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C4 Position (c4 + position)
Selected AbstractsH2O2 -mediated oxidation of tetrahydrobiopterin: Fourier transform Raman investigations provide mechanistic implications for the enzymatic utilization and recycling of this essential cofactorJOURNAL OF RAMAN SPECTROSCOPY, Issue 8 2002Jeremy Moore The oxidation of (6R)- L - erythro -5,6,7,8-tetrahydrobiopterin (6BH4) by H2O2 was examined by Fourier transform Raman spectroscopy. Initial investigations indicated that oxidation proceeds by incorporation of the H2O2 into the 6BH4 molecule without the formation of any additional water. In addition, the pyrimidine ring is affected with the shift of the double bond from the N1,C2 to the C2,N3 position. Such rearrangements of this double bond are observed after the production of either a carbinolamine or quinonoid species. Using deuterium exchange experiments, it was possible to substantiate that the oxidation of 6BH4 initially proceeds by the formation of a 4a-OH-carbinolamine intermediate prior to its spontaneous dehydration yielding the quinonoid dihydro species (qBH2). Furthermore, the hydrogen on the hydroxyl group of the carbinolamine interacts with the oxygen of the carbonyl group at the C4 position of the pyrimidine ring. It is proposed that this interaction facilitates the dehydration of the carbinolamine, thus explaining its instability. Furthermore, a mechanism for the dehydration reaction is suggested, wherein the 4a-hydroxyl group forms an H-bond to the carbonyl group, thus making the oxygen of the hydroxyl group more susceptible to attack by the proton at position N5 of the pyrazine ring, resulting in qBH2 production concomitant with the loss of a water molecule. Upon increasing the concentration of H2O2 the qBH2 converts to 7,8-BH2, which is further oxidized to L -biopterin. Taken together, our results do not support an earlier proposed mechanism implicating a hydroperoxide intermediate in this oxidation reaction. Copyright © 2002 John Wiley & Sons, Ltd. [source] Analysis of inhibitor binding in influenza virus neuraminidasePROTEIN SCIENCE, Issue 4 2001Brian J. Smith Abstract 2,3-didehydro-2-deoxy- N -acetylneuraminic acid (DANA) is a transition state analog inhibitor of influenza virus neuraminidase (NA). Replacement of the hydroxyl at the C9 position in DANA and 4-amino-DANA with an amine group, with the intention of taking advantage of an increased electrostatic interaction with a conserved acidic group in the active site to improve inhibitor binding, significantly reduces the inhibitor activity of both compounds. The three-dimensional X-ray structure of the complexes of these ligands and NA was obtained to 1.4 Ĺ resolution and showed that both ligands bind isosterically to DANA. Analysis of the geometry of the ammonium at the C4 position indicates that Glu119 may be neutral when these ligands bind. A computational analysis of the binding energies indicates that the substitution is successful in increasing the energy of interaction; however, the gains that are made are not sufficient to overcome the energy that is required to desolvate that part of the ligand that comes in contact with the protein. [source] Artificial Neural Networks and the Study of the Psychoactivity of Cannabinoid CompoundsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2010Káthia M. Honório Cannabinoid compounds have widely been employed because of its medicinal and psychotropic properties. These compounds are isolated from Cannabis sativa (or marijuana) and are used in several medical treatments, such as glaucoma, nausea associated to chemotherapy, pain and many other situations. More recently, its use as appetite stimulant has been indicated in patients with cachexia or AIDS. In this work, the influence of several molecular descriptors on the psychoactivity of 50 cannabinoid compounds is analyzed aiming one obtain a model able to predict the psychoactivity of new cannabinoids. For this purpose, initially, the selection of descriptors was carried out using the Fisher's weight, the correlation matrix among the calculated variables and principal component analysis. From these analyses, the following descriptors have been considered more relevant: ELUMO (energy of the lowest unoccupied molecular orbital), Log P (logarithm of the partition coefficient), VC4 (volume of the substituent at the C4 position) and LP1 (Lovasz,Pelikan index, a molecular branching index). To follow, two neural network models were used to construct a more adequate model for classifying new cannabinoid compounds. The first model employed was multi-layer perceptrons, with algorithm back-propagation, and the second model used was the Kohonen network. The results obtained from both networks were compared and showed that both techniques presented a high percentage of correctness to discriminate psychoactive and psychoinactive compounds. However, the Kohonen network was superior to multi-layer perceptrons. [source] Application of Selective Palladium-Mediated Functionalization of the Pyrido[3,,2,:4,5]pyrrolo[1,2- c]pyrimidine Heterocyclic System for the Total Synthesis of Variolin B and Deoxyvariolin B,EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 29 2010Alejandro Baeza Abstract The reaction of protected 3-bromo-2-(bromomethyl)-4-methoxypyrrolo[2,3- b]pyridine and tosylmethyl isocyanide (TosMIC) afforded a pyrido[3,,2,:4,5]pyrrolo[1,2- c]pyrimidine derivative in good yield. This compound was transformed through installation of the pyrimidine moiety in the C5 position, hydrolysis, and decarboxylation in an advanced intermediate for the total or formal synthesis of the naturalalkaloid variolin B. Reaction of 3-bromo-2-(bromomethyl)-4-chloropyrrolo[2,3- b]pyridine with N -tosylmethyl dichloroformimide as a synthetic TosMIC equivalent afforded trihalo-substituted pyrido[3,,2,:4,5]pyrrolo[1,2- c]pyrimidine. This compound was used in a new total synthesis of the alkaloid variolin B by selective and sequential C,N, C,C, and C,O palladium-mediated functionalization at the C9, C5, and C4 positions of the pyrido[3,,2,:4,5]pyrrolo[1,2- c]pyrimidine system. A formal synthesis of deoxyvariolin B is also described by using the same synthetic strategy. [source] | ||||||||||