ChemInform Abstract: NITROGEN‐15 NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY. THE NEBRAMYCIN AMINOGLYCOSIDES

Experimental Determination of the pKa Values of Clinically Relevant Aminoglycoside Antibiotics: Toward Establishing pKa─Activity Relationships

“…The pK a values of individual amino groups of the studied aminoglycosides were determined using a similar approach as described by Alkhzem et al 20 In short, the aminoglycoside samples were dissolved in D 2 O and titrated with DCl or NaOD. Changes in the 15 N and 1 H chemical shifts were monitored by using 15 N− 1 H HMBC and 1 H NMR spectroscopy. Assignment of the 1 H, 13 C, and 15 N resonances was performed based on 2D correlation spectra.…”

“…Changes in the 15 N and 1 H chemical shifts were monitored by using 15 N− 1 H HMBC and 1 H NMR spectroscopy. Assignment of the 1 H, 13 C, and 15 N resonances was performed based on 2D correlation spectra. The pK a s were calculated using Microsoft Excel Solver Add-in by fitting the experimental data to a theoretical model (see the Experimental Section for details).…”

“…Understanding structure−activity relationships of aminoglycosides requires knowing the protonation level of individual amino groups at a specific pH found at the site of infection. Traditional 15 N NMR titration methods have been used to measure the site-specific pK a values of amino groups in various aminoglycosides, including neomycin B, 14 apramycin, 15,16 isepamicin, 17 ribostamycin, 18 and tobramycin. 15,19 However, minor differences between the equipment and experimental approaches used in these separate studies complicates a direct comparison of the aminoglycosides in terms of ionization state at a particular pH.…”

“…Traditional 15 N NMR titration methods have been used to measure the site-specific pK a values of amino groups in various aminoglycosides, including neomycin B, 14 apramycin, 15,16 isepamicin, 17 ribostamycin, 18 and tobramycin. 15,19 However, minor differences between the equipment and experimental approaches used in these separate studies complicates a direct comparison of the aminoglycosides in terms of ionization state at a particular pH. Recently, Blagbrough and co-workers published two studies reporting individual pK a values for a total of nine selected aminoglycosides from Streptomyces and Micromonospora (tobramycin, kanamycin B, amikacin, sisomicin, netilmicin, neamine, neomycin, paromomycin, and streptomycin) by multinuclear NMR spectroscopy.…”

“…In this work, we determine the pK a values for individual amino groups of apramycin in comparison to the five clinically most relevant aminoglycoside antibiotics using 15 N− 1 H heteronuclear multiple-bond correlation (HMBC) and 1 H NMR titration experiments. Based on the pK a values, we calculate the pH dependent net charge of the aminoglycosides and the protonation levels of amino groups.…”