Efficient one-pot synthesis of highly substituted pyridin-2(1H)-ones via the Vilsmeier-Haack reaction of 1-acetyl,1-carbamoyl cyclopropanes

A facile and efficient one-pot synthesis of highly substituted pyridin-2(1H)-ones is developed via the Vilsmeier-Haack reaction of readily available 1-acetyl,1-carbamoyl cyclopropanes, and a mechanism involving sequential ring-opening, haloformylation, and intramolecular nucleophilic cyclization reactions is proposed.

Vilsmeier-Haack reactions of 2-arylamino-3-acetyl-5,6-dihydro-4H-pyrans toward the synthesis of highly substituted pyridin-2(1H)-ones

A facile and efficient one-pot synthesis of highly substituted pyridin-2(IH)-ones was developed via Vilsmeier-Haack reactions of readily available enaminones, 2-arylamino-3-acetyl-5,6-dihydro-4H-pyrans, and a mechanism involving sequential ring-opening, haloformylation, and intramolecular nucleophilic cyclization reactions is proposed.

Studies of the ortho effect in fragmentations of acetyl ion adducts of disubstituted benzenes

The ion-molecule reactions of disubstituted benzenes under chemical ionization conditions with acetyl chloride as reagent gas were examined, and the fragmentation reactions of the adduct ions (mostly proton and acetyl ion adducts) were studied by collision-induced dissociation. Electron-releasing substituents favored the adduct reactions, and electron-withdrawing groups did not. The position and properties of substituting groups had an effect on the relative abundances of the adduct ions. Several examples of the ortho effect were observed. The fragmentation reaction of the adduct ions formed by ortho-benzenediamine with the acetyl ion was similar to the reductive alkylation reaction of amines in the condensed phase. Copyright (C) 2001 John Wiley & Sons, Ltd.

Low temperature crystal structure of N-Acetyl-L-Glutamic acid: comparison with the DFT calculated structure

N-acetyl-L-glutamic acid, crystallizes in the orthorhombic space group P2(1)2(1)2(1) with unit cell parameters a = 4.747(3), b = 12.852(7), c = 13.906(7) Å, V = 848.5(8) Å3, Z = 4, density (calculated) = 1.481 mg/m3, linear absorption coefficient 0.127 mm−1. The crystal structure determination was carried out with MoKalpha X-ray data measured with liquid nitrogen cooling at 100(2) K temperature. In the final refinement cycle the data/restraints/parameter ratios were 1,691/0/131; goodness-of-fit on F(2) = 1.122. Final R indices for [I > 2sigma(I)] were R1 = 0.0430, wR2 = 0.0878 and R indices (all data) R1 = 0.0473, wR2 = 0.0894. The largest electron density difference peak and hole were 0.207 and −0.154 eÅ(−3). Details of the molecular geometry are discussed and compared with a model DFT structure calculated using Gaussian 98.

Leucine Aminopeptidase (Aminopeptidase-I) N-Acetyl-Beta-Hexosaminidase And Lysosomes In The Mussel Mytilus-Edulis-L In Response To Salinity Changes

The intracellular distribution of aminopeptidase-I in the intestinal and digestive cells of Mytilus edulishas been shown to be the same as the lysosomal marker enzymes β-glucuronidase and N-acetyl-β-hexosaminidase. Activity for these enzymes was also associated with the intestinal apical cytoplasm and microvillous border where there was pronounced staining for aminopeptidase-I. Experimental alterations of salinity induced changes in both microdensitometrically and spectrophotometrically determined aminopeptidase-I activity, as an increase with raised salinity and a decrease with lowered salinity. Lysosomal hexosaminidase showed similar changes in activity with altered salinity. Cytochemically determined lysosomal stability was also responsive to salinity changes, indicative of alterations in lysosomal functional capability. The lysosomal distribution of aminopeptidase-I is discussed in terms of the function of lysosomes in intracellular protein turnover, their high concentrations of free amino acids, and the possible roles which these might play in intracellular osmoregulation in response to salinity change.

The inactivation of bovine cathepsin B by novel N-chloro-acetyl-dipeptides. Application of the Houghten 'tea bag' methodology to inhibitor synthesis

In this study, a series of N-chloro-acetylated dipeptides were synthesised by the application of Houghten's methodology of multiple analog peptide syntheses. The peptides, all of which contain a C-terminal free acid, were tested as inactivators of bovine cathepsin B, in an attempt at exploiting the known and, amongst the cysteine proteinases, unique carboxy dipeptidyl peptidase activity of the protease. We have succeeded in obtaining a number of effective inactivators, the most potent of which-chloroacetyl-Leu-Leu-OH, inactivates the enzyme with an apparent second-order rate constant of 3.8 x 10(4) M-1 min(-1). In contrast, the esterified analog, chloroacetyl-Leu-Leu-OMe, inactivates the enzyme some three orders of magnitude less efficiently, lending credence to our thesis that a free carboxylic acid moiety is an important determinant for inhibitor effectiveness. This preliminary study has highlighted a number of interesting features about the specificity requirements of the bovine proteinase and we believe that our approach has great potential for the rapid delineation of the subsite specificities of cathepsin B-like proteases from various species. (c) 2005 Elsevier Inc. All rights reserved.

Improved stability, insulin-releasing activity and antidiabetic potential of two novel N-terminal analogues of gastric inhibitory polypeptide: N-acetyl-GIP and pGlu-GIP

Aims/hypothesis: This study examined the plasma stability, biological activity and antidiabetic potential of two novel N-terminally modified analogues of gastric inhibitory polypeptide (GIP).

Methods: Degradation studies were carried out on GIP, N-acetyl-GIP (Ac-GIP) and N-pyroglutamyl-GIP (pGlu-GIP) in vitro following incubation with either dipeptidylpeptidase IV or human plasma. Cyclic adenosine 3'5' monophosphate (cAMP) production was assessed in Chinese hamster lung fibroblast cells transfected with the human GIP receptor. Insulin-releasing ability was assessed in vitro in BRIN-BD11 cells and in obese diabetic (ob/ob) mice.

Results: GIP was rapidly degraded by dipeptidylpeptidase IV and plasma (t1/2 2.3 and 6.2 h, respectively) whereas Ac-GIP and pGlu-GIP remained intact even after 24 h. Both Ac-GIP and pGlu-GIP were extremely potent (p<0.001) at stimulating cAMP production (EC50 values 1.9 and 2.7 nmol/l, respectively), almost a tenfold increase compared to native GIP (18.2 nmol/l). Both Ac-GIP and pGlu-GIP (10–13–10–8 mmol/l) were more potent at stimulating insulin release compared to the native GIP (p<0.001), with 1.3-fold and 1.2-fold increases observed at 10–8 mol/l, respectively. Administration of GIP analogues (25 nmol/kg body weight, i.p.) together with glucose (18 mmol/kg) in (ob/ob) mice lowered (p<0.001) individual glucose values at 60 min together with the areas under the curve for glucose compared to native GIP. This antihyperglycaemic effect was coupled to a raised (p<0.001) and more prolonged insulin response after administration of Ac-GIP and pGlu-GIP (AUC, 644±54 and 576±51 ng·ml–1·min, respectively) compared with native GIP (AUC, 257±29 ng·ml–1·min).

Conclusion/interpretation: Ac-GIP and pGlu-GIP, show resistance to plasma dipeptidylpeptidase IV degradation, resulting in enhanced biological activity and improved antidiabetic potential in vivo, raising the possibility of their use in therapy of Type II (non-insulin-dependent) diabetes mellitus.

Multi component coupling reactions of N-acetyl-2-azetine

N-Acetyl-2-azetine undergoes Lewis acid catalysed formal [4+2]-cycloaddition with imines derived from aromatic amines to initially give an approximately 1: 1 mixture of exo-endo-diastereoisomeric 1-(2a,3,4,8b-tetrahydro-2H-1,4-diaza-cyclobuta[a]naphthalen-1-yl)-ethanone cycloadducts which were detected by proton NMR spectroscopy. These products, which were too unstable to isolate, and characterise, reacted further with aromatic amines to give 2,3,4-trisubstituted tetrahydroquinolines in good to excellent yield, predominantly as a single diastereoisomer, with the minor diastereoisomer converting to the major diastereoisomer on silica. The cycloaddition was irreversible and a mechanism is presented for the formation of the major diastereoisomer from the mixture of diastereoisomeric intermediates. A range of conditions is described for converting the 2,3,4-trisubsitituted tetrahydroquinolines into 2,3-disubstituted quinolines.

Three component coupling reactions of N-acetyl-2-azetine-rapid stereoselective entry to 2,3,4-trisubstituted tetrahydroquinolines

N-Acetyl-2-azetine undergoes Lewis acid catalysed [4 + 2]-cycloaddition with imines derived from aromatic amines and gave a 1:1 mixture of exo-endo diastereoisomeric azetidine cycloadducts which reacted further with aromatic amine, to give 2,3,4-trisubsitituted tetrahydroquinolines in good to excellent yield, predominantly as one diastereoisomer.

Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents

Acetaminophen [N-acetyl-p-aminophenol (APAP)] is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, we hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase activity, and cytokine and chemokine levels in the airways or skin. Inflammatory responses evoked by NAPQI and APAP are abated by TRPA1 antagonism or are absent in TRPA1-deficient mice. This novel pathway, distinguished from the tissue-damaging effect of NAPQI, may contribute to the risk of COPD and asthma associated with therapeutic APAP use.-Nassini, R., Materazzi, S., Andre, E., Sartiani, L., Aldini, G., Trevisani, M., Carnini, C., Massi, D., Pedretti, P., Carini, M., Cerbai, E., Preti, D., Villetti, G., Civelli, M., Trevisan, G., Azzari, C., Stokesberry, S., Sadofsky, L., McGarvey, L., Patacchini, R., Geppetti, P. Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation causes neurogenic inflammation in the airways and other tissues in rodents. FASEB J. 24, 4904-4916 (2010). www.fasebj.org