- Optimization of N-Phenylpropenoyl- l -amino Acids as Potent and Selective Inducible Nitric Oxide Synthase Inhibitors for Parkinson's Disease
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N-Phenylpropenoyl-l-amino acids (NPAs) are inducible nitric oxide synthase (iNOS) inhibitors possessing preventive effects for Parkinson's disease (PD). Here, structural modifications for improving the iNOS inhibitory activity and blood-brain barrier (BBB) permeability of NPAs were conducted, leading to 20 optimized NPA derivatives (1-20). Compound 18, with the most potent activity (IC50 = 74 nM), high BBB permeability (Pe = 19.1 × 10-6 cm/s), and high selectivity over other NOS isoforms, was selected as the lead compound. Further studies demonstrated that 18 directly binds to iNOS. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute PD model, the oral administration of 18 (1 and 2 mg/kg) exerted preventive effects by alleviating the loss of dopaminergic (DAergic) neurons. Notably, in the MPTP-/probenecid-induced chronic PD model, the same dose of 18 also displayed a therapeutic effect by repairing the damaged DAergic neurons. Finally, good pharmacokinetic properties and low toxicity made 18 a promising candidate for the treatment of PD.
- Hu, Xiao-Long,Lv, Xian-Yu,Wang, Rong,Long, Huan,Feng, Jia-Hao,Wang, Bao-Lin,Shen, Wei,Liu, Hao,Xiong, Fei,Zhang, Xiao-Qi,Ye, Wen-Cai,Wang, Hao
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Read Online
- Synthesis of structural analogues of GGT1-DU40, a potent GGTase-1 inhibitor
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A series of new substituted pyrazoles 2-12 have been synthesized. The synthesized compounds are structural analogues of GGT1-DU40 1, a highly potent and selective inhibitor of protein geranylgeranyltransferase I (GGTase-I) both in vitro and in vivo. The i
- Mansha, Muhammad,Ullah, Nisar,Alhooshani, Khalid
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Read Online
- Pyrazole-based potent inhibitors of GGT1: Synthesis, biological evaluation, and molecular docking studies
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In this study, a series of pyrazole-based structural analogues of GGTI-DU40 (1) have been synthesized and biologically evaluated for geranylgeranyltransferase 1 (GGT1) and farnesyltransferase (FT) inhibition. The screening results revealed that 2 (IC50?=?2.4?μM) and 5 (IC50?=?3.1?μM) are potent GGT1 inhibitors (GGTIs), possessing higher inhibitory activity compared to the control compound 1 (IC50?=?3.3?μM). The anti-proliferative efficacy of these compounds was further assayed against MDA-MB-231?cells which indicated a significantly higher activity of 2 (IC50?=?7.6?μM) compared to 1 (IC50?=?23.0?μM). To examine the capacity of the synthesized compounds to inhibit GGT1 in an intact cell, western blot analysis was performed on the MDA-MB-231?cell line, which revealed very high inhibitory cellular activity of 2 and 5 and demonstrated their capacity to inhibit prenylation of endogenous proteins. Molecular docking studies of 2 against the crystal structure of GGT1 complexed with a geranylgeranyl pyrophosphate (GGPP) Analog and a CaaX (C?=?cysteine, aa?=?aliphatic amino acids, and X?=?any amino acid) portion of the KKKSKTKCVIL peptide substrate revealed several hydrogen bonding interactions and π-π contacts between 2 and the binding pocket of GGT1. Together these data suggest that compound 2 could proceed to in?vivo investigation to further assess its efficacy and cytotoxicity.
- Mansha, Muhammad,Kumari, Udayappan Udhaya,Cournia, Zoe,Ullah, Nisar
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Read Online
- Development of sulfahydantoin derivatives as β-lactamase inhibitors
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Sulfahydantoin-based molecules may provide a means to counteract antibiotic resistance, which is on the rise. These molecules may act as inhibitors of β-lactamase enzymes, which are key in some resistance mechanisms. In this paper, we report on the synthe
- Paquet-C?té, Pierre-Alexandre,Alejaldre, Lorea,Lapointe Verreault, Camille,Gobeil, Sophie M.C.,Lamoureux, Rosalie,Bédard, Laurie,Normandeau, Charles-Olivier,Lemay-St-Denis, Claudèle,Pelletier, Joelle N.,Voyer, Normand
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supporting information
(2021/01/25)
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- Structure-Activity Relationships of cyclo(l -Tyrosyl- l -tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct
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A series of analogues of cyclo(l-tyrosyl-l-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-vis and electron paramagnetic resonance spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(l-tyrosyl-l-tyrosine) results in sub-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel antitubercular compounds.
- Rajput, Sunnia,McLean, Kirsty J.,Poddar, Harshwardhan,Selvam, Irwin R.,Nagalingam, Gayathri,Triccas, James A.,Levy, Colin W.,Munro, Andrew W.,Hutton, Craig A.
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supporting information
p. 9792 - 9805
(2019/11/13)
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- Rhodium-Catalyzed Enantioselective Synthesis of Oxazinones via an Asymmetric Ring Opening-Lactonization Cascade of Oxabicyclic Alkenes
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The rhodium-catalyzed asymmetric ring opening reaction of oxabicyclic alkenes is shown to be an efficient method for synthesizing chiral heterocycles. We demonstrate that the pairwise combination of chiral catalyst with chiral amino-acid-derived pronucleophiles results in a stereodivergent synthesis of diastereomeric hydroxyesters. A favorable conformational preference induces the subsequent lactonization of one diastereomer leading to the highly enantioselective synthesis of oxazinones.
- Yen, Andy,Pham, Anh Hoang,Larin, Egor M.,Lautens, Mark
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supporting information
p. 7549 - 7553
(2019/10/02)
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- CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
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Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.
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Paragraph 1647
(2018/04/17)
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- BENZOLACTAM COMPOUNDS AS PROTEIN KINASE INHIBITORS
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The invention provides a compound of formula (0): or a pharmaceutically acceptable salt, N-oxide or tautomer thereof. The compounds are inhibitors of ERK 1/2 kinases and will be useful in the treatment of ERKl/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.
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Page/Page column 281
(2017/08/01)
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- HETEROCYCLIC COMPOUNDS USEFUL IN THE TREATMENT OF DISEASE
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Heterocyclic compounds are described that are lysophosphatidic acid receptor ligands that are useful in the treatment of lysophosphatidic acid receptor-dependent diseases and conditions, including but not limited to diseases involving fibrosis, such as fibrosis of the heart, kidney, liver and lung, and scleroderma; inflammatory diseases such as diabetic nephropathy and inflammatory bowel disease; ocular diseases such as diseases involving retinal degeneration; nerve diseases such as pruritus and pain. Non-limiting examples of those compounds include (RS)-3-Cyclopropyl-2-{4-[3-methyl-4((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-benzyloxy}-propionic acid and (R)-1-(4′-{5-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-4-fluoro-pyrazol-1-yl}-2-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid.
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Paragraph 0598; 0626
(2016/02/18)
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- A new type of chiral-pyridoxamines for catalytic asymmetric transamination of α-keto acids
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A new type of chiral pyridoxamines bearing an adjacent chiral stereocenter has been developed via multi-step synthesis. The pyridoxamines displayed catalytic activity in asymmetric transamination of α-keto acids to give a variety of optically active amino acids in 27–78% yields with 34–62% ee's under very mild conditions. This work provides a synthetic strategy to construct new chiral pyridoxamines using bromopyridine 7 as a key synthon and also represents an early example of the applications of chiral pyridoxamines in asymmetric catalysis.
- Chen, Jianfeng,Zhao, Junyu,Gong, Xing,Xu, Dongfang,Zhao, Baoguo
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supporting information
p. 4612 - 4615
(2016/09/23)
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- Evaluation of two cyclic di-peptides as inhibitors of CCL2 induced chemotaxis
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Monocyte chemoattractant protein (CCL2) plays a major role in the recruitment of monocytes during inflammation. In this study we analysed properties of synthetic CCL2 inhibitors in inhibiting CCL2 mediated monocyte migration. Using trans-endothelial chemotaxis assays compounds C1 and C5 were found to significantly reduce CCL2 mediated migration. Flow based adhesion assays showed reduction in adhesion to VCAM-1 in the presence of 10 nM CCL2 and 50 μM C5 (p 0.05). Further studies with these compounds can aid in their development as anti-inflammatory therapies. The Royal Society of Chemistry 2013.
- Saleki, Mahsa,Colgin, Neil,Kirby, John A.,Cobb, Steven L.,Ali, Simi
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p. 860 - 864
(2013/08/26)
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- Synthesis and biological evaluation of new active For-Met-Leu-Phe-OMe analogues containing para-substituted Phe residues
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In the present study, we report synthesis and biological evaluation of the N-Boc-protected tripeptides 4a-l and N-For protected tripeptides 5a-l as new For-Met-Leu-Phe-OMe (fMLF-OMe) analogues. All the new ligands are characterized by the C-terminal Phe residue variously substituted at position 4 of the aromatic ring. The agonism of 5a-l and the antagonism of 4a-l (chemotaxis, superoxide anion production, lysozyme release as well as receptor binding affinity) have been examined on human neutrophils. No synthesized compounds has higher activity than the standard fMLF-OMe tripeptide to stimulate chemotaxis, although compounds 5a and 5c with -CH3 and -C(CH3)3, respectively, in position 4 on the aromatic ring, are better than the standard tripeptide to stimulate the production of superoxide anion, in higher concentration. Compounds 4f and 4i, containing -F and -I in position 4, respectively, on the aromatic ring of phenylalanine, exhibit significant chemotactic antagonism. The influence of the different substitution at the position 4 on the aromatic ring of phenylalanine is discussed.
- Mollica, Adriano,Feliciani, Federica,Stefanucci, Azzurra,Costante, Roberto,Lucente, Gino,Pinnen, Francesco,Notaristefano, Daniela,Spisani, Susanna
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experimental part
p. 418 - 426
(2012/08/28)
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- Enzymatic synthesis of chiral phenylalanine derivatives by a dynamic kinetic resolution of corresponding amide and nitrile substrates with a multi-enzyme system
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Mutant α-amino-ε-caprolactam (ACL) racemase (L19V/L78T) from Achromobacter obae with improved substrate specificity toward phenylalaninamide was obtained by directed evolution. The mutant ACL racemase and thermostable mutant D-amino acid amidase (DaaA) from Ochrobactrum anthropi SV3 co-expressed in Escherichia coli (pACLmut/pDBFB40) were utilized for synthesis of (R)-phenylalanine and non-natural (R)-phenylalanine derivatives (4-OH, 4-F, 3-F, and 2-F-Phe) by dynamic kinetic resolution (DKR). Recombinant E. coli with DaaA and mutant ACL racemase genes catalyzed the synthesis of (R)-phenylalanine with 84% yield and 99% ee from (RS)-phenylalaninamide (400 mM) in 22 h. (R)-Tyrosine and 4-fluoro-(R)-phenylalanine were also efficiently synthesized from the corresponding amide compounds. We also co-expresed two genes encoding mutant ACL racemase and L-amino acid amidase from Brevundimonas diminuta in E. coli and performed the efficient production of various (S)-phenylalanine derivatives. Moreover, 2-aminophenylpropionitrile was converted to (R)-phenylalanine by DKR using a combination of the non-stereoselective nitrile hydratase from recombinamt E. coli and mutant ACL racemase and DaaA from E. coli encoding mutant ACL racemase and DaaA genes. Copyright
- Yasukawa, Kazuyuki,Asano, Yasuhisa
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supporting information
p. 3327 - 3332
(2013/01/15)
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- Biocatalyzed enantioselective reduction of activated C=C bonds: Synthesis of enantiomerically enriched α-halo-β-arylpropionic acids
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The enantioselective biocatalyzed reduction of the C=C bond of some (Z)-methyl α-halo-β-arylacrylates was investigated. The reaction was performed by baker's yeast fermentation and Old Yellow Enzymes 1-3 mediated biotransformations. The final products wer
- Brenna, Elisabetta,Gatti, Francesco G.,Manfredi, Alessia,Monti, Daniela,Parmeggiani, Fabio
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p. 4015 - 4022
(2011/09/15)
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- Design, synthesis, and preliminary activity evaluation of novel peptidomimetics as aminopeptidase N/CD13 inhibitors
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The synthesis of a series of novel N-α-galloylated isoglutamic acid I-amide peptidomimetics is described. Their enzymatic inhibition against aminopeptidase N (APN/CD13) and matrix metalloproteinase-2 (MMP-2) was tested. The preliminary activity assay revealed that most of the compounds displayed selective inhibition against APN as compared with MMP-2, with IC50 values in a micromolar range. Within this series, compound 4 (IC 50a=10.2a±a.9μM) demonstrated comparable APN inhibition as compared with the positive control bestatin (IC 50a=a13.1aa0.7aμM), which might be a promising lead for further molecular optimizations. A new series of bi-peptide analogues containing amino acid or organic acid residues as elongated hydrophobic substituents inserting into S1 or S1 pocket was designed. Most of the target compounds showed potent and selective activities against APN/CD13 as compared with MMP-2. Compound 4 was comparable to bestatin and could be used as a potential lead for further development of APNIs.
- Li, Xun,Wang, Junli,Zhang, Lei,Xu, Wenfang
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experimental part
p. 494 - 504
(2011/11/04)
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- Oleanolic acid and its derivatives: New inhibitor of protein tyrosine phosphatase 1B with cellular activities
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Protein tyrosine phosphatase 1B is a key factor in the negative regulation of insulin pathway and a promising target for treatment of diabetes and obesity. Herein, a series of competitive inhibitors were optimized from oleanolic acid, a natural triterpenoid identified against PTP1B by screening libraries of traditional Chinese medicinal herbs. Modifying at 3 and 28 positions, we obtained compound 13 with a Ki of 130 nM, which exhibited good selectivity between other phosphatases involved in insulin pathway except T-cell protein tyrosine phosphatase. Further evaluation in cell models illustrated that the derivatives enhanced insulin receptor phosphorylation in CHO/hIR cells and also stimulated glucose uptake in L6 myotubes with or addition of without insulin.
- Zhang, Yi-Nan,Zhang, Wei,Hong, Di,Shi, Lei,Shen, Qiang,Li, Jing-Ya,Li, Jia,Hu, Li-Hong
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p. 8697 - 8705
(2008/12/23)
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- Piperazine derivatives
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This invention relates to piperazine derivatives of the formula: wherein each symbol is as defined in the description, and its pharmaceutically acceptable salt, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a use of the same for treating or preventing Tachykinin-mediated diseases in human being or animals.
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Page/Page column 18
(2010/02/15)
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- Electrochemical radiofluorination. 3. Direct labeling of phenylalanine derivatives with [18F]fluoride after anodic oxidation
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As an example of applying the electrochemical method in radiofluorination a new procedure was developed for preparing [18F]fluorophenylalanine by direct use of [18F]fluoride. Several protecting groups for amino and carboxylic functio
- Kienzle, Gabriele J.,Reischl, Gerald,Machulla, H.-Juergen
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p. 259 - 273
(2007/10/03)
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- Resolution of non-protein amino acids via the microbial protease-catalyzed enantioselective hydrolysis of their N-unprotected esters
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In the Aspergillus oryzae protease-catalyzed ester hydrolysis, substitution of N-unprotected amino acid esters for the corresponding N-protected amino acid esters resulted in a large enhancement of the hydrolysis rate, while the enantioselectivity was deteriorated strikingly when the substrates employed were the conventional methyl esters. This difficulty was overcome by employing esters bearing a longer alkyl chain such as the isobutyl ester. Utilizing this ester, amino acids carrying an aromatic side chain were resolved with excellent enantioselectivities (E=50 to >200). With amino acids bearing an aliphatic side chain also, good results in terms of the hydrolysis rate and enantioselectivity were obtained by employing such an ester as the isobutyl ester. Moreover, the enantioselectivity proved to be enhanced further by conducting the reaction at low temperature. This procedure was applicable to the case where the enantioselectivity was not high enough even by the use of the isobutyl ester.
- Miyazawa, Toshifumi,Imagawa, Kiwamu,Minowa, Hiroe,Miyamoto, Toyoko,Yamada, Takashi
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p. 10254 - 10261
(2007/10/03)
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- Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists
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A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and α-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50~1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.
- Kopka, Ihor E,Young, David N,Lin, Linus S,Mumford, Richard A,Magriotis, Plato A,MacCoss, Malcolm,Mills, Sander G,Riper, Gail Van,McCauley, Ermengilda,Egger, Linda E,Kidambi, Usha,Schmidt, John A,Lyons, Kathryn,Stearns, Ralph,Vincent, Stella,Colletti, Adria,Wang, Zhen,Tong, Sharon,Wang, Junying,Zheng, Song,Owens, Karen,Levorse, Dorothy,Hagmann, William K
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p. 637 - 640
(2007/10/03)
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- Beam-induced dehalogenation in LSIMS: Effect of halogen type and matrix chemistry
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The LSIMS beam-induced dehalogenation of several 4-halo-phenylalanine methyl esters (I, Br, Cl, F) was investigated and compared to that of atrazine using 12 different matrix compounds including diethyl phthalate for which the empirical electron affinity was known. The extent of dehalogenation, induced by a one-electron reduction process, is in agreement with the leaving group ability of the corresponding halogens (I > Br > Cl > F) and the dehalogenation inhibiting efficiency of the matrices. The latter is rationalized in terms of electron scavenging capacity and matrix structural features relating to that capacity. The extent of dehalogenation observed for 4-I-phenylalanine methyl ester is similar to that of atrazine, a chlorinated compound, which indicates that the halogen effect is not overwhelming in determining the extent of dehalogenation. The bracketing of matrix reduction potential was attempted based on the propensity of the matrices to induce M+. formation from analytes of known oxidation potentials. The ability of matrices to induce M+. formation parallels their dehalogenation and reduction inhibiting efficiencies. The last observation underlines the importance of matrix redox properties in effecting or inhibiting beam-induced processes, be they reductive or oxidative.
- Theberge,Bertrand
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p. 163 - 171
(2007/10/02)
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