The pK<sub>a</sub> Values of Some 2-Aminomidazolium Ions

Storey, Bayard T.; Sullivan, Walter Wade; Moyer, Calvin L.

doi:10.1021/jo01033a537

Cited by 67 publications

(33 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because imidazole has pK a = 7.0 and 2-aminoimidazole has pK a = 8.5 (35), we hypothesized that an analysis of the pH effects of chemical rescue by these compounds might provide information about the protonation state of the analog employed for chemical rescue. As shown in Figure 8, imidazole effects greater rescue of R367A AblKD than 2-aminoimidazole when both are studied at pH 6.8 and each is > 50% protonated.…”

Section: Resultsmentioning

confidence: 99%

Comparative Analysis of Mutant Tyrosine Kinase Chemical Rescue

et al. 2009

View full text Add to dashboard Cite

Protein tyrosine kinases are critical cell signaling enzymes. These enzymes have a highly conserved Arg residue in their catalytic loop which is present two residues or four residues downstream from an absolutely conserved Asp catalytic base. Prior studies on protein tyrosine kinases Csk and Src revealed the potential for chemical rescue of catalytically-deficient mutant kinases (Arg to Ala mutations) by small diamino compounds, particularly imidazole, however the potency and efficiency of rescue was greater for Src. This current study further examines the structural and kinetic basis of rescue for mutant Src as compared to mutant Abl tyrosine kinase. An X-ray crystal structure of R388A Src revealed the surprising finding that a histidine residue of the N-terminus of a symmetry-related kinase inserts into the active site of the adjacent Src and mimics the hydrogen bonding pattern seen in wild-type protein tyrosine kinases. Abl R367A shows potent and efficient rescue more comparable to Src, even though its catalytic loop is more like that of Csk. Various enzyme redesigns of the active sites indicate that the degree and specificity of rescue is somewhat flexible, but the overall properties of the enzymes and rescue agents play an overarching role. The newly discovered rescue agent 2-aminoimidazole is about as efficient as imidazole in rescuing R/A Src and Abl. Rate vs. pH studies with these imidazole analogs suggest that the protonated imidazolium is the preferred form for chemical rescue, consistent with structural models. The efficient rescue seen with mutant Abl points to the potential of this approach to be used effectively to analyze Abl phosphorylation pathways in cells.Protein tyrosine kinases (PTKs 1 ) are key enzymes in cell signaling and play roles in a wide range of diseases including cancer (1,2). Several PTKs, including Abl, are targeted clinically with therapeutic agents, and others are the subject of pharmaceutical development (3). As members of the protein kinase superfamily, PTKs share conserved sequences and folds (2), and yet they show distinct substrate selectivity (4,5) and modes of regulation (6). Evidence *To whom correspondence should be addressed: P.A.C.: Tel, Fax, suggests that the mechanism of PTK-catalyzed phosphoryl transfer is dissociative, in which the bond to the leaving group ADP is largely broken prior to tyrosine phenol attack on the gamma phosphorus of ATP (7). The alignment, orientation, and spacing of the tyrosine and ATP substrates by key active site residues are believed to be crucial in facilitating catalysis based on structural (8), mutagenic (9), and kinetic (10) studies.The catalytic loop sequence, DLAARN, is conserved throughout the vast majority of the 90 human PTKs, but differs in the nine members of the Src family, which have the sequence DLRAAN ( Figure 1A) (2). This relocation of the Arg from the D+4 position in most PTKs to the D+2 position in the Src family suggests an unusual functional plasticity. A crystal structure of an insulin receptor tyrosine kina...

show abstract

Section: Resultsmentioning

confidence: 99%

Comparative Analysis of Mutant Tyrosine Kinase Chemical Rescue

et al. 2009

View full text Add to dashboard Cite

show abstract

“…N-Benzyl-2-aminoacetamide was prepared by the reaction of N-benzyl-2-phthalylamidoacetamide with hydrazine (46). N-Benzyl-2-guanidinoacetamide was obtained as its sulfate salt (2RNHC(NH2)2.S04) by the reaction of N-benzyl-2-aminoacetamide with 2 -methyl -2 -thiopseudourea sulfate (47). NBenzyl-(2'-amino-4', 5'-dihydro-4', 5'-dihydroxy-1 '-imidazoy1)acetamide was prepared as the sulfate salt ( (~C )~.…”

Section: Methodsmentioning

confidence: 99%

4,5-Dihydro-4,5-dihydroxyimidazoles as products of the reduction of 2-nitroimidazoles. HPLC assay and demonstration of equilibrium transfer of glyoxal to guanine

Panicucci¹,

McClelland²

1989

Can. J. Chem.

View full text Add to dashboard Cite

RICK PAN~CUCC~ and ROBERT A. MCCLELLAND. Can. J. Chem. 67, 2 128 (1 989). An HPLC method has been employed to study the electrochemical reduction (mercury cathode at -800 mV with respect to calomel electrode) of the 2-nitroimidazole benznidazole (N-benzyl-(2'-nitro-1'-imidazoy1)acetamide). The principal product of this reduction is the cyclic guanidiniurn ion 3c (protonated N-benzyl-(2'-amino-4',5'-dihydro-4',5'-dihydroxy-l'-imidazoyl)acetamide), which forms in a linear fashion as the nitroimidazole is reduced and accounts for 75% of the product upon completion of the reduction. To perform the HPLC analysis quantitatively an authentic sample of this product (isolated as cis:trans isomers) was prepared as the sulfate salt through the reaction of N-benzyl-2-guanidinoacetamide sulfate with aqueous glyoxal. The two isomers of 3c arise through the nonreductive decomposition of the 2-hydroxylaminoimidazole, which is the product of a four-electron reduction of the nitroimidazole. Analysis of high field 'H NMR spectra also showed that the two isomers of 3c were the principal products following electrochemical reduction, neutral aqueous zinc reduction, and radiation chemical reduction. Previous investigations using NMR of the reductions of misonidazole (3-methoxy-1-(2'-nitro-1'-imidazoy1)-2-propanol) and 1-methyl-2-nitroimidazole have shown that the corresponding dihydroimidazoles 3a and 36 are the major products. The agreement of these various NMR and HPLC results suggests that the formation of dihydroimidazoles 3 is a general phenomenon for model reductions of 2-nitroimidazoles in neutral aqueous solution. Previous workers have shown that 2-nitroimidazole reduction mixtures, when treated with guanine derivatives, form the adduct 4 derived from the guanine and glyoxal. This work demonstrates that this adduct is also formed when authentic samples of 3 a , 3 6 , and 3c are reacted with 2'-deoxyguanosine. A quantitative HPLC analysis, however, demonstrates that the reaction does not proceed to completion, and in fact the equilibrium for formation of 4 is unfavorable. This suggests that guanines are not useful derivatizing agents for the quantitative assay of "glyoxal-like" products formed in chemical or biological reductions of 2-nitroimidazoles.Key words: nitroimidazole, reduction of nitroimidazoles, glyoxal from nitroimidazoles.RICK PANICUCCI et ROBERT A. MCCLELLAND. Can. J. Chem. 67, 2128 (1989). On a utilisC une mtthode de CLHP pour Ctudier la rCduction Clectrochimique (cathode de mercure h -800 mV par rapport a l'tlectrode de calomel) de la 2-nitroimidazole benznidazole (N-benzyl-(2'-nitro-I '-imidazoy1)acttamide). Le produit principal de cette rCduction est l'ion guanidinium cyclique 3c (N-benzyl-(2'-amino-4',5'-dihydro-4',5'-dihydroxy-l'-imidazoyl)acCtamide protonC) qui se forme d'une faqon linCaire au fur et h mesure que le nitroimidazole est rtduit et qui forme 75% du produit ? I la fin de la riduction. Afin de rCaliser l'analyse quantitative par CLHP, on a prCparC un Cchantillon authentique de ce produit (is016 s...

show abstract

“…This aspect of the problem has not been considered for the synthesis of peptides containing 4-azido-L-phenylalanine derivatives [4] which also uses a final diazotization step. However, in that work an aromatic amine with lower pK, values compared to the 2-amino-lH-imidazolium group (pK, of 8.46 [22]) was transformed which might be responsible for selectivity of the diazotization.…”

Section: Selective Deprotections Of Boc-hist(2-nh2-t-tos)-ome (4; Schmentioning

confidence: 91%

Synthesis and Properties of a 2‐Diazohistidine Derivative: A New Photoactivatable Aromatic Amino‐Acid Analog

Jaganathen

Ehret‐Sabatier

Bouchet

et al. 1990

Helvetica Chimica Acta

View full text Add to dashboard Cite

Na[(tert-Butoxy)carbonyl]-2-diazo-~-histidine methyl ester 1 was synthesized starting from the corresponding L-histidine derivative. The physico-chemical properties of this new photoactivatable amino-acid derivative were established. The synthetic precursor of 1,2-amino-~-histidine derivative 3, was best isolated and characterized as 2-amino-Nr-[(tert-butoxy)carbonyl]-~T-tosyl-~-histidine methyl ester (4). Selective deprotections of 4 (N"-Boc, N'-Tos, COOMe) were achieved, thus allowing the use of the corresponding products in peptide synthesis. The optically active dipeptides 8 and 9 were synthesized by coupling 2-amino-Nr-tosyl-~-histidine methyl ester ( 5 ) with N-[(tert-butoxy)cdrbonyl]-L-alanine and N'-[(rert-buto~y)carbonyl]-N~-tosyl-~-histidine (6) with L-alanine methyl ester, respectively. The question of selective diazotization of a 2-aminohistidine residue in a synthetic peptide was studied using competitive diazotizations between 2-amino-lH-imidazole and several amino-acid derivatives susceptible to undergo nitrosylation. The results show that synthetic photoactivatable peptides incorporating a 2-diazohistidine residue might become useful photoaffinity probes.Introduction. -The discovery of numerous peptides involved in the recognition and modulation of hormone or neuromediator receptors stimulated the design and the synthesis of peptide analogs in order to study ligand-receptor interactions. Among these probes, photoactivatable structures were conceived to label irreversibly the receptor at a target binding site by means of photoaffinity labelling experiments [l]. Two major results are expected from this approach, either to identify and characterize an unknown receptor or to define at a molecular level the ligand-receptor interactions.The synthesis of photoactivatable peptides was first conceived by tagging a photosensitive group to an existing peptide. Most of the described examples used electrophilic reagents bearing an arylazido or a benzophenone moiety, the coupling of the reagent to the peptide being generally directed towards the C-terminal [2] or towards nucleophilic residues existing on the peptide such as the primary amino group of a lysine side chain [3]. Besides the problem of selectivity of modification which can arise, the major limitation of this method is the consequent structural changes caused by the attachment of the photosensitive group on the natural ligand which often induces a loss in binding affinity. The design of a photosensitive amino-acid analog structurally related to a natural amino acid and which could be incorporated in the peptide during the synthesis (solid phase or in solution), would overcome the above mentioned limitations. As such, the 4'-azidophenylalanine derivative [4] has been developed and used as a substitute for phenylalanine in several peptides [5]. The syntheses of those peptides used a 4'-nitrophenylalanine precursor which was subsequently transformed to the corresponding 4'-azido derivative.

show abstract

The pK_a Values of Some 2-Aminomidazolium Ions

Cited by 67 publications

References 3 publications

Comparative Analysis of Mutant Tyrosine Kinase Chemical Rescue

Comparative Analysis of Mutant Tyrosine Kinase Chemical Rescue

4,5-Dihydro-4,5-dihydroxyimidazoles as products of the reduction of 2-nitroimidazoles. HPLC assay and demonstration of equilibrium transfer of glyoxal to guanine

Synthesis and Properties of a 2‐Diazohistidine Derivative: A New Photoactivatable Aromatic Amino‐Acid Analog

Contact Info

Product

Resources

About

The pKa Values of Some 2-Aminomidazolium Ions

Cited by 67 publications

References 3 publications

Comparative Analysis of Mutant Tyrosine Kinase Chemical Rescue

Comparative Analysis of Mutant Tyrosine Kinase Chemical Rescue

4,5-Dihydro-4,5-dihydroxyimidazoles as products of the reduction of 2-nitroimidazoles. HPLC assay and demonstration of equilibrium transfer of glyoxal to guanine

Synthesis and Properties of a 2‐Diazohistidine Derivative: A New Photoactivatable Aromatic Amino‐Acid Analog

Contact Info

Product

Resources

About

The pK_a Values of Some 2-Aminomidazolium Ions