The pH-dependent (1)H NMR characteristics of a series of Co(III)-(polyamin)-aqua and Co(III)-(polyamin)-(polyalcohol) complexes, [Co(tach)(ino-kappa(3)-O(1,3,5))](3+) (1(3+)), [Co(tach)(ino-kappa(3)-Omicron(1,2,6))](3+) (2(3+)), [Co(tach)(taci-kappa-Nu(1)-kappa(2)-O(2,6))](3+) (3(3+)), [Co(ditame)(H(2)O)](3+) (4(3+)), and [Co(tren)(H(2)O)(2)](3+) (5(3+)), were studied in D(2)O by means of titration experiments (tach = all-cis-cyclohexane-1,3,5-triamine, ino = cis-inositol, taci = 1,3,5-triamino-1,3,5-trideoxy-cis-inositol, tren = tris(2-aminoethyl)amine, ditame = 2,2,6,6-tetrakis-(aminomethyl)-4-aza-heptane). A characteristic shift was observed for H(-C) hydrogen atoms in the alpha-position of a coordinated amino group upon deprotonation of a coordinated oxygen donor. For a cis-H-C-N-Co-O-H arrangement, deprotonation of the oxygen donor resulted in an additional shielding (shift to lower frequency) of the H(-C) proton, whereas for a trans-H-C-N-Co-O-H arrangement, deprotonation resulted in a deshielding (shift to higher frequency). The effect appears to be of rather general nature: it is observed for primary (1(3+)-5(3+)), secondary (4(3+)), and tertiary (5(3+)) amino groups, and for the deprotonation of an alcohol (1(3+)-3(3+)) or a water (4(3+), 5(3+)) ligand. Spin-orbit-corrected density functional calculations show that the high-frequency deprotonation shift for the trans-position is largely caused by a differential cobalt-centered spin-orbit effect on the hydrogen nuclear shielding. This effect is conformation dependent due to a Karplus-type behavior of the spin-orbit-induced Fermi-contact shift and thus only significant for an approximately antiperiplanar H-C-N-Co arrangement. The differential spin-orbit contribution to the deprotonation shift in the trans-position arises from the much larger spin-orbit shift for the protonated than for the deprotonated state. This is in turn due to a trans-effect of the deprotonated (hydroxo or alkoxo) ligand, which weakens the trans Co-N bond and thereby interrupts the Fermi-contact mechanism for transfer of the spin-orbit-induced spin polarization to the hydrogen nucleus in question. The unexpectedly large long-range spin-orbit effects found here for 3d metal complexes are traced back to small energy denominators in the perturbation theoretical expressions of the spin-orbit shifts.
In peritoneal dialysis (PD), glucose degradation products (GDPs), which are formed during heat sterilization of dialysis fluids, lead to structural and functional changes in the peritoneal membrane, which eventually result in the loss of its ultrafiltration capacity. To determine the molecular mechanisms behind these processes, the present study tested the influence of the six major α-dicarbonyl GDPs in PD fluids, namely, glyoxal, methylglyoxal, 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), and glucosone with respect to their potential to impair the enzymatic activity of RNase A as well as their effects on cell viability. For comprehensive risk assessment, the α-dicarbonyl GDPs were applied separately and in concentrations as present in conventional PD fluids. Thus, it was shown that after 5 days, glucosone impaired RNase A activity most distinctly (58% remaining activity, p < 0.001 compared to that of the control), followed by 3,4-DGE (62%, p < 0.001), 3-DGal (66%, p < 0.001), and 3-DG (76%, p < 0.01). Methylglyoxal and glyoxal caused weaker inactivation with significant effects only after 10 days of incubation (79%, 81%, p < 0.001). Profiling of the advanced glycation end products formed during the incubation of RNase A with methylglyoxal revealed predominant formation of the arginine modifications imidazolinone, CEA/dihydroxyimidazoline, and tetrahydropyrimidine at Arg10, Arg33, Arg39, and Arg85. Particularly, modification at Arg39 may severely affect the active site of the enzyme. Additionally, structure- and concentration-specific assessment of the cytotoxicity of the α-dicarbonyl GDPs was performed. Although present at very low concentration, the cytotoxic effect of PD fluids after 2 days of incubation was exclusively caused by 3,4-DGE (14% cell viability, p < 0.001). After 4 days of incubation, 3-DGal (13% cell viability, p < 0.001), 3-DG (24%, p < 0.001), and, to a lower extent, glyoxal and methylglyoxal (both 57%, p < 0.01) also reduced cell viability significantly. In conclusion, 3,4-DGE, 3-DGal, and glucosone appear to be the most relevant parameters for the biocompatibility of PD fluids.
Metal complex formation of the two cyclic triamines 6-methyl-1,4-diazepan-6-amine (MeL(a)) and all-cis-2,4,6-trimethylcyclohexane-1,3,5-triamine (Me(3)tach) was studied. The structure of the free ligands (H(x)MeL(a))(x+) and H(x)Me(3)tach(x+) (0 ≤ x ≤ 3) was investigated by pH-dependent NMR spectroscopy and X-ray diffraction experiments. The crystal structure of (H(2)Me(3)tach)(p-O(3)S-C(6)H(4)-CH(3))(2) showed a chair conformation with axial nitrogen atoms for the doubly protonated species. In contrast to a previous report, Me(3)tach was found to be a stronger base than the parent cis-cyclohexane-1,3,5-triamine (tach); pK(a)-values of H(3)Me(3)tach(3+) (25 °C, 0.1 M KCl): 5.2, 7.4, 11.2. The crystal structures of (H(3)MeL(a))(BiCl(6))·2H(2)O and (H(3)MeL(a))(ClO(4))Cl(2) exhibited two distinct twisted chair conformations of the seven membered diazepane ring. [Co(MeL(a))(2)](3+) (cis: 1(3+), trans: 2(3+)), trans-[Fe(MeL(a))(2)](3+) (3(3+)), [(MeL(a))ClCd(μ(2)-Cl)](2) (4), trans-[Cu(MeL(a))(2)](2+) (5(2+)), and [Cu(HMeL(a))Br(3)] (6) were characterized by single crystal X-ray analysis of 1(ClO(4))(3)·H(2)O, 2Br(3)·H(2)O, 3(ClO(4))(3)·0.8MeCN·0.2MeOH, 4, 5Br(2)·0.5MeOH, and 6·H(2)O. Formation constants and redox potentials of MeL(a) complexes were determined by potentiometric, spectrophotometric, and cyclovoltammetric measurements. The stability of [M(II)(MeL(a))](2+)-complexes is low. In comparison to the parent 1,4-diazepan-6-amine (L(a)), it is only slightly enhanced. In analogy to L(a), MeL(a) exhibited a pronounced tendency for forming protonated species such as [M(II)(HMeL(a))](3+) or [M(II)(MeL(a))(HMeL(a))](3+) (see 6 as an example). In contrast to MeL(a), Me(3)tach forms [M(II)L](2+) complexes (M = Cu, Zn) of very high stability, and the coordination behavior corresponds mainly to an "all-or-nothing" process. Molecular mechanics calculations showed that the low stability of L(a) and MeL(a) complexes is mainly due to a large amount of torsional strain within the pure chair conformation of the diazepane ring, required for tridentate coordination. This behavior is quite contrary to Me(3)tach and tacn (tacn =1,4,7-triazacyclononane), where the main portion of strain is already preformed in the free ligand, and the amount, generated upon complex formation, is comparably low.
Heat sterilization of peritoneal dialysis (PD) fluids leads to partial degradation of the osmotic agent to form reactive carbonyl structures, which significantly reduce the biocompatibility of PD fluids and impair long-term PD therapy. Hence, it is important to know the exact composition of the degradation products to improve biocompatibility of PD fluids. Our study conducted targeted screening for degradation products in polyglucose (icodextrin)-containing PD fluids (pGDPs) by applying o-phenylenediamine (OPD) to form stable derivatives, which were analyzed by ultrahigh-performance liquid chromatography with hyphenated diode array tandem mass spectrometry (UHPLC–DAD–MS/MS). For the first time, specific degradation products of polyglucose, namely, 4-deoxyglucosone (4-DG) and 3,4-dideoxypentosone (3,4-DDPS), could be identified in PD fluids. Further, a reaction product of 5-hydroxymethylfurfural (5-HMF) and OPD could be characterized to be (5-(1H-benzo[d]imidazol-2-yl)furan-2-yl)methanol. Additionally, 3-deoxyglucosone (3-DG) and 3-deoxygalactosone (3-DGal), both known to be present in glucose-based PD fluids, were also detected in polyglucose-containing fluids. Trapping a hitherto unknown degradation product with OPD yielded 1,4-bis(1H-benzo[d]imidazol-2-yl)-3,4-dihydroxybutan-1-one, which was present in heat- as well as filter-sterilized PD fluids.
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