Urban Frey

Hydrolysis products of cisplatin: pKa determinations via[1H, 15N] NMR spectroscopy

The pKa values of cis-[PtCl(H2O)(NH3)2]+(6.41) and cis-[Pt(H2O)2(NH3)2]2+(5.37 and 7.21) have been determined at 300 K via the use of 15N-edited 1H NMR spectroscopy and [1H, 15N] heteronuclear multiple quantum coherence spectroscopy; this allows rapid measurements at low (millimolar) concentrations, and so avoids some of the problems associated with other methods.

High-pressure, high-resolution NMR probe working at 400 MHZ

Abstract A probe for obtaining high-resolution multinuclear NMR spectra at elevated pressures with a Bruker AM-400 spectrometer is described. The probe is designed for pressures up to 200 MPa and has been used between -40 to 150°C. We obtain routinely a resolution of about 1 Hz for proton (400 MHz) spectra using deuterium as an internal field lock. This probe is easily interchangeable with a commercial probe. We also describe a simple sample tube made of a 5 mm commercial NMR tube and a machinable glass cap with a total volume of about 1 cm3.

1H, 15N N.M.R. KINETIC STUDIES OF REACTIONS OF CIS- AND TRANS-PTCL2(15NH3)(C-C6H1115NH2) WITH GUANOSINE 5'-MONOPHOSPHATE

cis-[PtCl2(15NH3)(c-C6H11NH2)] is an active metabolite of the oral platinum(IV) anticancer drug cis,trans,cis-[PtCl2(CH3CO2)2(NH2)(c-C6H11NH2)]. Since it is likely that guanine bases on DNA are targets for this drug, we have analysed the kinetics of reaction of this platinum(II) metabolite with guanosine 5′-monophosphate (5′-GMP) at 310 K, pH 7, using [1H, 15N] n.m.r. methods. Reactions of the trans isomer are reported for comparison. The reactions proceed via aquated intermediates, and, for the cis isomer, the rates of aquation and substitution of H2O by 5′-GMP are 2-5 times faster trans to the amine ligand (c-C6H11NH2) compared to trans to NH3 for both the first and second steps. For the trans complex, the first aquation step is c. 3 times faster than for the cis complex, as expected from the higher trans influence of Cl¯, whereas the rate of the second aquation step (trans to N7 of 5′-GMP) is comparable to that trans to NH3. These findings have implications for the courses of reactions with DNA.

[Pd(CBDCA-O,O′)(NH3)2]: the PdII analogue of a platinum anticancer drug (CBDCA = cyclobutane-1,1-dicarboxylate)

The X-ray crystal structure of [Pd(CBDCA-O,O′)(NH3)2] shows that it is isostructural with the anticancer drug carboplatin ‘Paraplatin’; the mechanism of formation of this complex from reaction of [Pd(NH3)4]2+ with H2CBDCA has been elucidated by NMR spectroscopy.

Fast water exchange on a Pt(II) center: variable temperature and pressure17O NMR study at 14.1 tesla of the ionic arylplatinum species [PtC6H3(CH2NMe2)2-2,6 (OH2)]+ (OSO2CF3)−

Abstract The water-soluble ionic aryl platinum species [PtC 6 H 3 (CH 2 NMe 2 ) 2 )-2,6(OH 2 )] + undergoes water exchange at a rate 10 7 times faster than the coordination complex [Pt(OH 2 ) 4 ] 2+ ; a clear-cut example of the trans effect of the C-bonded organic group. Lineshape analysis of high pressure 17 O NMR data acquired in a 14.1 tesla magnet are indicative for an associative mode of activation for this water exchange.

UV degradation of sesquiterpene lactones in chicory extract: Kinetics and identification of reaction products by HPLC-MS

Inulin, a valuable food ingredient, can be extracted from chicory roots (Cichorium intybus L.). However, the direct use of this material is limited, because of the presence of extremely bitter, co-extracted sesquiterpene lactones. Lactucin, a major component, has been degraded by UV irradiation, a process which showed neither temperature (293- 313 K) nor initial concentration dependence. An overall half life time of ca. 45 min was determined. The degradation product was identified by HPLC-MS and 1 H NMR and was the result of the addition of a water molecule on the lactucin C(1)-C(10) double bond, with the OH group located at the C(10) position.

The first high-pressure high-resolution NMR probe for a normal bore cryomagnet1

Abstract We describe a high-pressure high-resolution NMR probe fitting into a 4.7 Tesla normal bore (50 mm O) cryomagnet used with a Bruker AC-200 spectrometer. The probe is designed for a pressure range from 0.1 to 200 MPa and can be used in a temperature domain from -50 to + 120°C. Eguipped with a double tuned frequeney adapter circuit the probe is used for 1H (200 MHz) observation and 2H (30.7 MHz) field locking for easy homogeneity adjustment. The resolution obtained routinely is better than 1 Hz (< 5′10−9). Other frequencies, e.g. 27.1 MHz for 17O observation, can easily be obtained by changing and according the frequency adapter box.

Chelate-ring-opened adducts of[Pt(en)(Me-Mal-O,O′)](en = ethane-1,2-diamine,Me-Mal = 2-methylmalonate) with methionine derivatives:relevance to the biological activity of platinum anticanceragents

The anticancer drug carboplatin [Pt(cbdca-O,O′)(NH 3 ) 2 ] which contains the chelated dicarboxylate ligand cbdca, cyclobutane-1,1-dicarboxylate, may be activated in vivo by reaction with sulfur ligands. The reactions between the analogue [Pt(en)(Me-Mal-O,O′)] 1 (en = ethane-1,2-diamine, Me-Mal = 2-methylmalonate) and the methionine derivatives N-acetyl-L-methionine (Ac-Met), glycyl-L-methionine (Gly-Met) and L-methionylglycine (Met-Gly) have been studied at pH 7 and 4, 310 K, using 1 H and two-dimensional [ 1 H, 15 N] heteronuclear single quantum coherence NMR spectroscopy and HPLC. The ring-opened species [Pt(en)(Me-Mal-O)(L-S)] (L = Ac-Met, Gly-Met or Met-Gly) containing monodentate malonate and S-bound monodentate methionine ligands were predominant in solution after 2 h. The second-order rate constant for the ring-opening reaction of 1 with Ac-Met at pH 6.56 was determined to be (1.48 ± 0.03) × 10 - 1 s -1 M -1 , and was similar for reactions with Gly-Met. Methylmalonate α-CH deuteriation rates were determined to be free Me-Met > ring-opened complex 1. Molecular-mechanics modelling suggested that hydrogen bonding between the free carboxylate group of monodentate Me-Mal and the co-ordinated amine groups, and between the two ring-opened ligands may contribute to the stability of the mixed-ligand adducts. However, in the case of Met-Gly, the ring-opening rate [(5.26 ± 0.10) × 10 -2 s -1 M -1 ] was nearly three times slower than that for the reaction of 1 with Ac-Met. In contrast, the ring-closure rate of [Pt(en)(Me-Mal-O)(Met-Gly-S)] [k 1 = (1.37 ± 0.03) × 10 -4 s -1 ] to give the S,N-chelated adduct was faster than that of [Pt(en)(Me-Mal-O)(Ac-Met-S)] - 2 [(2.27 ± 0.04) × 10 -5 s -1 ]. The S,N-chelated adducts [Pt(en)(Ac-MetH -1 -S,N)] 3, [Pt(en)(Gly-MetH -1 -S,N)] + and [Pt(en)(Met-GlyH -1 -S,N)] + became the predominant products of the reactions after about 24 h. Ring-opened adducts of chelated dicarboxylate platinum anticancer complexes with methionine derivatives could play a significant role in their mechanism of action.

Kinetic study and crystal structure of tetrakis(1,4-thioxane)palladium(II). A comparison between platinum(II) and palladium(II) reactivity

Abstract The compound [Pd(1,4-thioxane)4](BF4)2·4CH3NO2 crystallizes in the monoclinic space group P21/c with a=9.474(2), b=9.529(5), c=21.945(9) A, β=99.77(3)°, Z=2; final R=0.051 for 4325 observed reflections (Pd, C, S and O anisotropically refined). The thioxane ligands around Pd form a square-planar arrangement, with two nitromethane molecules at a distance of 3.115(2) A occupying sites perpendicular to the square-plane formed by the sulfur-bonding thioxanes giving an overall tetragonal bipyramidal coordination around Pd. Intermolecular exchange of 1,4-thioxane on [Pd(1,4-thioxane)4](BF4)2 in deuterated nitromethane and intramolecular interconversion in the bound ligand have been studied as a function of temperature and pressure by 1H NMR lineshape analysis. The first-order rate constant and activation parameters obtained for the intramolecular process, assigned to sulfur inversion, are as follows: ki298=294±26 s−1, ΔHi≠=61.9±1.9 kJ mol−1, ΔSi≠=+10.2±6.5 J K−1 mol−1, ΔVi≠=+2.7±0.2 cm3 mol−1. The intermolecular process yielded the following second-order rate constant and activation parameters: k2298=920±40 m−1 s−1, ΔH2≠=39.5±0.9 kJ mol−1, ΔS2≠=−55.6±2.8 J K−1 mol−1, ΔV2≠=−9.5±0.3 cm3 mol−1. Second-order kinetics and negative values for the entropy and volume of activation indicate an associative Ia or A exchange mechanism. The reactivity of the analogous Pt2+ compound is estimated using the proposed empirical linear correlation function ΔG≠(Pt)=−32.1+1.92ΔG≠(Pd). The calculated second-order rate constant and free energy of activation are 0.3 m−1 s−1 and 76 kJ mol−1, respectively. This relationship indicates also that the well established reactivity order Pd2+≫Pt2+ could be reversed for better π-accepting ligands than MeNC and that, in this case, five-coordinated species on Pt(II) are more stable than the Pd(II) analogue.

Formation and in situ characterization of the first dihydrogen aqua complex: [Ru(H2O)5(H2)]2+

The product of the reaction between [Ru(H2O)6]2+ and pressurized H2 in water is [Ru(H2O)5(H2)]2+ whose nature was unambiguously demonstrated by 1H and 17O NMR and which is the first characterized dihydrogen aqua complex.