36743-66-5Relevant articles and documents
Synthesis and use of a phosphonate amidine to generate an anti-phosphoarginine-specific antibody
Fuhrmann, Jakob,Subramanian, Venkataraman,Thompson, Paul R.
, p. 14715 - 14718 (2015)
Protein arginine phosphorylation is a post-translational modification (PTM) that is important for bacterial growth and virulence. Despite its biological relevance, the intrinsic acid lability of phosphoarginine (pArg) has impaired studies of this novel PTM. Herein, we report for the first time the development of phosphonate amidines and sulfonate amidines as isosteres of pArg and then use these mimics as haptens to develop the first high-affinity sequence independent anti-pArg specific antibody. Employing this anti-pArg antibody, we further showed that arginine phosphorylation is induced in Bacillus subtilis during oxidative stress. Overall, we expect this antibody to see widespread use in analyzing the biological significance of arginine phosphorylation. Additionally, the chemistry reported here will facilitate the generation of pArg mimetics as highly potent inhibitors of the enzymes that catalyze arginine phosphorylation/dephosphorylation. Arginine phosphorylation: Synthesis of stable phosphoarginine analogues enabled the generation of high-affinity sequence-independent anti-phosphoarginine antibodies. These antibodies can be used to directly detect and isolate arginine-phosphorylated proteins.
A click chemistry mediated in vivo activity probe for dimethylarginine dimethylaminohydrolase
Yun, Wang,Shougang, Hu,Fast, Walter
, p. 15096 - 15097 (2009)
(Chemical Equation Presented) Asymmetric Nω,N ω-dimethyl-L-arginine (ADMA) is an endogenously produced inhibitor of human nitric oxide synthase and an emerging biomarker for cardiovascular disease. Concentrations of ADMA are controlled by two isoforms of its catabolic enzyme dimethylarginine dimethylaminohydrolase (DDAH), the dysregulation of which has been studied as a mediating factor for endothelial dysfunction. A two-part, click-chemistry mediated activity-based probe, N-but-3-ynyl-2-chloroacetamidine, is shown to label myc-tagged DDAH-1 expressed in HEK 293T cells, but not an inactive mutant or inhibited enzyme. A two-color Western blotting technique is used to determine the in vivo IC50 value for a reversible inhibitor of DDAH-1, N5-(1-iminopropyl)-L- ornithine, indicating this compound's bioavailability and its competition for binding to the active site. This probe provides a novel tool for the analysis of DDAH-1 activity in normal and pathophysiological states and should allow more meaningful studies of the etiology of endothelial dysfunction.
Interrogation of the active sites of protein arginine deiminases (PAD1, -2, and -4) using designer probes
Bello, Angelica M.,Wasilewski, Ewa,Wei, Lianhu,Moscarello, Mario A.,Kotra, Lakshmi P.
, p. 249 - 253 (2013)
Protein arginine deiminases (PADs) are involved in a number of cellular pathways, and they catalyze the transformation of peptidyl arginine residue into a citrulline as part of post-translational modifications. To understand ligand preferences, a group of probe molecules were investigated against PAD1, PAD2, and PAD4. These probe molecules carried a well-known covalent modifier of the catalytic cysteine residue, 2-chloroacetamidine moiety, which was tethered to an α-amino acid via a carbon linker. The chain length for the linker varied from 0 to 4. Time-dependent assays indicated that 2-chloroacetamidine (2CA) with no linker inhibited all PAD enzymes with a similar trend in the second-order rate constants, although with poor affinity. Among the other three probe molecules, compound 3 with a three-carbon linker exhibited the best second-order rate constants for optimal ligand reactivity with the binding site. These analyses provide insights into the relative patterns of covalent inactivation of PAD isozymes and the design of novel inhibitors targeting PAD enzymes as potential therapeutic targets.
Dissection, Optimization, and Structural Analysis of a Covalent Irreversible DDAH1 Inhibitor
Burstein-Teitelbaum, Gayle,Er, Joyce A.V.,Monzingo, Arthur F.,Tuley, Alfred,Fast, Walter
, p. 4574 - 4582 (2018)
Inhibitors of the human enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH1) can control endogenous nitric oxide production. A time-dependent covalent inactivator of DDAH1, N5-(1-imino-2-chloroethyl)-l-ornithine (KI = 1.3 μM, kinact = 0.34 min-1), was conceptually dissected into two fragments and each characterized separately: l-norvaline (Ki = 470 μM) and 2-chloroacetamidine (KI = 310 μM, kinact = 4.0 min-1). This analysis suggested that the two fragments were not linked in a manner that allows either to reach full affinity or reactivity, prompting the synthesis and characterization of three analogues: two that mimic the dimethylation status of the substrate, N5-(1-imino-2-chloroisopropyl)-l-ornithine (kinact/KI = 208 M-1 s-1) and N5-(1-imino-2-chlorisopropyl)-l-lysine (kinact/KI = 440 M-1 s-1), and one that lengthens the linker beyond that found in the substrate, N5-(1-imino-2-chloroethyl)-l-lysine (Cl-NIL, KI = 0.19 μM, kinact = 0.22 min-1). Cl-NIL is one of the most potent inhibitors reported for DDAH1, inactivates with a second order rate constant (1.9 × 104 M-1 s-1) larger than the catalytic efficiency of DDAH1 for its endogenous substrate (1.6 × 102 M-1 s-1), and has a partition ratio of 1 with a >100000-fold selectivity for DDAH1 over arginase. An activity-based protein-profiling probe is used to show inhibition of DDAH1 within cultured HEK293T cells (IC50 = 10 μM) with cytotoxicity appearing only at higher concentrations (ED50 = 118 μM). A 1.91 ? resolution X-ray crystal structure reveals specific interactions made with DDAH1 upon covalent inactivation by Cl-NIL. Dissecting a covalent inactivator and analysis of its constituent fragments proved useful for the design and optimization of this potent and effective DDAH1 inhibitor.
Anti-oligomerization sheet molecules: Design, synthesis and evaluation of inhibitory activities against α-synuclein aggregation
Liu, Hao,Chen, Li,Zhou, Fei,Zhang, Yun-Xiao,Xu, Ji,Xu, Meng,Bai, Su-Ping
supporting information, p. 3089 - 3096 (2019/06/14)
Aggregation of α-synuclein (α-Syn) play a key role in the development of Parkinson Disease (PD). One of the effective approaches is to stabilize the native, monomeric protein with suitable molecule ligands. We have designed and synthesized a series of sheet-like conjugated compounds which possess different skeletons and various heteroatoms in the two blocks located at both ends of linker, which have good π-electron delocalization and high ability of hydrogen-bond formation. They have shown anti-aggregation activities in vitro towards α-Syn with IC50 down to 1.09 μM. The molecule is found binding in parallel to the NACore within NAC domain of α-Syn, interfering aggregation of NAC region within different α-Syn monomer, and further inhibiting or slowing down the formation of α-Syn oligomer nuclei at lag phase. The potential inhibitor obtained by our strategy is considered to be highly efficient to inhibit α-Syn aggregation.
Synthetic method of 3-chloromethyl-1,2,4-triazolin-5-one
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Paragraph 0019; 0020, (2019/04/26)
The invention relates to a synthetic method of 3-chloromethyl-1,2,4-triazolin-5-one. The 3-chloromethyl-1,2,4-triazolin-5-one is prepared by mixing chloroacetonitrile, an alcohol and a solvent A. Compared with a conventional process, the synthesis method has the advantages that the raw materials with low price are selected, and production cost is remarkably reduced. For the whole technological process, the synthetic route is shortened, and production efficiency is improved. Production operation and quality control are more convenient while the production process is simplified.
Synthesis, antifungal activities and molecular docking studies of benzoxazole and benzothiazole derivatives
Luo, Bo,Li, Ding,Zhang, An-Ling,Gao, Jin-Ming
, (2018/10/05)
Based on benzoxazole and benzothiazole scaffold as an important pharmacophore, two series of 2-(aryloxymethyl) benzoxazole and benzothiazole derivatives were synthesized and their antifungal effects against eight phytopathogenic fungi were evaluated. Compounds 5a, 5b, 5h, and 5i exhibited significant antifungal activities against most of the pathogens tested. Especially 5a, 5b, 5h, 5i, 5j, and 6h inhibited the growth of F. solani with IC50 of 4.34–17.61 μg/mL, which were stronger than that of the positive control, hymexazol (IC50 of 38.92 μg/mL). 5h was the most potent inhibitor (IC50 of 4.34 μg/mL) against F. Solani, which was about nine times more potent than hymexazol. Most of the test compounds displayed significant antifungal effects against B. cinerea (IC50 of 19.92–77.41 μg/mL), among them, 5a was the best one (IC50 of 19.92 μg/mL). The structure-activity relationships (SARs) were compared and analyzed. The result indicates that the electron-drawing ability and position of the substituents have a significant impact on biological activities. Furthermore, docking studies were carried out on the lipid transfer protein sec14p from S. cerevisiae, and preliminarily verified the antifungal activities. Taken together, these results provide 2-(phenoxymethyl)benzo[d]oxazole as an encouraging framework that could lead to the development of potent novel antifungal agents.
The Hydroxyalkyl Moiety As a Protecting Group for the Stereospecific Alkylation of Masked Secondary Phosphine-Boranes
Lemouzy, Sébastien,Jean, Marion,Giordano, Laurent,Hérault, Damien,Buono, Gérard
supporting information, p. 140 - 143 (2016/01/15)
The synthesis of functionalized tertiary phosphine-boranes has been developed via a chemodivergent approach from readily accessible (hydroxymethyl) phosphine-boranes under mild conditions. O-Alkylation or decarbonylative P-alkylation product could be excl
Identification of Multiple Structurally Distinct, Nonpeptidic Small Molecule Inhibitors of Protein Arginine Deiminase 3 Using a Substrate-Based Fragment Method
Jamali, Haya,Khan, Hasan A.,Stringer, Joseph R.,Chowdhury, Somenath,Ellman, Jonathan A.
supporting information, p. 3616 - 3621 (2015/03/30)
The protein arginine deiminases (PADs) are a family of enzymes that catalyze the post-translational hydrolytic deimination of arginine residues. Four different enzymologically active PAD subtypes have been characterized and exhibit tissue-specific expression and association with a number of different diseases. In this Article we describe the development of an approach for the reliable discovery of low molecular weight, nonpeptidic fragment substrates of the PADs that then can be optimized and converted to mechanism-based irreversible PAD inhibitors. The approach is demonstrated by the development of potent and selective inhibitors of PAD3, a PAD subtype implicated in the neurodegenerative response to spinal cord injury. Multiple structurally distinct inhibitors were identified with the most potent inhibitors having >10,000 min-1 M-1 kinact/KI values and ≥10-fold selectivity for PAD3 over PADs 1, 2, and 4. (Figure Presented).
Discovery and extensive in vitro evaluations of NK-HDAC-1: A chiral histone deacetylase inhibitor as a promising lead
Hou, Jingli,Li, Zhonghua,Fang, Qinghong,Feng, Congran,Zhang, Hanwen,Guo, Weikang,Wang, Huihui,Gu, Guoxian,Tian, Yinping,Liu, Pi,Liu, Ruihua,Lin, Jianping,Shi, Yi-Kang,Yin, Zheng,Shen, Jie,Wang, Peng George
supporting information; experimental part, p. 3066 - 3075 (2012/06/01)
Herein, further SAR studies of lead compound NSC746457 (Shen, J.; Woodward, R.; Kedenburg, J. P.; Liu, X. W.; Chen, M.; Fang, L. Y.; Sun; D. X.; Wang. P. G.J. Med. Chem. 2008, 51, 7417-7427) were performed, including the replacement of the trans-styryl moiety with a 2-substituted benzo-hetero aromatic ring and the introduction of a substituent onto the central methylene carbon. A promising chiral lead, S-(E)-3-(1-(1-(benzo[d]oxazol-2-yl)-2-methylpropyl)-1H-1,2,3- triazol-4-yl)-N-hydroxyacrylamide (12, NK-HDAC-1), was discovered and showed about 1 order of magnitude more potency than SAHA in both enzymatic and cellular assays. For the in vitro safety tests, NK-HDAC-1 was far less toxic to nontransformed cells than tumor cells and showed no significant inhibition activity against CYP-3A4. The pharmaceutical properties (LogD, solubility, liver micrsomal stability (t1/2), plasma stability (t1/2), and apparent permeability) strongly suggested that NK-HDAC-1 might be superior to SAHA in bioavailability and in vivo half-life.
