- Solid-state NMR of N-acylureas derived from the reaction of hyaluronic acid with isotopically-labeled carbodiimides
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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.
- Pouyani, Tara,Kuo, Jing-Wen,Harbison, Gerard S.,Prestwich, Glenn D.
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- Method for preparing isothiocyanate from ethyl chloroformate
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The invention relates to a method for preparing isothiocyanate from ethyl chloroformate. The method comprises the following steps: taking a compound as shown in specification as a starting material, reacting with carbon disulfide to prepare inner salt, and then reacting the inner salt with ethyl chloroformate in an organic solvent at the temperature of 0-40 DEG C to prepare thio-mixed anhydride, wherein in the compound as shown in specification, n is 1, 2, 3, 4 or 5; and adding the mixed anhydride in an inorganic aqueous alkali, and hydrolyzing at the temperature of minus 5-30 DEG C to preparethe corresponding isothiocyanate. According to the preparation method, the mixed anhydride is synthesized at first, and then is hydrolyzed with inorganic alkali, application of organic alkali is avoided effectively, side reaction of the isothiocyanate and alcohol is relieved, and the reaction yield of the isothiocyanate and the purity of the product are improved.
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- 1 - (3-dimethylamino-propyl) - 3-ethyl carbodiimide hydrochloride preparation method
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The invention belongs to the field of organic chemical industry, and particularly relates to a preparation method of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The method comprises the following steps: enabling N,N'-dimethyl-1,3-propanediamine and carbon disulfide as raw materials to react in an organic solvent to generate an intermediate 1; enabling the intermediate 1 and ethyl chloroformate to react in the organic solvent, and preparing an intermediate 2 from triethylamine as an acid-binding agent; enabling the intermediate 2 and ethylamine to react in the organic solvent, so as to prepare an intermediate 3; adding a catalyst to the intermediate 3, oxidizing one time with an oxidant, so as to obtain a crude product 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, extracting and separating, so as to obtain an intermediate 4; and carrying out salt exchange reaction on the intermediate 4 and hydrochloride, so as to prepare the product 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The method has the advantages of relatively high conversion rate and relatively high total recovery rate and is simple to operate and suitable for industrial production.
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- Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders
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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.
- Dolles, Dominik,Nimczick, Martin,Scheiner, Matthias,Ramler, Jacqueline,Stadtmüller, Patricia,Sawatzky, Edgar,Drakopoulos, Antonios,Sotriffer, Christoph,Wittmann, Hans-Joachim,Strasser, Andrea,Decker, Michael
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supporting information
p. 1270 - 1283
(2016/07/27)
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- Regioselective covalent modification of hemoglobin in search of antisickling agents
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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.
- Park, Soobong,Hayes, Brittany L.,Marankan, Fatima,Mulhearn, Debbie C.,Wanna, Linda,Mesecar, Andrew D.,Santarsiero, Bernard D.,Johnson, Michael E.,Venton, Duane L.
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p. 936 - 953
(2007/10/03)
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- Synthesis of new alkylaminoalkyl thiosemicarbazones of 3-acetylindole and their effect on DNA synthesis and cell proliferation
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The preparation of a number of thiobemicarbazones of 3-acetylindole is described. These compounds were evaluated in vitro for their effect on proliferation and cell-division delays in cultured human peripheral blood lymphocytes, and their effect on DNA synthesit in T-cell leukemia Molt-4 cells.
- Siatra-Papastaikoudi,Tsotinis,Raptopoulou,Sambani,Thomou
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p. 107 - 114
(2007/10/02)
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- Synthesis of 4-Substituted Thiosemicarbazones of 3-Methyl-4-phenylpyridine-2-carboxaldehyde as Antitumor Agents
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A convenient synthesis of 3-methyl-4-phenylpyridine-2-carboxaldehyde (4) is described.Reaction of 4 with 4-substituted thiosemicarbazides (6) gives thiosemicarbazones (7) some of which (7b, 7g, 7i and 7j) exhibit significant antitumor activity in animals.Thiosemicarbazides (6e - 6j) have been prepared from the corresponding isothiocyanates (5) (which result from sodium chlorite oxidation of the addition products of CS2 and the appropriate amine) and hydrazine.Isomerisation of 1,3-dimethyl-4-phenyl-1,2,3,6-tetrahydropyridine (Δ4-isomer) to 1,2,5,6-tetrahydro analog (Δ3-isomer, 1) has been effected with refluxing conc.HCl.
- Rahman, M. F.
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p. 828 - 830
(2007/10/02)
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