Moran E.E.,Concordia University at Montreal |
Timerghazin Q.K.,Concordia University at Montreal |
Timerghazin Q.K.,Marquette University |
Kwong E.,Merck Frosst Canada Ltd. |
English A.M.,Concordia University at Montreal
Journal of Physical Chemistry B | Year: 2011
The denitrosation of three primary S-nitrosothiols (RSNO; S-nitrosocysteine, S-nitroso-N-acetylcysteine, and S-nitrosoglutathione) and two tertiary RSNOs (S-nitrosopenicillamine and S-nitroso-N-acetylpenicillamine) was investigated in 3.75 M H2SO4 to probe the mechanism of acid-catalyzed RSNO hydrolysis and its dependence on RSNO structure. This reversible reaction was forced to proceed in the denitrosation direction by trapping the nitrosating agent with HN3. The primary RSNOs exhibited hydrolysis kobs values of ∼2 × 10-4 s -1, and the tertiary RSNO kobs values were an order of magnitude higher. Product analysis by HPLC revealed that the parent thiols (RSHs) were formed in 90-100% yield on 79-99% RSNO denitrosation. Possible hydrolysis mechanisms were studied computationally at the CBS-QB3 level using S-nitrosomethanethiol (MeSNO) as a model RSNO. Consideration of RSNOs as a combination of conventional R-S-N=O, zwitterionic R-S+=N-O -, and RS-/NO+ ion-pair resonance structures was key in understanding the mechanistic details of acid-catalyzed hydrolysis. Protonation of the S-nitroso oxygen or nitrogen activates the sulfur and nucleophilic attack by H2O at this atom leads to the formation of the sulfoxide-protonated N-hydroxysulfinamide, MeS+(OH)NHOH, with barriers of 19 and 29 kcal/mol, respectively. Proton loss and reprotonation at the nitrogen lead to secondary hydrolysis that produces the sulfinic acid MeS(=O)OH and NH2OH. Notably, no low-energy RSNO hydrolysis pathway for HNO release was found in the computational analysis. Protonation of the S-nitroso sulfur gives rise to NO+ release with a low activation barrier (ΔH‡calc ≈ 6 kcal/mol) and the formation of MeSH in agreement with experiment. The experimental kobs can be expressed as Kak1, where Ka is the acid dissociation constant for protonation of the S-nitroso sulfur and k1 the pseudo-first-order hydrolysis rate constant. Given the low ΔH ‡calc for denitrosation of the S-protonated isomer, the observed slow rates of acid-catalyzed RSNO hydrolysis must be controlled by the magnitude of Ka. The 10-fold higher Ka calculated for Me3CS(H+)NO (∼10-15) compared to MeS(H+)NO (10-16) is consistent with the order of magnitude larger kobs reported here for the tertiary vs primary RSNOs. © 2011 American Chemical Society. Source
Bouffard J.,Ecole Polytechnique de Montreal |
Bertrand F.,Ecole Polytechnique de Montreal |
Chaouki J.,Ecole Polytechnique de Montreal |
Dumont H.,Merck Frosst Canada Ltd.
Computers and Chemical Engineering | Year: 2013
Powder flow in a spheronizer is characterized by a toroidal motion and the flow patterns depend on the disc velocity and the fill level, but also on the particle properties. This work investigates numerically, with a discrete element method (DEM), the impact of these parameters on segregation patterns and the flow dynamics for bidisperse particle size distributions. Characterization of the segregation, by means of a mixing index and the relation with the shear stress in the toroidal domain, is presented. Characteristics, such as mixing curves, concentration profiles and azimuthal velocity correlations, are discussed. A logarithmic expression has been developed to account for the shear stress on the evolution of the azimuthal velocity inside the particulate bed. The combination of the mixing indexes and the concentration profiles is used to quantify the changes observed on the segregation when the fill level and the rotational rate of the spheronizer disk are varied. © 2012 Elsevier Ltd. Source
Sumarah M.W.,Carleton University |
Puniani E.,Carleton University |
Sorensen D.,Carleton University |
Sorensen D.,Merck Frosst Canada Ltd. |
And 2 more authors.
Phytochemistry | Year: 2010
The extracts of a selection of 150 foliar fungal endophytes isolated from Picea rubens (red spruce) needles were screened by LC-MS and assayed for toxicity. Three of these strains that were toxic to the forest pest Choristoneura fumiferana (eastern spruce budworm) in dietary bioassays were selected for further study. Their culture extracts were analyzed by LC-NMR spectroscopy, and the major metabolites were isolated by LC-MS-SPE or PTLC/column chromatography and characterized. The structures were elucidated by spectroscopic analyses including 2D NMR, HRMS and by comparison to literature data. Compounds 1 and 5-7 are hitherto unknown whereas compounds 2 and 3 are natural products described for the first time. Compound 4 is reported for the first time as a fungal metabolite and 8-9 were identified as known fungal metabolites in genera. © 2010 Elsevier Ltd. All rights reserved. Source
Merck Frosst Canada Ltd. and Axys Pharmaceuticals Inc. | Date: 2014-05-20
This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
Merck Frosst Canada Ltd. | Date: 2011-10-10
The present invention relates to renin inhibitor compounds having the structure and their use in treating cardiovascular events and renal insufficiency.