Nitrogen-15 nuclear magnetic resonance spectroscopy. The nebramycin aminoglycosides

Dorman, Douglas E.; Paschal, Jonathan W.; Merkel, K.E.

doi:10.1021/ja00438a020

Cited by 69 publications

(75 citation statements)

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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%

“…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.…”

Section: Tobramycin (mentioning

confidence: 99%

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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%

Section: Tobramycin (mentioning

confidence: 99%

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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“…(and a-L-ta1o)-octofuranosyl]-3-methyluracil (24) Hydrolysis of 23 (0.18 g, 0.33 mmol) was performed as described above for 14 and afforded, after preparative tlc (toluene-acetone, 2:3 (vlv)), 24 as a glass (0.13 g, 75%) having R, 0.36 (solvent A); ir (film) v,,,: 3410, 1710, 1670, 1630, 1360, 1 1 8 0~m -~; uv h,,, (EtOH): 227 (E 13 000), 259 (12 000) nm; 'Hmr 6: 1.66-2.01 (4H, m, 2(H-5')'s, 2(H-6')s), 2.46 (3H, s, PhMe), 3.29 (3H,s,NMe),[2][3][4][5][6][7][8]'s, 2OH's), 5.64(1H, d, J 1 * , 2 3 = 3.5 HZ, H-l'), 5.82(1H,d,J5,6= 8.OHz,7.27 (lH,d,m,aromatic H's).…”

Section: -[8-o-aceryl-56-dideoxy-7-0-ptolylsulfonyl-p-~allomentioning

confidence: 99%

“…The product was isolated by the procedure which was used for 14 to give 28 as a syrup (0.75 g, 94%). An analytical sample was obtained by preparative tlc using toluene-acetone, 2:l (vlv) as eluent; ir (film) v, , : 1710, 1670, 1630, 1360, 1180cm-I; uv [2][3][4][5][6][7][8])'s, 2 allylic H's, 2 terminal vinylic H's), m,vinylic H),5.54 (lH,d,J1',2'= 2.0Hz,5.68(1H,d,J5,6= 8 . 0 H~,aromatic H's,.…”

Section: -[8-0-allyl-56-dideoxy-23-o-isopropylidene-7-o-p-mentioning

confidence: 99%

“…Added impetus has, in recent years, been given to this area of carbohydrate chemistry, by the development of new methods of chain extension (3) and by the EIIV-J discovery of various important antibiotics con-O< / R taining highly complex, higher-carbon sugars, such as lincomycin (4), celesticetin (9, apramycin (6), oxyapramycin (7), the ezomycins (8), mildiomycin (9), tunicamycin (lo), and hikizimycin (1 1).…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of 3′,7′-anhydrooctose nucleosides related to the ezomycins and the octosyl acids

Kim¹,

Szarek²

1981

Can. J. Chem.

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Several novel 3′,7′-anhydrooctose nucleosides, including a 3′,7′-anhydroocturonic acid nucleoside, namely l-(3,7-anhydro-5,6-dideoxy-β-D-allo-octofuranosyluronic acid)-3-methyluracil (40), have been synthesized. The synthetic sequence leading to 40 consists of three key steps: preparation of an octose nucleoside by a chain extension of an uridine derivative using a Wittig reaction, conversion of the octose nucleoside into a bicyclic-octose nucleoside by an intramolecular cyclization, and elaboration of a carboxylic acid function at the C-8′ position of the bicyclic-octose nucleoside. The structures of the 3′,7′-anhydrooctose nucleosides have been established by their uv, 1Hmr, 13Cmr, and mass spectral data.

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RNA‐Aminoglycosid‐Wechselwirkungen: Design und Synthese von „Amino‐aminoglycosiden”︁ und deren Bindung an RNA

Wang

Tor

1998

Angewandte Chemie

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Nitrogen-15 nuclear magnetic resonance spectroscopy. The nebramycin aminoglycosides

Cited by 69 publications

References 1 publication

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

Synthesis of 3′,7′-anhydrooctose nucleosides related to the ezomycins and the octosyl acids

RNA‐Aminoglycosid‐Wechselwirkungen: Design und Synthese von „Amino‐aminoglycosiden”︁ und deren Bindung an RNA

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