Abstract
Unambiguous assignments have been made for each individual pKa value of the amino group and guanidine substituents on 2-deoxystreptamine, neamine, neomycin, paromomycin, and streptomycin by pH-titration evaluation of their 1H, 13C, and 15N (by 1H-15N heteronuclear multiple-bond correlation (HMBC) spectra) NMR chemical shifts (δXs) as the reporter nuclei. These data require minor revisions of the literature data in terms of the assignment order for neomycin and paromomycin. In situ titrations and NMR spectroscopy are shown to be a powerful combination for rapidly (minutes) obtaining each distinct pKa value of the similar amine and guanidine functional groups, which decorate aminoglycoside antibiotics.
Highlights
Aminoglycosides are polyamine natural products consisting of amino sugars linked by glycosidic bonds, their class name.[1]
The nuclear magnetic resonance (NMR) shifts seen are explained by inductive effects, but note that this is not the intuitive inductive effect, as the shift for 13C goes in the “wrong” direction, as discussed previously.[16]
1H, 13C, and 1H-15N HMBC NMR spectroscopies with in situ pH titration is shown to be a powerful technique for the measurement of distinct pKa values that are accurate to
Summary
Aminoglycosides are polyamine natural products consisting of amino sugars linked by glycosidic bonds, their class name.[1]. The pKa values of each individual nitrogen atom of neamine, shown in Figure 2 and Table 2, were extracted from the inflection points of the nonlinear sigmoidal curves. The pKa values of individual nitrogen atoms of paromomycin (Figure 4 and Table 4) were extracted from the inflection points of the nonlinear sigmoidal curves. The individual pKa values of the two guanidine groups (N-1 and N3) and the secondary amine (N-methyl) of streptomycin (Figure 5 and Table 5) were extracted from the inflection points of the nonlinear sigmoidal curves. The three average pKa values after calculating using 1H, 13C, and 1H-15N HMBC NMR spectroscopic data of the two guanidine groups (N-1 and N-3) and the secondary amine (Nmethyl, N-2′) on streptomycin are as follows: N-1 (guanidine) = 13.06, N-3 (guanidine) = 12.06, and N-2′ = 8.16. These pKa values are consistent in the assignment order with those reported in the literature.[32]
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