685897-68-1Relevant articles and documents
Impaired Chaperone Activity of Human Heat Shock Protein Hsp27 Site-Specifically Modified with Argpyrimidine
Matveenko, Maria,Cichero, Elena,Fossa, Paola,Becker, Christian F. W.
, p. 11397 - 11402 (2016)
Non-enzymatic posttranslational modifications (nPTMs) affect at least ～30 % of human proteins, but our understanding of their impact on protein structure and function is limited. Studies of nPTMs are difficult because many modifications are not included in common chemical libraries or protein expression systems and should be introduced site-specifically. Herein, we probed the effect of the nPTM argpyrimidine on the structure and function of human protein Hsp27, which acquires argpyrimidine at residue 188 in vivo. We developed a synthetic approach to an argpyrimidine building block, which we then incorporated at position 188 of Hsp27 through protein semisynthesis. This modification did not affect the protein secondary structure, but perturbed the oligomeric assembly and impaired chaperone activity. Our work demonstrates that protein function can be altered by a single nPTM and opens up a new area of investigation only accessible by methods that allow site-selective protein modification.
Inhibition of colitis by ring-modified analogues of 6-acetamido-2,4,5-trimethylpyridin-3-ol
Chaudhary, Chhabi Lal,Chaudhary, Prakash,Dahal, Sadan,Bae, Dawon,Nam, Tae-gyu,Kim, Jung-Ae,Jeong, Byeong-Seon
, (2020/08/05)
6-Aminopyridin-3-ol scaffold has shown an excellent anti-inflammatory bowel disease activity. Various analogues with the scaffold were synthesized in pursuit of the diversity of side chains tethering on the C(6)-position. Structure-activity relationship among the analogues was investigated to understand the effects of the side chains and their linkers on their anti-inflammatory activities. In this study, structural modification moved beyond side chains on the C(6)-position and reached to pyridine ring itself. It expedited us to synthesize diverse ring-modified analogues of a representative pyridine-3-ol, 6-acetamido-2,4,5-trimethylpyridin-3-ol (9). In the evaluation of compounds on their inhibitory actions against TNF-α-induced adhesion of monocytic cells to colonic epithelial cells, an in vitro model mimicking colon inflammation, the effects of compounds 9, 17, and 19 were greater than tofacitinib, an orally available anti-colitis drug, and compound 17 showed the greatest activity. In addition, TNF-α-induced angiogenesis, which permits more inflammatory cell migration into inflamed tissues, was significantly blocked by compounds 17 and 19 in a concentration-dependent manner. In the comparison of in vivo therapeutic effects of compounds 9, 17, and 19 on dextran sulfate sodium (DSS)-induced colitis in mice, compound 17 was the most potent and efficacious, and compound 19 was better than compound 9 which showed a similar degree of inhibitory effect to tofacitinib. Taken together, it seems that either the trimethyl system or the hydroxyl group on the pyridinol ring is essential to the activity. This finding might become a new milestone in the development of pyridinol-based anti-inflammatory bowel disease agents.
Synthetic Approach to Argpyrimidine as a Tool for Investigating Nonenzymatic Posttranslational Modification of Proteins
Matveenko, Maria,Becker, Christian F. W.
, p. 1950 - 1955 (2017/09/13)
Nonenzymatic posttranslational modifications (nPTMs) of proteins are involved in age-related, metabolic and other diseases and need to be investigated at the molecular level. Here, we describe how we used organic synthesis to enable the study of the effect of argpyrimidine (Apy), an nPTM that forms at arginine residues, on one of its target proteins. We developed an efficient approach to Apy as a universal building block for Fmoc-based solid-phase peptide synthesis that allows for the construction of peptides containing this nPTM in predetermined positions. Moreover, a straightforward one-step synthesis of protecting-group-free Apy was achieved, which enabled the preparation of gram-quantities of this noncanonical amino acid that can serve as a biomarker or a feedstock in construction of Apy-containing proteins via the expanded genetic code methods.
Photolysis and photocatalytic decomposition of sulfamethazine antibiotics in an aqueous solution with TiO2
Tzeng, Tai-Wei,Wang, Shan-Li,Chen, Chiing-Chang,Tan, Chen-Chung,Liu, Yu-Ting,Chen, Tsan-Yao,Tzou, Yu-Min,Chen,Hung
, p. 69301 - 69310 (2016/08/05)
Photo-decomposition of sulfamethazine (SMT) involves photolytic and photo-catalytic reactions, which occur simultaneously. The relative contributions of these two reactions to the overall SMT photo-decompositions by TiO2 and the intermediates of SMT photo-decompositions were systematically examined with the effects of TiO2 loading, and the pH and the initial SMT concentrations in the solutions. The apparent rate constants of SMT photo-decomposition reactions, which were well described by the pseudo-first-order kinetic model, ranged from 0.24 to 1.61 h-1. The overall photo-decomposition efficiencies of 0.072 mM SMT were the highest at pH 5.5 with 0.5 g L-1 TiO2 due to the adsorption-induced photocatalytic decomposition of SMT on TiO2. However, the SMT photolysis occurred more rapidly at pH 10. Two reactive species of holes and hydroxyl radicals concurrently participated in the photocatalytic decomposition of SMT, and the latter dominated the oxidative reactions of SMT on TiO2. Eight intermediates of SMT photo-decomposition were determined using LC-MS. Their time-dependent distributions indicated that the photo-decomposition of SMT was triggered by hydroxylation on aniline and dimethylpyrimidinyl moieties, followed by the cleavage of the S-N bond of SMT. Our results illustrated that the intermediates with dimethylpyrimidinyl groups possess strong resistance to photo-decomposition and played a determinant role in the photo-decomposition of SMT.
An expeditious access to 5-pyrimidinol derivatives from cyclic methylglyoxal diadducts, formation of argpyrimidines under physiological conditions and discovery of new CFTR inhibitors
Renard, Brice-Lo?c,Boucherle, Benjamin,Maurin, Bruno,Molina, Marie-Carmen,Norez, Caroline,Becq, Frédéric,Décout, Jean-Luc
experimental part, p. 1935 - 1941 (2011/05/02)
In the study of previously reported modulators of CFTR chloride channels that are cyclic methylglyoxal (MG) diadducts (CMGD) to aromatic α-aminoazaheterocycles, we optimized a new expeditious one pot route for preparing in water novel aromatic polycyclic azaheterocycles and described 5-pyrimidinols antioxidants through the formation of 2-oxoaldehyde diadducts to aromatic α-aminoazaheterocycles, amidines, guanidines and thiourea. In regard to the importance as biomarkers of diabetic complications of the 5-pyrimidinols "argpyrimidines" formed in proteins from MG and arginine residues, we demonstrated that argpyrimidines are slowly formed under physiological conditions from CMGD to arginine derivatives according to the synthesis route described. Among the 5-pyrimidinol derivatives prepared, two polycyclic derivatives appeared to inhibit strongly the activity of CFTR channels in wt-CHO cells.
Peroxyl radical clocks
Roschek Jr., Bill,Tallman, Keri A.,Rector, Christopher L.,Gillmore, Jason G.,Pratt, Derek A.,Punta, Carlo,Porter, Ned A.
, p. 3527 - 3532 (2007/10/03)
A series of peroxyl radical clocks has been developed and calibrated based on the competition between the unimolecular β-fragmentation (k β) of a peroxyl radical and its bimolecular reaction with a hydrogen atom donor (kH). These clocks are based on either methyl linoleate or allylbenzene and were calibrated directly with α-tocopherol or methyl linoleate, which have well-established rate constants for reaction with peroxyl radicals (kH-tocopherol = 3.5 × 10-6 M-1 s-1, kH-linoieate = 62 M-1 s-1). This peroxyl radical clock methodology has been successfully applied to determine inhibition and propagation rate constants ranging from 10° to 107 M-1 s-1.
Biaryl guanidine inhibitors of in vitro HCV-IRES activity
Jefferson, Elizabeth A.,Seth, Punit P.,Robinson, Dale E.,Winter, Dana K.,Miyaji, Alycia,Osgood, Stephen A.,Swayze, Eric E.,Risen, Lisa M.
, p. 5139 - 5143 (2007/10/03)
An SAR study on a high-throughput screening lead for HCV-IRES translation inhibition led to the identification of low μM inhibitors.
