230. Nitric esters. Part I. Characterisation of the isomeric glycerol dinitrates

Dunstan, I.; Griffiths, J. V.; Harvey, S. A.

doi:10.1039/jr9650001319

Cited by 36 publications

(11 citation statements)

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“…2-(N,N-Diethylamino)-diazenenolate-2-oxide (DEA/NO) was purchased from Cayman Chemical Company, Ann Arbor, MI. GTN was synthesized according to the method of Dunstan (22). GMPCPP was a gift from Jonathan Winger, University of California, Berkeley, CA.…”

Section: Methodsmentioning

confidence: 99%

Effects of Nitroglycerin on Soluble Guanylate Cyclase

Artz¹,

Schmidt²,

McCracken³

et al. 2002

Journal of Biological Chemistry

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Soluble guanylate cyclase (sGC) is a heterodimeric hemoprotein that catalyzes the conversion of GTP to cGMP. Upon binding NO to its heme cofactor, purified sGC was activated 300-fold. sGC was only activated 67-fold by nitroglycerin (GTN) and Cys; and in the absence of Cys, GTN did not activate sGC. Electronic absorption spectroscopy studies showed that upon NO binding, the Soret of ferrous sGC shifted from 431 to 399 nm. The data also revealed that activation of sGC by GTN/Cys was not via the expected ferrous heme-NO species as indicated by the absence of the 399 nm heme Soret. Furthermore, EPR studies of the reaction of GTN/Cys with sGC confirmed that no ferrous heme-NO species was formed but that there was heme oxidation. Potassium ferricyanide is known to oxidize ferrous sGC to the ferric oxidation state. Spectroscopic and activity data for the reactions of sGC with GTN alone or with K 3 Fe(CN) 6 were indistinguishable. These data suggest the following: 1) GTN/Cys do not activate sGC via GTN biotransformation to NO in vitro, and 2) in the absence of added thiol, GTN oxidizes sGC.

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Section: Methodsmentioning

confidence: 99%

Effects of Nitroglycerin on Soluble Guanylate Cyclase

Artz¹,

Schmidt²,

McCracken³

et al. 2002

Journal of Biological Chemistry

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“…Metabolites were detected at 210 nm. NG concentrations were determined by comparison of peak areas with those of a NG standard curve, while concentrations of the DNG and MNG isomers were estimated from the NG standard curve by scaling the absorbance of each compound according to published molar absorptivity values (10,11). Nitrite production was analyzed colorimetrically as previously described (7).…”

Section: Methodsmentioning

confidence: 99%

Regioselectivity of nitroglycerin denitration by flavoprotein nitroester reductases purified from two Pseudomonas species

et al. 1997

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Two species of Pseudomonas capable of utilizing nitroglycerin (NG) as a sole nitrogen source were isolated from NG-contaminated soil and identified as Pseudomonas putida II-B and P. fluorescens I-C. While 9 of 13 laboratory bacterial strains that presumably had no previous exposure to NG could degrade low concentrations of NG (0.44 mM), the natural isolates tolerated concentrations of NG that were toxic to the lab strains (1.76 mM and higher). Whole-cell studies revealed that the two natural isolates produced different mixtures of the isomers of dinitroglycerol (DNG) and mononitroglycerol (MNG). A monomeric, flavin mononucleotide-containing NG reductase was purified from each natural isolate. These enzymes catalyzed the NADPH-dependent denitration of NG, yielding nitrite. Apparent kinetic constants were determined for both reductases. The P. putida enzyme had a K m for NG of 52 ؎ 4 M, a K m for NADPH of 28 ؎ 2 M, and a V max of 124 ؎ 6 M ⅐ min ؊1 , while the P. fluorescens enzyme had a K m for NG of 110 ؎ 10 M, a K m for NADPH of 5 ؎ 1 M, and a V max of 110 ؎ 11 M ⅐ min ؊1 . Anaerobic titration experiments confirmed the stoichiometry of NADPH consumption, changes in flavin oxidation state, and multiple steps of nitrite removal from NG. The products formed during time-dependent denitration reactions were consistent with a single enzyme being responsible for the in vivo product distributions. Simulation of the product formation kinetics by numerical integration showed that the P. putida enzyme produced an Ϸ2-fold molar excess of 1,2-DNG relative to 1,3-DNG. This result could be fortuitous or could possibly be consistent with a random removal of the first nitro group from either the terminal (C-1 and C-3) positions or middle (C-2) position. However, during the denitration of 1,2-DNG, a 1.3-fold selectivity for the C-1 nitro group was determined. Comparable simulations of the product distributions from the P. fluorescens enzyme showed that NG was denitrated with a 4.6-fold selectivity for the C-2 position. Furthermore, a 2.4-fold selectivity for removal of the nitro group from the C-2 position of 1,2-DNG was also determined. The MNG isomers were not effectively denitrated by either purified enzyme, which suggests a reason why NG could not be used as a sole carbon source by the isolated organisms.Nitroglycerin (NG, glycerol trinitrate) is an aliphatic nitrate ester-containing compound that is an important component of dynamite and other propellants (36,42). In addition, nitrosubstituted compounds, including nitroaromatics, are used as explosives, agricultural chemicals, and dyes (18, 32, 39). Consequently, compounds containing nitro functional groups have become widely distributed in the environment. Since naturally occurring nitro functional groups are rare (18, 32), the molecules containing these groups have typically been classified as xenobiotics. Consistent with this classification, a number of early studies of the environmental fate of NG revealed toxicity to algae, invertebrates, and vertebrates (42) and furth...

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“…3-Phenylpropane-1,2-diyl dinitrate (5). Iodine (1.07 g, 4.23 mmol) was added in one portion to a stirred solution of fresh distilled allyl benzene (0.50 g, 4.23 mmol) and AgNO 3 (2.15 g, 12.66 mmol) in CH 3 CN (30 ml) kept at 08C.…”

Section: Erythro-1-phenylpropane-123-triyl Trinitrate (3a)mentioning

confidence: 99%

Synthesis, chiral HPLC resolution and configuration assignment of 1‐phenylglyceryl trinitrate stereomers

et al. 2006

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As an introductory study of in vitro vasodilating activity, the access to the four stereomers of 1-phenylglyceryl trinitrate is described using achiral and chiral chromatography. For semi-preparative separation of the enantiomers, a Chiralcel OD (250 3 10 mm, 10 lm) was used. Catalytic reduction leading to the corresponding stereomers of 1-phenylglycerol allowed absolute configuration assignments. The same methods were used for the separation and configuration assignment of the enantiomers of 3-phenylpropane-1,2-diyl dinitrate. The organic esters of nitric acid, the nitrates, are a heterogeneous class of products widely used for the treatment of a number of cardiovascular diseases, including congestive heart failure and coronary heart disease. 1These products act through a common mechanism which implies the activation of the soluble guanylate cyclase (sGC), with consequent increase of intracellular cGMP. This increase in the vascular smooth muscle results in vasodilation. The prototype of nitrates is glyceryl trinitrate (GTN, nitroglycerin). It was introduced in therapy for relief of angina pectoris pain in 1876.2 The major limit in the practical application of this drug is an early development of the tolerance. In this article, we describe the synthesis, isolation, and configuration assignment of the four stereomers of the new nitrate 3 (Ph-GTN) obtained by introducing a phenyl ring on the terminal methylene group of achiral GTN. The related nitrate 5 formally obtained from 3 by elimination of one nitrooxy groups is also described (Scheme 1).The overall Energy Release Potential (ERP), a parameter that evaluates the explosive hazard of a compound, calculated using the ASTM Program CHEAT AH 7.2, was found to be high for compound 3, as well as for the other nitric esters studied in the present work. Consequently, we always treated only small amounts of these substances with a great caution, although we never observed violent decomposition induced by thermal and mechanical shock. MATERIAL AND METHODS GeneralAll compounds were routinely checked by IR (Shimadzu FT-IR 8101 M). 1 H and 13 C-NMR spectra were recorded on a Bruker Avance 300 at 300 and 75 MHz, respectively, using Si(CH 3 ) 4 as an internal standard. The following abbreviations were used to indicate the peak multiplicity: s ¼ singlet, d ¼ doublet, and m ¼ multiplet. Low-resolution mass spectra were recorded with a Finnigan-Mat TSQ-700. Mass spectra in Desorption Chemical Ionization (DCI) of the derivatives 3a, 3b were obtained with a Finnigan-Mat 8400 spectrometer using iso-butane as reacting gas. Accurate molecular mass of 5 was determined by peak matching using perfluorokerosene (PFK) as an internal standard on a Finnigan-Mat 8400 spectrometer. Melting points were determined with a capillary apparatus (Büchi 540) and are uncorrected. Flash column chromatography was performed on silica gel (Merck Kieselgel 60, 230-400 mesh ASTM) using the indicated eluents. Petroleum ether 40-608C (PE) was used as coeluent. The progress of the reactions was follow...

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230. Nitric esters. Part I. Characterisation of the isomeric glycerol dinitrates

Cited by 36 publications

References 0 publications

Effects of Nitroglycerin on Soluble Guanylate Cyclase

Effects of Nitroglycerin on Soluble Guanylate Cyclase

Regioselectivity of nitroglycerin denitration by flavoprotein nitroester reductases purified from two Pseudomonas species

Synthesis, chiral HPLC resolution and configuration assignment of 1‐phenylglyceryl trinitrate stereomers

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