Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1995-02-14
1998-02-24
Nutter, Nathan M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 231, 536 271, 536 281, 536 286, C07H 1900, C07H 2100
Patent
active
057213500
DESCRIPTION:
BRIEF SUMMARY
This application is filed under 35 USC 371 as a U.S. National Stage of International (PCT) application PCT/SE92/00450, filed 18 Jun. 1992.
The present invention relates to deuterated nucleosides and nucleotides in a first aspect.
The invention also relates to a process for chemical deuteration of furanosides in a second aspect, and to the preparation of deuterated nucleoside and nucleotide units based on said deuterated furanosides in a third aspect.
The invention additionally relates to a Raney Nickel catalyst useable for achieving sufficiently efficient deuteration.
The invention further relates to the use of said deuterated compounds in NMR applications, especially for the study of RNA and DNA by means of a technique designated as NMR-window technique.
BACKGROUND OF THE INVENTION
The importance of structure and dynamics of DNA and RNA in understanding the biological function has been investigated by a variety of physico-chemical techniques. Amongst these techniques, Nuclear Magnetic Resonance (NMR) spectroscopy has emerged as one of the most powerful tools.sup.1 because it provides conformational information on the implication of variation of local structures and the dynamics under a biological condition. This has been possible due to extensive developments achieved both in hardware (increasing magnetic field, more powerful computers) and spectral editing methodologies (two.sup.1f,2 /three.sup.3a-c or higher.sup.3d -dimensional NMR). With increasing magnetic field, the higher sensitivity reduces the amount of an oligomer needed to obtain a good quality spectrum, and increases the dispersion of resonance signals reducing the spectral complexity due to resonance overlap (from second order J couplings to first order). Homonuclear two-dimensional (2D) correlated spectroscopy (COSY) provides a direct proof of the existance of resolved scalar or dipolar couplings (.sup.3 J.sub.HH), and correlate the chemical shifts of coupling partner through the single or multiple coherence transfer of nuclear spins from one transition to another (as in DQFCOSY) or by the migration of coherences in an oscillatory manner through the entire spin (TOCSY) which visualize the structure of the spin system in a most direct and informative manner.sup.2,4. On the other hand, 2D nuclear Overhauser enhancement (NOESY).sup.5 result from the transfer of magnetization due to motional processes causing cross relaxation of dipolar-coupled spins which fall off with the sixth power of the distance between two relaxing protons interconversions of conformations when the NMR measurements were being made).sup.5b-5e. Thus NMR has the capabilities of yielding both interproton distances and bond torsion angles which in conjunction of various computational methods (e.g. distance geometry, energy minimization and molecular dynamics) can give the solution structure of oligonucleotides (i.e. conformations of sugars, glycosidic bonds, phosphate backbone, H-bonding, stackings etc)..sup.1d In these efforts to collect conformational informations, it is ideal that each resonance line and cross-peak due to two interacting protons is clearly separated in homonuclear proton-proton, heteronuclear proton-carbon, proton-phosphorus, carbon-phosphorus, NOESY and ROESY experiments. Although such first order informations are possible to extract from the 2D and 3D NMR experiments of a smaller oligonucleotide, it is simply impossible to collect all of this information in a non-prejudicial manner from a large molecule bigger than 14-16 mer duplex DNA and 7-10 mer single stranded RNA. These problems are associated with spectral overlap which becomes more and more complex due to overcrowding of resonances particularly from the repeating pentose moieties with increasing chain length. It is clear that any technique that simplifies spectral complexities would have a considerable impact in future structural studies of larger DNA or RNA molecules that embody specific biological function. The problem due to severe spectral overlap of protons in absorption assignments and nOe
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