On the interference of J (HH) modulation in HSQMBC‐IPAP and HMBC‐IPAP experimentsSaurí, Josep; Parella, Teodor
doi: 10.1002/mrc.3977pmid: 23780917
The effects of phase modulation due to homonuclear proton–proton coupling constants in HSQMBC‐IPAP and HMBC‐IPAP experiments are experimentally evaluated. We show that accurate values of small proton–carbon coupling constants, nJCH, can be extracted even for phase‐distorted cross‐peaks obtained from a selHSQMBC experiment applied simultaneously on two mutually J‐coupled protons. On the other hand, an assessment of the reliability of nJCH measurement from distorted cross‐peaks obtained in broadband IPAP versions of equivalent HMBC and HSQMBC experiments is also presented. Finally, we show that HMBC‐COSY experiments could be an excellent complement to HMBC for the measurement of small nJCH values. Copyright © 2013 John Wiley & Sons, Ltd.
Semi‐preparative LC‐SPE‐cryoflow NMR for impurity identifications: use of mother liquor as a better source of impuritiesRinaldi, Frank; Fan, Junying; Pathirana, Charles; Palaniswamy, Venkatapurim
doi: 10.1002/mrc.3979pmid: 23788325
Unambiguous structural elucidation of active pharmaceutical ingredients (API) impurities is a particularly challenging necessity of pharmaceutical development, particularly if the impurities are low level (0.1% level). In many cases, this requires acquiring high‐quality NMR data on a pure sample of each impurity. High‐quality, high signal‐to‐noise (S/N) one‐ and two‐dimensional NMR data can be obtained using liquid chromatography‐solid phase extraction‐cryoflow NMR (LC‐SPE‐cryoflow NMR) with a combination of semi‐preparative column for separation and mother liquor as a source of concentrated impurities. These NMR data, in conjunction with mass spectrometry data, allowed for quick and unambiguous structural elucidations of four impurities found at low level in the crystallized API but found at appreciable levels in the mother liquor that was used as the source for these impurities. These data show that semi‐preparative columns can be used at lower than ideal flow rates to facilitate trapping of HPLC components for LC‐SPE‐cryoflow NMR analysis without compromising chromatographic resolution. Also, despite the complex chromatography encountered with the use of mother liquor as a source of impurities, acceptably pure analytes were obtained for acquiring NMR data for unambiguous structure elucidations. Copyright © 2013 John Wiley & Sons, Ltd.
Systematic assignment of NMR spectra of 5‐substituted‐4‐thiopyrimidine nucleosidesZhang, Xiaohui; Wang, Jian; Xu, Yao‐Zhong
doi: 10.1002/mrc.3980pmid: 23794140
Unambiguous characterization of 5‐substituted‐4‐thiopyrimidine nucleosides (ribonucleosides and 2'‐deoxynucleosides) was performed using NMR spectroscopy. Assignments of all proton and carbon signals of 5‐bromo‐4‐thiouridine and related nucleosides were systematically carried out and firmly established by COSY and HMQC techniques. The NMR data of various 4‐thiopyrimidine nucleosides are compared, and the key contributing factors discussed. The approach presented here is applicable to other modified nucleosides and nucleotides, as well as nucleobases. Copyright © 2013 John Wiley & Sons, Ltd.
Use of diffusion‐ordered NMR spectroscopy and HPLC–UV–SPE–NMR to identify undeclared synthetic drugs in medicines illegally sold as phytotherapiesSilva, Lorena M. A.; Filho, Elenilson G. A.; Thomasi, Sérgio S.; Silva, Bianca F.; Ferreira, Antonio G.; Venâncio, Tiago
doi: 10.1002/mrc.3984pmid: 23818305
The informal (and/or illegal) e‐commerce of pharmaceutical formulations causes problems that governmental health agencies find hard to control, one of which concerns formulas sold as natural products. The purpose of this work was to explore the advantages and limitations of DOSY and HPLC–UV–SPE–NMR. These techniques were used to identify the components of a formula illegally marketed in Brazil as an herbal medicine possessing anti‐inflammatory and analgesic properties. DOSY was able to detect the major components present at higher concentrations. Complete characterization was achieved using HPLC–UV–SPE–NMR, and 1D and 2D NMR analyses enabled the identification of known synthetic drugs. These were ranitidine and a mixture of orphenadrine citrate, piroxicam, and dexamethasone, which are co‐formulated in a remedy called Rheumazim that is used to relieve severe pain, but it is prohibited in Brazil because of a lack of sufficient pharmacokinetic and pharmacodynamic information. Copyright © 2013 John Wiley & Sons, Ltd.
NMR‐based metabolomics coupled with pattern recognition methods in biomarker discovery and disease diagnosisZhang, Ai‐hua; Sun, Hui; Qiu, Shi; Wang, Xi‐jun
doi: 10.1002/mrc.3985pmid: 23828598
Molecular biomarkers could detect biochemical changes associated with disease processes. The key metabolites have become an important part for improving the diagnosis, prognosis, and therapy of diseases. Because of the chemical diversity and dynamic concentration range, the analysis of metabolites remains a challenge. Assessment of fluctuations on the levels of endogenous metabolites by advanced NMR spectroscopy technique combined with multivariate statistics, the so‐called metabolomics approach, has proved to be exquisitely valuable in human disease diagnosis. Because of its ability to detect a large number of metabolites in intact biological samples with isotope labeling of metabolites using nuclei such as H, C, N, and P, NMR has emerged as one of the most powerful analytical techniques in metabolomics and has dramatically improved the ability to identify low concentration metabolites and trace important metabolic pathways. Multivariate statistical methods or pattern recognition programs have been developed to handle the acquired data and to search for the discriminating features from biosample sets. Furthermore, the combination of NMR with pattern recognition methods has proven highly effective at identifying unknown metabolites that correlate with changes in genotype or phenotype. The research and clinical results achieved through NMR investigations during the first 13 years of the 21st century illustrate areas where this technology can be best translated into clinical practice. In this review, we will present several special examples of a successful application of NMR for biomarker discovery, implications for disease diagnosis, prognosis, and therapy evaluation, and discuss possible future improvements. Copyright © 2013 John Wiley & Sons, Ltd.
One‐bond 29 Si‐ 1 H spin‐spin coupling constants in the series of halosilanes: benchmark SOPPA and DFT calculations, relativistic effects, and vibrational correctionsRusakov, Yury Yu.; Krivdin, Leonid B.
doi: 10.1002/mrc.3986pmid: 23836682
A number of most representative second order polarization propagator approach (SOPPA) based wavefunction methods, SOPPA, SOPPA(CC2) and SOPPA(CCSD), and density functional theory (DFT) based methods, B3LYP, PBE0, KT2, and KT3, have been benchmarked in the calculation of the one‐bond 29Si‐1H spin‐spin coupling constants in the series of halosilanes SiHnX4−n (X = F, Cl, Br, I), both at the non‐relativistic and full four‐parameter Dirac's relativistic levels taking into account vibrational corrections. At the non‐relativistic level, the wavefunction methods showed much better results as compared with those of DFT. At the DFT level, out of four tested functionals, the Perdew, Burke, and Ernzerhof's PBE0 showed best performance. Taking into account, relativistic effects and vibrational corrections noticeably improves wavefunction methods results, but generally worsens DFT results. Copyright © 2013 John Wiley & Sons, Ltd.
15 N NMR spectra and reactivity of 2,4,6‐triazidopyridines, 2,4,6‐triazidopyrimidine and 2,4,6‐triazido‐s‐triazineChapyshev, Sergei V.; Ushakov, Evgeny N.; Chernyak, Alexander V.
doi: 10.1002/mrc.3987pmid: 23877844
2,4,6‐Triazido‐s‐triazine, 2,4,6‐triazidopyrimidine and six different 2,4,6‐triazidopyridines were studied by 15N NMR spectroscopy. The assignment of signals in the spectra was performed using the gauge‐independent atomic orbital (GIAO)–Tao‐Perdew‐Staroverov‐Scuseria exchange‐correlation functional (TPSS)h/6‐311+G(d,p) calculations on the M06‐2X/6‐311+G(d,p) optimized molecular geometries. The Truhlar and coworkers' continuum solvation model called SMD was applied to treat solvent effects. With this approach, the root mean square error in estimations of the 15N chemical shifts for the azido groups was just 1.9 ppm. It was shown that the different reactivity of the α‐ and γ‐azido groups in pyridines correlates well with the chemical shifts of the Nα signals of these groups. Of two nonequivalent azido groups of azines, the azido group with the most shielded Nα signal is the most electron‐deficient and reactive toward electron‐rich reagents. By contrast, the azido group of azines with the most deshielded Nα signal is the most reactive toward electron‐poor reagents. Copyright © 2013 John Wiley & Sons, Ltd.
1H, 13C and 15N NMR data for indolo(2,3‐ b )quinolines, a novel potent anticancer drug familyBednarek, E.; Sitkowski, J.; Bocian, W.; Łuniewski, W.; Kobylińska, M.; Kaczmarek, Ł.; Kozerski, L.
doi: 10.1002/mrc.3975pmid: 23788283
The complete NMR signal assignment of title compounds were carried out by extensive use of 1D and 2D NMR techniques (1H, 13C, COSY, HSQC and HMBC). Copyright © 2013 John Wiley & Sons, Ltd.