27421-70-1Relevant articles and documents
Solid-state NMR of N-acylureas derived from the reaction of hyaluronic acid with isotopically-labeled carbodiimides
Pouyani, Tara,Kuo, Jing-Wen,Harbison, Gerard S.,Prestwich, Glenn D.
, p. 5972 - 5976 (1992)
Hyaluronic acid (HA) is a naturally-occurring linear polysaccharide consisting of alternating D-glucuronic acid and N-acetyl-D-glucosamine residues. Reaction of the carboxyl group of the glucuronate residues with l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) in the presence of primary amines yielded only the N-acylurea adducts rather than the expected amide coupling products. To determine the nature of this linkage unambiguously and to deduce the primary structure of the N-acylurea products, 13C- and 15N-labeled l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide were synthesized. The isotopically-labeled carbodiimides were coupled to the carboxyl group of HA (molecular size ca. 2 000 000 Da) in water at pH = 4.75. The modified polysaccharides were then isolated, purified, and examined by cross polarization and magic angle spinning (CP-MAS) solid-state 13C and 15N NMR. The chemical shifts and states of protonation of the nitrogens confirmed the presence of two isomeric N-acylureas in unequal amounts and ruled out the presence of any unrearranged O-acylurea product.
Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders
Dolles, Dominik,Nimczick, Martin,Scheiner, Matthias,Ramler, Jacqueline,Stadtmüller, Patricia,Sawatzky, Edgar,Drakopoulos, Antonios,Sotriffer, Christoph,Wittmann, Hans-Joachim,Strasser, Andrea,Decker, Michael
supporting information, p. 1270 - 1283 (2016/07/27)
A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB2R) agonist and verified it as a first-generation lead for respective dual-acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led to the identification of aminobenzimidazoles as second-generation leads with micro- or sub-micromolar activities at both targets and excellent selectivity over hCB1and AChE, respectively. Computational studies of the first- and second-generation lead structures by applying molecular dynamics (MD) on the active hCB2R model, along with docking and MD on hBChE, has enabled an explanation of their binding profiles at the protein levels and opened the way for further optimization. Dual-acting compounds with “balanced” affinities and excellent selectivities could be obtained that represent leads for treatment of both cognitive and pathophysiological impairment occurring in neurodegenerative disorders.
Regioselective covalent modification of hemoglobin in search of antisickling agents
Park, Soobong,Hayes, Brittany L.,Marankan, Fatima,Mulhearn, Debbie C.,Wanna, Linda,Mesecar, Andrew D.,Santarsiero, Bernard D.,Johnson, Michael E.,Venton, Duane L.
, p. 936 - 953 (2007/10/03)
Although the molecular defect in sickle hemoglobin that produces sickle cell disease has been known for decades, there is still no effective drug treatment that acts on hemoglobin itself. In this work, a series of diversely substituted isothiocyanates (R-NCS) were examined for their regioselective reaction with hemoglobin in an attempt to alter the solubility properties of sickle hemoglobin. Electrospray mass spectrometry, molecular modeling, X-ray crystallography, and conventional protein chemistry were used to study this regioselectivity and the resulting increase in solubility of the modified hemoglobin. Depending on the attached R-group, the isothiocyanates were found to react either with the Cysβ93 or the N-terminal amine of the α-chain. One of the most effective compounds in the series, 2-(N,N-dimethylamino)ethyl isothiocyanate, selectively reacts with the thiol of Cysβ93 which, in conjunction with the cationic group, was seen to perturb the local hemoglobin structure. This modified HbS shows an approximately 30% increase in solubility for the fully deoxygenated state, along with a significant increase in oxygen affinity. This compound and a related analogue appear to readily traverse the erythrocyte membrane. A discussion of the relation of these structural changes to inhibition of gelation is presented. The dual activities of increasing HbS oxygen affinity and directly inhibiting deoxy HbS polymerization, in conjunction with facile membrane traversal, suggest that these cationic isothiocyanates show substantial promise as lead compounds for development of therapeutic agents for sickle cell disease.
