Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-08-09
1998-06-09
Kunz, Gary L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 253, 536 261, 536 553, C07H 102, C07H 1910, C07H 1920, C07H 2100
Patent
active
057635994
DESCRIPTION:
BRIEF SUMMARY
This case is filed under 35 USC 371 as the U.S. stage of PCT/EP95/04976 filed Dec. 15, 1995.
BACKGROUND OF THE INVENTION
The present invention relates to nucleoside derivatives with photolabile protective groups and a method for their preparation.
Photolabile protective groups for the hydroxy and phosphate functions in nucleosides and nucleotides are of particular interest since they are suitable for example for light-controlled parallel syntheses of oligonucleotides on a solid carrier (cf. S.P.A. Fodor et al. Science 1991, 251, p. 767 et seq.). They enable the production of so-called DNA chips (i.e. carrier plates on the surface of which a great number of many different oligonucleotides are arranged), which in turn are required in molecular biology for a rapid DNA sequence analysis.
In the prior art, the o-nitrobenzyl group and its derivatives have so far mainly been used as photolabile protective groups in nucleoside and nucleotide chemistry (cf. V.N.R. Pillai, Org. Photochem. 1987, 9, p. 225 et seq. and J. W. Walker et al., J. Am. Chem. Soc. 1988, 110, p. 7170 et seq.). The slow and partially only incomplete deprotection of the corresponding nucleoside and nucleotide derivatives proved to be a particular disadvantage of these protective groups. Furthermore, undesirable by-products in the form of toxic nitrosophenyl compounds are also obtained to some extent during the cleavage of the o-nitrobenzyl compounds.
According to the article by W. Pfleiderer et al. in "Biophosphates and Their Analogues--Synthesis, Structure, Metabolism and Activity", Elsevier Science Publishers B.V. (Amsterdam) 1987, p. 133 et seq., the 2-(o-nitrophenyl)ethyl group which however is introduced solely as a protective group in the base part, particularly in O.sup.6 position of a guanosine, was also recommended as another photolabile protective group for nucleosides. The same publication also describes the p-nitrophenylethoxycarbonyl (NPEOC) and the 2,4-dinitrophenylethoxycarbonyl (DNPEOC) groups both as protective groups for the amino function and for the hydroxyl functions in the sugar part, though elimination of these groups has been carried out solely by means of base-catalyzed .beta.-elimination.
The present invention therefore has as its object to develop nucleoside derivatives with photolabile protective groups for the 5-OH function in the sugar part, which derivatives do not exhibit the named disadvantages of the prior art, but can be deprotected comparatively quickly, quantitatively and without the formation of undesirable by-products.
THE INVENTION
This object was solved according to the invention by means of nucleoside derivatives of the general formula (I). Surprisingly, it was in fact shown that the protective groups according to the invention can be eliminated much more quickly and completely than for example the o-nitrobenzyl groups. It has so far not been possible to find any undesirable by-products during deprotection, which had not been predictable either.
The nucleoside derivatives according to the invention are represented by the following general formula (I): ##STR2## wherein the radicals R.sup.1, R.sup.2 and R.sup.3 at the phenyl ring may have the following meaning: with 1 to 4 C atoms .dbd.OCH.sub.3.
The radical R.sup.4 located on the C.sub.2 atom of the o-nitrophenylethyl group may be either H, halogen, OCH.sub.3 or an alkyl radical with 1 to 4 C atoms. The alkyl radical may in this regard be linear or branched, substituted (particularly with one or more halogen atoms) or unsubstituted as well as saturated or unsaturated; the same also applies to the alkyl and alkoxyalkyl radicals in R.sup.1. R.sup.4 preferably represents a methyl radical. In the event that R.sup.4 .noteq.H, the substituents R.sup.1, R.sup.2 and R.sup.3 at the phenyl ring are preferably hydrogen radicals. Furthermore, in case that R.sup.2 .dbd.OCH.sub.3, R.sup.3 represents in particular a hydrogen radical.
In this application, halogen consistently means F, Cl, Br, I and preferably F, Cl or Br.
The nucleoside part of the compounds accord
REFERENCES:
Proc. Natl. Acad. Sci. USA, Bd. 91, May 1 1994, pp. 5022-5026, XP002003499, A.C. Pease et al.: "Light-Generated Oligonucleotide Arrays For Rapid DNA Sequence Analysis".
W. Pfleiderer et al.: "New Protecting Groups In Nucleoside and Nucleotide Chemistry" in: Biophosphates and Their Analogues-Synthesis, Structure, Metabolism and Activity, 1987, pp. 133-142, K.S. Bruzik and W.J. STEC, XP002003501.
J. Org. Chem., Bd. 60, Mar. 10, 1995, pp. 1116-1117, XP002003500, M.C. Pirrung and J-C. Bradley: "Dimethoxybenzoin Carbonates: Photochemically-Removable Alcohol Protecting Groups Suitable For Phosphoramidite-Based DNA Synthesis".
Giegrich Heiner
Pfleiderer Wolfgang
Kunz Gary L.
Pfleiderer Wolfgang
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