Dissociation constants of Br∅nsted acids in D2O and H2O: studies on polyaza and polyoxa-polyaza macrocycles and a general correlation

Delgado, Rita; Silva, J.J.R.Fraústo Da; Amorim, M. T. Pessoa de; Cabral, M. Fátima; Chaves, Sı́lvia; Costa, Judite

doi:10.1016/s0003-2670(00)80232-9

Cited by 97 publications

(74 citation statements)

References 25 publications

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“…The values determined by the 1 H NMR and 15 N NMR titrations are in close agreement with each other. Our values agree with those found by the previous 15 N NMR titration 11 (performed in H 2 O), after correcting for the deuterium isotope effect 16 for our titrations performed in D 2 O (Table 2). However, only tentative assignments were made for N1 and N3 in that study and we found the assignments of N1 and N3 to be interchanged.…”

Section: Resultssupporting

confidence: 90%

Structural characterization of the tobramycin–piperacillin reaction product formed at pH 6.0

Pagano¹,

Gong²,

Kong

et al. 2011

J Antibiot

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Tobramycin is an aminoglycoside antibiotic that loses a significant amount of activity in the presence of Zosyn at pH 6. As part of our investigation into ways to improve the compatibility of tobramycin with Zosyn (which contains piperacillin and tazobactam in an 8:1 ratio buffered at pH 6 by sodium citrate) by lowering the pH, we identified the reaction product of tobramycin and piperacillin at pH 6.0 and the order of the pK a values of tobramycin. The structure of the main reaction product of tobramycin and piperacillin at pH 6.0 was determined by 2D NMR to be the product of 3 00 -NH 2 reacting with the b-lactam of piperacillin. The order of the pK a values of the nitrogens of tobramycin was determined by 1 H and 15 N NMR titrations to be 6¢-NH 2 42¢-NH 2 41-NH 2 E3 00 -NH 2 43-NH 2 . At pH 4.0, the reaction between tobramycin and Zosyn was almost negligible for a period of up to 2 h. The pH can be lowered by adding an acid such as HCl or citric acid to Zosyn to make a pH 4.0 buffer. The Journal of Antibiotics (2011) 64, 673-677; doi:10.1038/ja.2011.72; published online 3 August 2011Keywords: piperacillin; protonation constants; structure elucidation; tobramycin; Y-site co-administration; Zosyn INTRODUCTION Tobramycin (Figure 1) is an aminoglycoside antibiotic produced by Streptomyces tenebrarius 1 used to treat infections caused by susceptible Gram-negative microorganisms. 2 It is often used in combination with penicillins, such as piperacillin (Figure 2), to treat severe infections caused by Gram-negative bacteria. 3 It is well known that tobramycin reacts with b-lactams, including piperacillin, causing a significant loss of aminoglycoside activity. 4 The inactivation mechanism is thought to involve nucleophilic attack and ring opening of the penicillin b-lactam ring by an amino group of the aminoglycoside. 5,6 The rate of aminoglycoside inactivation is dependent on temperature, time, concentration of the b-lactam and composition of the medium. [7][8][9] Another important factor to consider is the pH of the solution. As the degree of protonation of an amino group increases, it should become less nucleophilic. The amino groups of tobramycin have different pK a values, 10,11 hence, it is logical to assume the reaction would be affected by pH of the solution. Therefore, knowledge of the protonation constants of the amino groups and their order is important in understanding the reactivity of tobramycin with piperacillin at different pHs.Zosyn is an intravenously administered antibiotic, which contains piperacillin and tazobactam (a b-lactamase inhibitor) in an 8:1 ratio. It also contains EDTA and sodium citrate, which is used to buffer the solution at around pH 6. 12 It has been approved for Y-site coadministration with the aminoglycosides amikacin and gentamicin. 13 It has not been approved for co-administration with tobramycin,

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Section: Resultssupporting

confidence: 90%

Structural characterization of the tobramycin–piperacillin reaction product formed at pH 6.0

Pagano¹,

Gong²,

Kong

et al. 2011

J Antibiot

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“…[45] The overall iron complex stability constants were determined with the PSEQUAD program, [22] by fitting of the spectrophotometric data and including the Fe 3 + hydrolytic species [43] in the equilibrium model.…”

Section: Spectroscopic Titrationsmentioning

confidence: 99%

New Tris(hydroxypyridinones) as Iron and Aluminium Sequestering Agents: Synthesis, Complexation and In Vivo Studies

Chaves¹,

Marques²,

Matos³

et al. 2010

Chemistry A European J

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Two new tripodal tris(3-hydroxy-4-pyridinone) hexadentate chelators-NTA(BuHP)(3) and NTP(PrHP)(3) (NTA=nitrilotriacetic acid, NTP=nitrilotripropionic acid, HP=hydroxypyridone)-have been developed and studied in solution for their iron and aluminium binding affinity, and also assayed in vivo for their capacity to remove metal from an animal model that is overloaded. These chelators are positional isomers, possessing identical general structures based on aminotricarboxylic acid skeletons attached to three bidentate 3-hydroxy-4-pyridinones (3,4-HPs), but differing in the position of the amide linkage along the chelating "arm". In spite of expected differences in the tripodal ligands, such as acidity and hydrogen-bonding networks, they share important properties, namely, a mild hydrophilic character (log P ca. -1.2 to -1.4) and a strong chelating affinity for Fe and Al (pFe=27.9 and pAl=22.0 for NTA(BuHP)(3); pFe=29.4 and pAl=22.4 for NTP(PrHP)(3)). They also evidenced identical effects on the biodistribution and on the excretion of a radiotracer ((67)Ga) previously administered to mice, as models of iron overload animals. Comparison of the new compounds with reported analogues shows good improvement in terms of solution and in vivo sequestering properties, thus giving support to expectations about their potential clinical application as metal removal agents.

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“…Both quantities are ionic strength-dependent. The proposed empirical equations yield significantly different results and seem very arbitrary: relationships depend on the nature and number of compounds studied [24][25][26]. It is observed that the activity coefficient products undergo significant changes when one goes from light to heavy water [27].…”

Section: Chemical Shiftsmentioning

confidence: 99%

Guidelines for NMR measurements for determination of high and low pKa values (IUPAC Technical Report)

Popov

Rönkkömäki

Lajunen

2006

Pure and Applied Chemistry

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Factors affecting the NMR titration procedures for the determination of pKa values in strongly basic and strongly acidic aqueous solutions (2 > pH > 0 and 14 > pH > 12) are analyzed. Guidelines for experimental procedure and publication protocols are formulated. These include: calculation of the equilibrium H+ concentration in a sample; avoidance of measurement with glass electrode in highly acidic (basic) solutions; exclusion of D2O as a solvent; use of an individual sample isolated from air for each pH value; use of external reference and lock compounds; use of a medium of constant ionic strength with clear indication of the supporting electrolyte and of the way the contribution of any ligand to the ionic strength of the medium is accounted for; use of the NMR technique in a way that eliminates sample heating to facilitate better sample temperature control (e.g., 1H-coupled NMR for nuclei other than protons, GD-mode, CPD-mode, etc.); use of Me4NCl/Me4NOH or KCl/KOH as a supporting electrolyte in basic solution rather than sodium salts in order to eliminate errors arising from NaOH association; verification of the independence of the NMR chemical shift from background electrolyte composition and concentration; use of extrapolation procedures.

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Dissociation constants of Br∅nsted acids in D2O and H2O: studies on polyaza and polyoxa-polyaza macrocycles and a general correlation

Cited by 97 publications

References 25 publications

Structural characterization of the tobramycin–piperacillin reaction product formed at pH 6.0

Structural characterization of the tobramycin–piperacillin reaction product formed at pH 6.0

New Tris(hydroxypyridinones) as Iron and Aluminium Sequestering Agents: Synthesis, Complexation and In Vivo Studies

Guidelines for NMR measurements for determination of high and low pKa values (IUPAC Technical Report)

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