of amine-containing metabolites. The selectivity of the reaction was determined with model metabolites and was shown to also be applicable to thiol and phenol moieties. The potential for relative quantitation was evaluated in cell extracts and the method was then applied to quantify metabolic perturbations occurring in human cultured cells under normal vs. oxidative stress conditions. Results A total of 279 derivatized features were detected in HL60 cell extracts, 77 of which yielded significant concentration changes upon oxidative stress treatment. Based on accurate mass measurements and MS/MS spectral matching with reference standard solutions, 10 metabolites were clearly identified. Derivatized compounds were found to have diagnostic fragment ions from the reagent itself, as well as structurally informative ions useful for metabolite identification. Conclusions This simple derivatization reaction can be applied to the relative quantitation of amine-, thiol- and phenol-containing compounds, with improved sensitivity and chromatographic peak shapes due to the increased hydrophobicity of polar metabolites not readily amenable to reversed-phase LC/MS analysis.
In vivo neurochemical monitoring using benzoyl chloride derivatization and liquid chromatography-mass spectrometry
Song, Peng,Mabrouk, Omar S.,Hershey, Neil D.,Kennedy, Robert T.
experimental part, p. 412 - 419 (2012/03/11)
In vivo neurochemical monitoring using microdialysis sampling is important in neuroscience because it allows correlation of neurotransmission with behavior, disease state, and drug concentrations in the intact brain. A significant limitation of current practice is that different assays are utilized for measuring each class of neurotransmitter. We present a high performance liquid chromatography (HPLC)-tandem mass spectrometry method that utilizes benzoyl chloride for determination of the most common low molecular weight neurotransmitters and metabolites. In this method, 17 analytes were separated in 8 min. The limit of detection was 0.03-0.2 nM for monoamine neurotransmitters, 0.05-11 nM for monoamine metabolites, 2-250 nM for amino acids, 0.5 nM for acetylcholine, 2 nM for histamine, and 25 nM for adenosine at sample volume of 5 μL. Relative standard deviation for repeated analysis at concentrations expected in vivo averaged 7% (n = 3). Commercially available 13C benzoyl chloride was used to generate isotope-labeled internal standards for improved quantification. To demonstrate utility of the method for study of small brain regions, the GABAA receptor antagonist bicuculline (50 μM) was infused into a rat ventral tegmental area while recording neurotransmitter concentration locally and in nucleus accumbens, revealing complex GABAergic control over mesolimbic processes. To demonstrate high temporal resolution monitoring, samples were collected every 60 s while neostigmine, an acetylcholine esterase inhibitor, was infused into the medial prefrontal cortex. This experiment revealed selective positive control of acetylcholine over cortical glutamate.
Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonists
Aoki, Tomiyoshi,Asaki, Tetsuo,Hamamoto, Taisuke,Sugiyama, Yukiteru,Ohmachi, Shinji,Kuwabara, Kenji,Murakami, Kohji,Todo, Makoto
, p. 2128 - 2132 (2008/12/21)
A new series of 1,3-dioxane-2-carboxylic acid derivatives was synthesized and evaluated for agonist activity at human peroxisome proliferator-activated receptor (PPAR) subtypes. Structure-activity relationship studies led to the identification of 2-methyl-c-5-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid 4b as a potent PPARα agonist with high subtype selectivity at human receptor subtypes. This compound exhibited a substantial hypolipidemic effect in type 2 diabetic KK-Ay mice.
A general approach to 3-n-butyl-5-alkylindolizidines: Total synthesis of (-)-indolizidine 195B
Angle, Steven R.,Kim, Musong
, p. 8791 - 8796 (2008/03/13)
(Chemical Equation Presented) Indolizidine type alkaloids have been attractive synthetic targets due to their biological activity. The total synthesis of (-)-indolizidine 195B via a general route, which could potentially be used to prepare other indolizid
A practical method for selective cleavage of a tert-butoxycarbamoyl N-protective group from N,N-diprotected α-amino acid derivatives using montmorillonite K-10
Hernandez, J. Nicolas,Crisostomo, Fernando R. Pinacho,Martin, Tomas,Martin, Victor S.
, p. 5050 - 5058 (2008/03/18)
A new, practical, and mild procedure for the selective cleavage of a tert-butoxycarbonyl group (Boc) in N-Boc-N-acyl-diprotected amines is described. When applied to α-amino acids, complete integrity of the stereochemistry was observed. The use of N,N-di-Boc-α-amino-δ- and γ-hydroxy esters provided both δ- and γ-lactones in very good yields. The method is based on the use of Montmorillonite K-10 either in CH 2Cl2 at room temperature or in toluene at 65°C and is compatible with the presence of a large range of functional and other protecting groups in the substrates. In most cases virtually pure samples are obtained after filtration and removal of solvents. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
Unique oxidation reaction of amides with pyridine-N-oxide catalyzed by ruthenium porphyrin: Direct oxidative conversion of N-acyl-L-proline to N-acyl-L-glutamate
Ito, Rina,Umezawa, Naoki,Higuchi, Tsunehiko
, p. 834 - 835 (2007/10/03)
Oxidations of alkanes, alkenes, and aromatic rings with pyridine N-oxides are efficiently catalyzed by ruthenium porphyrins under mild conditions. We show here that the oxidation of N-acyl cyclic amines with RuIVtetraarylporphyrin dichloride-2,6-substituted pyridine N-oxides directly gives N-acyl amino acids in modest to good yield via oxidative C-N bond cleavage. N-Acylpyrrolidines and N-acylpiperidines were converted to N-acyl-γ-aminobutyric acids and N-acyl-δ-aminovaleric acids, respectively. This type of reaction is a novel one in which the C-N bond is cleaved selectively at the less substituted carbon. Notably, the proline residue in proline-containing peptides was selectively converted to glutamate. A large intramolecular kinetic isotope effect (kH/kD = 9.8) was observed in the oxidation of N-benzoyl[2,2,-d2]pyrrolidine, indicating that the reaction should involve an α-hydrogen atom abstraction process as the rate-determining step. N-Acylcarbaldehyde, the putative intermediate ring-opened form of α-hydroxylated N-acyl cyclic amine, was readily oxidized with the oxidizing system to afford the corresponding N-acylamino acid in good yield. Further, lactams (1-methyl-2-pyrrolidone and 1-methyl- 2-piperidone) were also oxidized to give the corresponding imides (1-methylsuccinimide and 1-methylpiperidine-2,6-dione). Copyright
The utilization of alanine, glutamic acid, and serine as amino acid substrates for glycine N-acyltransferase.
van der Westhuizen,Pretorius,Erasmus
, p. 102 - 109 (2007/10/03)
The conjugation of benzoyl-CoA with the aliphatic and acidic amino acids by glycine N-acyltransferase, as well as the amides of the latter group, was investigated. Bovine and human liver benzoyl-amino acid conjugation were investigated using electrospray ionization tandem mass spectrometry (ESI-MS-MS). Bovine glycine N-acyltransferase catalyzed conjugation of benzoyl-CoA with Gly (Km(Gly) = 6.2 mM), Asn (Km(Asn) = 129 mM), Gln (Km(Gln) = 353 mM), Ala (Km(Ala) = 1573 mM), Glu (Km(Glu) = 1148 mM) as well as Ser in a sequential mechanism. In the case of the human form, conjugation with Gly (Km(Gly) = 6.4 mM), Ala (Km(Ala) = 997 mM), and Glu was detected. The presence of these alternative conjugates did not inhibit bovine glycine N-acyltransferase activity significantly. Considering the relatively low levels at which these conjugates are formed, it is unlikely that they will have a significant contribution to acyl-amino acid conjugation under normal conditions in vivo. However, their cumulative contribution to acyl-amino acid conjugation under metabolic disease states may prove to have a useful contribution to detoxification of elevated acyl-CoAs.
Beauveria bassiana ATCC 7159 contains an L-specific α-amino acid benzamidase
Holland, Herbert L.,Andreana, Peter R.,Salehzadeh-Asl, Reza,Van Vliet, Aaron,Ihasz, Nancy J.,Brown, Frances M.
, p. 667 - 672 (2007/10/03)
Biotransformation of a series of racemic N-benzoyl α-amino acids by the fungus Beauveria bassiana ATCC 7159 results in isolation of the corresponding D-amino acid benzamides in high enantiomeric purity and yield.
