WO1991013902A2 - Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling - Google Patents

Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling Download PDF

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WO1991013902A2
WO1991013902A2 PCT/US1991/001531 US9101531W WO9113902A2 WO 1991013902 A2 WO1991013902 A2 WO 1991013902A2 US 9101531 W US9101531 W US 9101531W WO 9113902 A2 WO9113902 A2 WO 9113902A2
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oligodeoxynucleotide
internucleoside linkage
protected
nucleotide sequence
group
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PCT/US1991/001531
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French (fr)
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WO1991013902A3 (en
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Sudhir Agrawal
Jinyan Tang
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Worcester Foundation For Experimental Biology
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Definitions

  • the present invention relates to a method of site specific functionalization of oligodeoxy- nucleotides for non-radioactive labelling, as well as to functionalized oligodeoxynucleotides and non-radioactively labelled oligodeoxynucleotides produced by the method.
  • This method makes it possible to modify one or more selected internucleoside phosphate(s) in a synthetic oligodeoxynucleotide in such a manner that it (they) can be used to incorporate a non-radioactive material into the synthetic oligodeoxynucleotide.
  • the method of the present invention is used to modify one or more selected internucleoside phosphates in a synthetic oligodeoxynucleotide, to give aminoalkylphosphoramidate residues or aminoalkylphosphotri ester residues.
  • the amino group(s) of the resulting modified residue(s) is. then further reacted with a non-radioactive label, such as biotin, fluorescein or rhodamine (e.g., N-hydroxysuccinimide ester of biotin, N-caproyl amidobiotin, and a variety of fluorophore isothiocyanates), to produce a non-radioactive label, such as biotin, fluorescein or rhodamine (e.g., N-hydroxysuccinimide ester of biotin, N-caproyl amidobiotin, and a variety of fluorophore isothiocyanates), to produce a non-radioactive label, such as bio
  • non-radioactively labelled oligodeoxynucleotide in which the label is present at a predetermined location or locations.
  • an H-phosphonate internucleoside linkage is oxidized with an appropriately protected diamine, such as.
  • the resulting phosphoramidate internucleoside linkage is stable under oligonucleotide assembly conditions using phosphoramidite chemistry (Caruthers, M.H. e t al., Methods in Enzymology, 154:287-313 (1987)) and to subsequent deprotection steps..
  • the H-phosphonate internucleoside can be oxidized, to give a phosphotriester internucleoside linkage, with an appropriately protected aminoalkyl alcohol in N-methylimidazole-triethylamine-carbon
  • tetrachloride e.g., 5:5:90.
  • the present method can be used to produce non-radioactively labelled oligodeoxynucleotides which include a non-radioactive material at one or more sites and are useful in research and in the diagnosis and treatment of diseases and conditions of interest.
  • Figure 1 is a graphic representation of results of HPLC of pligomers 1, 2 and 5.
  • Figure 1A shows results of analytical ion exchange chromatogram of oligomers 1 (a); 2 (b); and 5 (c).
  • Figure 1B shows results of reversed phase HPLC of ion exchange purified oligomers 1 (chromatogram (d)); 2
  • Figure 2 shows reversed phase HPLC traces of oligomer 2 (a); reaction mixture of oligomer 2 with biotin N-hydroxysuccinimide (b); oligomer 5 (c); and reaction mixture of oligomer 5 with biotin
  • the present invention relates to a method of producing oligodeoxynucleotides which have a desired (selected) nucleotide sequence and which are
  • one or more selected internucleoside phosphate residues are modified to produce aminoalkylphosphoramidate residues or aminoalkylphosphotriester residues which are present in an oligodeoxynucleotide at selected positions.
  • the amino group(s) in such modified (functionalized) residues is further reacted with a label or reporter group, resulting in production of a
  • non-radioactively labelled oligodeoxynucleotide labelled internally at selected location(s).
  • the present method is carried out by oxidizing an H-phosphonate internucleoside linkage using an appropriately protected diamine,
  • X is a base labile protecting group and n can be 2 or more.
  • n can be 2 or more.
  • internucleoside linkage is oxidized using
  • N-1-trifluoroacetylhexanediamine (CF 3 CONH(CH 2 ) 6 NH 2 ) in the presence of an appropriate solvent, such as anhydrous carbon tetrachloride.
  • an appropriate solvent such as anhydrous carbon tetrachloride.
  • a primary aliphatic amine is incorporated at the internucleoside phosphate as phosphoramidate.
  • oxidation is carried out using a suitably protected amino
  • XNH(CH 2 ) n OH a base labile protecting group
  • n can be 2 or more.
  • an H-phosphonate internucleoside linkage is oxidized using
  • the protecting group present on the primary aliphatic amine is removed.
  • the unmasked amino group can now react with one or more selected labels or reporter groups.
  • the oligodeoxynucleotide is labelled, non-radioactively, at one or more selected internal locations.
  • One or both amino groups present in the diamine react with the selected label.
  • the method of the present invention is represented in a series of steps below. The following is an explanation of those steps, with reference to the respective reactants and steps represented below.
  • (II) is subsequently oxidized by being combined with an appropriately protected diamine in the presence of a suitable solvent, resulting in formation of a phosphoramidate internucleoside linkage or a phosphotriester internucleoside linkage (and linking of the protected diamine to the dinucleoside through the unprotected amino group of the diamine).
  • the resulting product is designated (III).
  • the protecting group Y present on the diamine is removed and the compound is removed from the solid support. This results in production of an unbound functionalized oligodeoxynucleotide (i.e., an aminoaliphatic oligomer or an oligodeoxynucleotide having a desired nucleotide sequence and an alkyl amino group present at the selected internucleoside phosphate(s) as a phosphoramidate or phosphotriester).
  • an unbound functionalized oligodeoxynucleotide i.e., an aminoaliphatic oligomer or an oligodeoxynucleotide having a desired nucleotide sequence and an alkyl amino group present at the selected internucleoside phosphate(s) as a phosphoramidate or phosphotriester.
  • oligodeoxynucleotide labelled site specifically with a non-radioactive material.
  • non-radioactive material can be a fluorophore, a spin label, an enzyme, a chelator, a
  • heterocyclic molecule a protein, a lipid, a drug derivative, an antigen, an intercalator or other organic or inorganic moiety.
  • non-radioactively labelled oligodeoxynucleotides the following steps were carried out to produce a non-radioactively labelled oligodeoxynucleotide:
  • the support-bound dinucleoside H-phosphonate was oxidized, using N-1-trifluoroacetyldi- aminohexane (NH(CH 2 ) 6 NH-CO-CF 3 ) in carbon tetrachloride-dioxane, resulting in formation of a phosphoramidate internucleoside linkage between Nu 2 and Nu 1 .
  • the remainder of the nucleotide sequence of the oligodeoxynucleotide was produced in a two-step procedure in which the dimethoxytrityl residue [DMTrO] was removed from the nucleotide now bound to the solid support (Nu 2 in the reaction scheme above) and the desired nucleotides were added stepwise (i.e., to the now free end of the dinucleoside which, for convenience, can be referred to as the 5' end). 4.
  • the protecting group (-CO-CF 3 ) present on NH(CH 2 ) 6 NH-CO-CF 3 was removed during
  • oligodeoxynucleotide of the desired sequence in which there is an aminoalkylphosphotriester residue present at the desired internucleoside phosphate linkage(s) can be produced.
  • the non-radioactive material becomes bound to the amino group of the aminoalkylphosphotriester
  • the oligodeoxynucleotide backbone can be unmodified (e.g., as it occurs in nature) or modified (e.g., amidate, methylphosphate,
  • the label present at two or more sites can be the same (e.g., biotin) or different and can be present at as many sites as desired. As described in the
  • nucleotides can be joined, using art-recognized techniques such as H-phosphonate chemistry, before modification of a selected internucleoside phosphate linkage is carried out. This has been carried out, as described in the Exemplification, to produce a 17-mer functionalized at a central internal site (oligomer 3) and a 17-mer functionalized at two internal phosphate linkages (oligomer 5).
  • H-phosphonate chemistry for example, an internal nucleotide (e.g., a support-bound nucleotide such as Nu 1 ) can be added to, resulting in production of a longer sequence (e.g., Nu 10 Nu 9 ...Nu 1 ).
  • the longer sequence can then be functionalized, by the method described above, resulting in production of a functionalized oligodeoxynucleotide (e.g.,
  • the modified oligodeoxynucleotide can then be further elongated by addition of selected
  • nucleotides to produce a modified oligodeoxynucleotide of desired sequence can be removed, as described above.
  • the functionalized oligodeoxynucleotide initially produced can be extended (by addition of selected nucleotides), one or more additional internucleoside phosphate linkages can be modified and a functionalized oligodeoxynucleotide which has two or more sites at which non-radioactive material can be added is, thus, produced.
  • the linker present between the two amino groups in the diamine used can be of any suitable length
  • the length used in a particular case can be determined empirically.
  • the diame can be branched or unbranched and
  • CF 3 CONH(CH 2 ) 6 NH 2 was prepared by adding ethyltrifluoroacetate (1.2 ml, 10 mmol) dropwise over one hour to a stirred mixture of hexanediamine (1.16g; 10 mmol) and triethylamine (1 ml; 7 mmol) in 20 ml methanol. The solution was stirred overnight.
  • the first coupling (represented by (a) in the above reaction) was carried out using H-phosphonate chemistry. This resulted in a production of a support-bound dinucleoside H-phosphonate (II), which was then oxidized with 4%
  • oligodeoxynucleotide sequence was carried out (step (c)) using phosphoramidite or H-phosphonate
  • oligomer 2 When ion exchange HPLC purified oligomer 2 was checked on reversed phase HPLC, it gave a doublet peak in ratio of 1:2 (Figure le) compared to 1 ( Figure 1d). This results from the diastereoisomeric nature of phosphoramidate internucleoside linkage. Similarly, oligomer 5 eluted as a broad peak because of two such diastereoisomeric linkages ( Figure 1f). Both oligomers 2 and 5 had retention times longer than that of oligomer 1 because of the hydrophobic nature of the alkyl chain present in oligomers 2 and 5.
  • the method described herein provides a way for functionalizing oligonucleotides at one or more selected or specified sites.
  • the subject method of introducing reporter groups has been carried out by reaction of the
  • labelling may increase the sensitivity of detection in diagnostic assays.

Abstract

A method of producing a synthetic oligodeoxynucleotide of selected nucleotide sequence which is internally labelled with a nonradioactive material at at least one selected location, as well as oligodeoxynucleotides produced by the method.

Description

SITE-SPECIFIC FUNCTIONALIZATION OF
OLIGODEOXYNUCLEOTIDES FOR NON-RADIOACTIVE LABELLING
Description
Background of the Invention
There is at present growing interest in
non-radioactively labelled modified oligodeoxy- nucleotides. Biotin (Agrawal. S. et al., Nucleic Acid Research, 14:6227-6245 (1986); Agrawal, S. Tet. Lett., 30:7025-7028 (1989)), florophores (Cardullo, R. A. et al., Proc . Natl . Acad . S c i . USA ,
85 : 8790 - 8794 (1988); Agrawal, S. et al., J. Cell Biology , 107:468 (1988); Haralambidis, J. et al., Nucleic Acids Res., 18(3):501-505 (1989)),
intercalating (Helene, C. and J.J. Toulme,
Oligodeoxynucleotides-Antisense Inhibitors of Gene Expression, Ed. J.S. Cohen, Macmillan Press, 137-166 (1989)) and chelating (Oser, A. et al., G. Nucleic Acid Research, 16:1181-1196 (1988)) reagents
attached to synthetic oligonucleotides are becoming important tools of molecular biology. A variety of enzymatic and chemical procedures have been
developed for their synthesis (Matthews, J.S. and L.J. Kricka, AnaI. Biochem., 169:1-25 (1988)).
Central to some of these procedures are (a) the introduction of a reactive group at either the 3'- or 5'-terminus of the oligonucleotide (Agrawal. S. et al., Nucleic Acid Research, 14:6227-6245 (1986); Agrawal, S. Tet. Lett., 30:7025-7028 (1989);
Fidanza, J.A. and L.W. McLaughlin, J. Am. Chem.
Soc., 111:9117-9119 (1989); Nelson, P.S. et al.,
Nucleic Acid Research, 17:7187-7194 (1989)) or (b) the synthesis of modified xiucleosides which contain the masked reactive group and are incorporated into the nucleic acid (Fidanza, J.A. and L.W. McLaughlin, J. Am. Chem. Soc., 111:9117-9119 (1989)). The presently-available methods are useful, but are limited in their usefulness for site specific internal non-radioactive labelling of synthetic oligonucleotides possible.
Summary of the Invention
The present invention relates to a method of site specific functionalization of oligodeoxy- nucleotides for non-radioactive labelling, as well as to functionalized oligodeoxynucleotides and non-radioactively labelled oligodeoxynucleotides produced by the method. This method makes it possible to modify one or more selected internucleoside phosphate(s) in a synthetic oligodeoxynucleotide in such a manner that it (they) can be used to incorporate a non-radioactive material into the synthetic oligodeoxynucleotide. In particular, the method of the present invention is used to modify one or more selected internucleoside phosphates in a synthetic oligodeoxynucleotide, to give aminoalkylphosphoramidate residues or aminoalkylphosphotri ester residues. The amino group(s) of the resulting modified residue(s) is. then further reacted with a non-radioactive label, such as biotin, fluorescein or rhodamine (e.g., N-hydroxysuccinimide ester of biotin, N-caproyl amidobiotin, and a variety of fluorophore isothiocyanates), to produce a
non-radioactively labelled oligodeoxynucleotide in which the label is present at a predetermined location or locations.
in the present method, an H-phosphonate internucleoside linkage is oxidized with an appropriately protected diamine, such as.
N-1-trifluoroacetylhexanediamine, (CF3CO
NH(CH2)6NH2), in the presence of an appropriate solvent, such as carbon tetrachloride, to give a phosphoramidate internucleos ide linkage (Zwierzak, A., Sunthesis, 507-508 (1975); Froehler, B. et al.,Nucleic Acid Research, 16:4831-4839 (1989);
Letsinger, R.L. et al., J . Am Chem. Soc.,
110:4470-4471 (1988); Agrawal, S. et al., Proc.
Natl. Acad. Sci. USA, 85:7079-7083 (1988); Jager, A. et al., Biochemistry, 27:7237-7246 (1988)). The resulting phosphoramidate internucleoside linkage is stable under oligonucleotide assembly conditions using phosphoramidite chemistry (Caruthers, M.H. e t al., Methods in Enzymology, 154:287-313 (1987)) and to subsequent deprotection steps.. Alternatively, the H-phosphonate internucleoside can be oxidized, to give a phosphotriester internucleoside linkage, with an appropriately protected aminoalkyl alcohol in N-methylimidazole-triethylamine-carbon
tetrachloride (e.g., 5:5:90). The present method can be used to produce non-radioactively labelled oligodeoxynucleotides which include a non-radioactive material at one or more sites and are useful in research and in the diagnosis and treatment of diseases and conditions of interest.
Brief Description of the Drawings
Figure 1 is a graphic representation of results of HPLC of pligomers 1, 2 and 5. Figure 1A shows results of analytical ion exchange chromatogram of oligomers 1 (a); 2 (b); and 5 (c). Figure 1B shows results of reversed phase HPLC of ion exchange purified oligomers 1 (chromatogram (d)); 2
(chromatogram (e)); and 5 (chromatogram (f)).
Figure 2 shows reversed phase HPLC traces of oligomer 2 (a); reaction mixture of oligomer 2 with biotin N-hydroxysuccinimide (b); oligomer 5 (c); and reaction mixture of oligomer 5 with biotin
N-hydroxysuccinimide (d). Detailed Description of the Invention
The present invention relates to a method of producing oligodeoxynucleotides which have a desired (selected) nucleotide sequence and which are
labelled internally with a non-radioactive material or reporter group at one or more internucleoside linkages. In the method of the present invention, one or more selected internucleoside phosphate residues are modified to produce aminoalkylphosphoramidate residues or aminoalkylphosphotriester residues which are present in an oligodeoxynucleotide at selected positions. The amino group(s) in such modified (functionalized) residues is further reacted with a label or reporter group, resulting in production of a
non-radioactively labelled oligodeoxynucleotide labelled internally at selected location(s).
Briefly, the present method is carried out by oxidizing an H-phosphonate internucleoside linkage using an appropriately protected diamine,
represented by the formula XCONH(CH2)nNH2, in which
X is a base labile protecting group and n can be 2 or more. For example, an H-phosphate
internucleoside linkage is oxidized using
N-1-trifluoroacetylhexanediamine (CF3CONH(CH2)6NH2) in the presence of an appropriate solvent, such as anhydrous carbon tetrachloride. As a result, a primary aliphatic amine is incorporated at the internucleoside phosphate as phosphoramidate. In the case of phosphotriester linkages, oxidation is carried out using a suitably protected amino
alcohol, represented by the formula XNH(CH2)nOH, in which X is a base labile protecting group and n can be 2 or more. For example, an H-phosphonate internucleoside linkage is oxidized using
N-1-fluoroenylmethyoxcarbonylaminohexanol
F-MOC-NH(CH2)6OH in the presence of
N-methylimidazole-triethylamine-carbon
tetrachloride. The remaining nucleotides needed to produce the desired nucleotide sequence are added using art-recognized techniques, such as
phosphoramidate, H-phosphonate chemistry or methyl phosphoramidate. (Caruthers, M.H. et al., Methods in Enzymology, 154:287-313 (1987); co-pending U.S. patent application Serial No. 07/334,679 (Method of Synthesizing Oligonucleotides and Their Analogs Adaptable to Large Scale Synthesis, by S. Agrawal and P. Zamecnik, filed April 6, 1989, the teachings of which are incorporated herein by reference;
Agrawal, S. and J. Goodchild, Tet. Lett.,
28(31):3539-3542 (1987)). After the desired oligodeoxynucleotide is produced, the protecting group present on the primary aliphatic amine is removed. The unmasked amino group can now react with one or more selected labels or reporter groups. As a result, the oligodeoxynucleotide is labelled, non-radioactively, at one or more selected internal locations. One or both amino groups present in the diamine react with the selected label.
The method of the present invention is represented in a series of steps below. The following is an explanation of those steps, with reference to the respective reactants and steps represented below.
Figure imgf000009_0001
1. Initial coupling of two nucleotides (designated Nu1 and Nu2) is carried out, using
H-phosphonate chemistry. Generally, Nu. is bound to a solid support, such as CPG and terminates in a dimethoxytrityl residue (designated X). As a result, a support-bound dinucleoside H-phosphonate is produced (designated (II)).
2. The support-bound dinucleoside H-phosphonate
(II) is subsequently oxidized by being combined with an appropriately protected diamine in the presence of a suitable solvent, resulting in formation of a phosphoramidate internucleoside linkage or a phosphotriester internucleoside linkage (and linking of the protected diamine to the dinucleoside through the unprotected amino group of the diamine). The resulting product is designated (III).
3. The dimethoxytrityl residue present on the
unbound end of (I) is removed and the remaining deoxynucleotides of the desired oligodeoxynucleotide to be produced are added at the now free end, using phosphoramidate chemistry or H-phosphonate chemistry, producing a support- bound oligodeoxynucleotide (IV) which includes the phosphoramidate linkage produced in step (2).
4. The protecting group Y present on the diamine is removed and the compound is removed from the solid support. This results in production of an unbound functionalized oligodeoxynucleotide (i.e., an aminoaliphatic oligomer or an oligodeoxynucleotide having a desired nucleotide sequence and an alkyl amino group present at the selected internucleoside phosphate(s) as a phosphoramidate or phosphotriester).
5. The unbound functionalized oligodeoxynucleotide is reacted with an appropriate form of a non-radioactive material, which becomes bound to the amino group and serves as a label or reporter group on the oligodeoxynucleotide. This results in production of an
oligodeoxynucleotide labelled site specifically with a non-radioactive material. The
non-radioactive material can be a fluorophore, a spin label, an enzyme, a chelator, a
heterocyclic molecule, a protein, a lipid, a drug derivative, an antigen, an intercalator or other organic or inorganic moiety.
In a specific embodiment of the present
invention, which has been used to produce
non-radioactively labelled oligodeoxynucleotides, the following steps were carried out to produce a non-radioactively labelled oligodeoxynucleotide:
1. Initially, (I) and Nu2 were coupled, using
art-recognized H-phosphonate chemistry,
resulting in production of a support-bound dinucleoside H-phosphonate.
2. The support-bound dinucleoside H-phosphonate was oxidized, using N-1-trifluoroacetyldi- aminohexane (NH(CH2)6NH-CO-CF3) in carbon tetrachloride-dioxane, resulting in formation of a phosphoramidate internucleoside linkage between Nu2 and Nu1.
3. The remainder of the nucleotide sequence of the oligodeoxynucleotide was produced in a two-step procedure in which the dimethoxytrityl residue [DMTrO] was removed from the nucleotide now bound to the solid support (Nu2 in the reaction scheme above) and the desired nucleotides were added stepwise (i.e., to the now free end of the dinucleoside which, for convenience, can be referred to as the 5' end). 4. The protecting group (-CO-CF3) present on NH(CH2)6NH-CO-CF3 was removed during
deprotection of oligonucleotides in aqueous ammonia, resulting in production of a
functionalized oligodeoxynucleotide (one in which the previously protected amino group is unprotected) of the desired sequence, in which there is an aminoalkylphosphoramidate residue of the formula
Figure imgf000012_0001
present at the desired internucleoside
phosphate linkage(s).
5. The unbound modified oligodeoxynucleotide with the aminoalkylphosphoramidate residue was reacted with a non-radioactive material, such as biotin, fluorescein or rhodamine in
appropriate form (e.g., N-hydroxysuccinimide ester of biotin, N-caproyl amidobiotin, fluorophore isothiocyanates), which becomes bound to the amino group of the
aminoalkylphosphoramidate internucleos ide linkage.
Alternatively, a functionalized
oligodeoxynucleotide of the desired sequence, in which there is an aminoalkylphosphotriester residue present at the desired internucleoside phosphate linkage(s) can be produced. In this case, the non-radioactive material becomes bound to the amino group of the aminoalkylphosphotriester
internucleoside linkage.
The production of oligodeoxynucleotides
labelled at a selected site or sites by the present method is described in greater detail in the
Exemplification.
It is possible, using the present method, to produce oligodeoxynucleotides of desired sequence which are labelled internally at one or more
nucleosides. The oligodeoxynucleotide backbone can be unmodified (e.g., as it occurs in nature) or modified (e.g., amidate, methylphosphate,
phosphothioate, phosphotriester backbones). The label present at two or more sites can be the same (e.g., biotin) or different and can be present at as many sites as desired. As described in the
Exemplification, a 17-mer of the sequence shown has been produced, functionalized at a selected site or sites and labelled at the site(s) with a
non-radioactive material.
In the above description of the present method, two single nucleotides (designated Nu1 and Nu2) are initially joined using H-phosphonate chemistry and the resulting oligodeoxynucleotide is functionalized at the internucleoside phosphate linkage formed between Nu1 and Nu2. However, any number of
nucleotides can be joined, using art-recognized techniques such as H-phosphonate chemistry, before modification of a selected internucleoside phosphate linkage is carried out. This has been carried out, as described in the Exemplification, to produce a 17-mer functionalized at a central internal site (oligomer 3) and a 17-mer functionalized at two internal phosphate linkages (oligomer 5). Using H-phosphonate chemistry, for example, an internal nucleotide (e.g., a support-bound nucleotide such as Nu1) can be added to, resulting in production of a longer sequence (e.g., Nu10Nu9...Nu1). The longer sequence can then be functionalized, by the method described above, resulting in production of a functionalized oligodeoxynucleotide (e.g.,
Nu10 Nu9...Nu1, in which the internucleoside
Figure imgf000014_0001
phosphate linkage between Nu9 and Nu10 is modified). The modified oligodeoxynucleotide can then be further elongated by addition of selected
nucleotides to produce a modified oligodeoxynucleotide of desired sequence. The protecting group present can be removed, as described above.
Alternatively, the functionalized oligodeoxynucleotide initially produced can be extended (by addition of selected nucleotides), one or more additional internucleoside phosphate linkages can be modified and a functionalized oligodeoxynucleotide which has two or more sites at which non-radioactive material can be added is, thus, produced.
Protecting groups other than trifluoroacetyl (-CO-CF3), as described above, can also be used to protect the diamine. Other base labile protecting groups, such as F-moc and t-boc, may also be used. The linker present between the two amino groups in the diamine used can be of any suitable length
(e.g., -(CH2)2- to -(CH2)n-); the length used in a particular case can be determined empirically.
The diame can be branched or unbranched and
bi-functional or multifunctional. EXEMPLIFICATION Preparation of N-1-trifluoroacetylhexanediamine andIts Use for Site-Specific Introduction of AminoGroups into oligodeoxynucleotides
N-1-trifluoroacetylhexanediamine,
CF3CONH(CH2)6NH2, was prepared by adding ethyltrifluoroacetate (1.2 ml, 10 mmol) dropwise over one hour to a stirred mixture of hexanediamine (1.16g; 10 mmol) and triethylamine (1 ml; 7 mmol) in 20 ml methanol. The solution was stirred overnight.
After removal of solvents, the reaction mixture was flash chromatographed on silica using 0-25% methanol in dichloromethane. The fractions containing the desired product were pooled and concentrated to give a colorless powder (1.1 gm, yield-42.6%), M.pt. 52°. 1H NMR (CDCl3, d, TMS-0.00) 7.1-7.2 (m, 3H, NH2, NH) 3.2-3.3 (m, 2H, CO-NH-CH2), 2.8-2.9 (m 2H , CH2-NH2) 1.2-1.6 (m, 8H,-CH2-(CH2)2-CH2-).
To test the efficacy of (CF3CONH(CH2)6NH2) for amino group introduction at specific sites of oligonucleotides, a 17-mer sequence, GTA AAA CGA CGG CCA GT, (oligomer 1) was made. Oligomers
(designated 2-5 below) carrying aminohexyl residues at different sites, as shown by were also made.
Figure imgf000015_0001
Oligomer # Sequence
1 GTA AAA CGA CGG CCA GT
2 GTA AAA CGA CGG CCA
Figure imgf000016_0002
3 GTA AAA
Figure imgf000016_0004
CGG CCA GT
4 AAA CGA CGG CCA GT
Figure imgf000016_0005
5
Figure imgf000016_0006
* AAA CGA CGG CCA
Figure imgf000016_0003
T
The steps involved for labelling, for sequence 2, are shown below:
~~ £P s
Figure imgf000016_0001
The first coupling (represented by (a) in the above reaction) was carried out using H-phosphonate chemistry. This resulted in a production of a support-bound dinucleoside H-phosphonate (II), which was then oxidized with 4%
N-1-trifluoroacetyldiaminohexane (I) in carbon tetrachloride-dioxane (8:2, v/v) for 30 minutes, resulting in production of (III). After oxidation with CF3CONH(CH2)6NH2 (step (b) of the above
reaction), the assembly of the rest of the
oligodeoxynucleotide sequence was carried out (step (c)) using phosphoramidite or H-phosphonate
chemistry. This resulted in production of the oligonucleotide (IV), which was deprotected in aqueous ammonia for 6 hours at 55°C (step (d)), resulting in formation of the aminohexyl oligomer (V).
Assessment of the oligomers 1-5 was carried out. Analytical ion exchange HPLC of oligomer 2 showed the major peak eluting earlier than that of oligomer 1 with the same gradient (Figure 1a and 1b), confirming that in oligomer2, one of the internucleoside linkages is a phosphoramidate linkage, which is non-ionic at phosphores.
Sequences 3 and 4, which are functionalized at different sites, also showed a HPLC profile similar to that of oligomer 2. Oligomer 5, which is
functionalized at two sites, was eluted even earlier (Figure 1c).
When ion exchange HPLC purified oligomer 2 was checked on reversed phase HPLC, it gave a doublet peak in ratio of 1:2 (Figure le) compared to 1 (Figure 1d). This results from the diastereoisomeric nature of phosphoramidate internucleoside linkage. Similarly, oligomer 5 eluted as a broad peak because of two such diastereoisomeric linkages (Figure 1f). Both oligomers 2 and 5 had retention times longer than that of oligomer 1 because of the hydrophobic nature of the alkyl chain present in oligomers 2 and 5.
Reaction of oligomer 2 was carried out with biotin N-hydroxysuccinimide using reported
conditions (Agrawal, S. et al., Nucleic Acid
Research, 14:6227-6245 (1986)). The reaction mixture after gel filtration (Sephadex G-25) showed two new peaks of the diastereomeric biotin adducts (Figure 2b). Similarly, reaction of oligomer 5 gave a broad peak as a doublet eluting later than the unreacted material (Figure 2c and Figure 2d).
The method described herein provides a way for functionalizing oligonucleotides at one or more selected or specified sites. As described above, the subject method of introducing reporter groups has been carried out by reaction of the
functionalized oligodeoxynucleotide with biotin active ester, resulting in production of an
oligodeoxynucleotide labelled at the selected site(s) with biotin. In addition, the aminohexyl residue present was reacted in high yield with fluorescein and rhodamine isothiocyanate, to produce a fluorescent hybridization probe. Multiple
labelling may increase the sensitivity of detection in diagnostic assays.

Claims

1. A method of producing a synthetic
oligodeoxynucleotide of selected nucleotide sequence which is internally labelled at at least one selected internucleoside linkage, comprising the steps of:
a) modifying at least one internucleoside
linkage of the synthetic oligodeoxynucleotide to produce an aminoalkyl residue selected from the group consisting of aminoalkylphosphoramidate residues and aminoalkylphosphotriester residues, in which a protected primary alkyl amine is present;
b) deprotecting the protected primary
alkyl amine present in the aminoalkyl residue, thereby producing a functionalized synthetic oligodeoxynucleotide with a deprotected amino group; and
c) reacting the functionalized synthetic
oligodeoxynucleotide with a deprotected amino group with a selected non-radioactive label, under conditions appropriate for joining of the selected non-radioactive label and the deprotected amino group, thereby producing a synthetic oligodeoxynucleotide in which the amino group is joined with the non-radioactive label.
2. A synthetic oligodeoxynucleotide of selected nucleotide sequence which is internally
labelled at at least one selected
internucleoside linkage, produced by the method of Claim 1.
3. A method of producing a synthetic oligodeoxynucleotide, having a selected nucleotide sequence, which is internally labelled at at least one selected H-phosphonate internucleoside linkage, comprising the steps of:
a) producing a support-bound
oligodeoxynucleotide having an
H-phosphonate internucleoside linkage present between the two nucleotides present at the unbound end of the support-bound oligodeoxynucleotide;
b) combining the support-bound oligodeoxynucleotide with an appropriately protected diamine and an appropriate solvent, under conditions appropriate for oxidation of the H-phosphonate internucleoside linkage to produce an aminoalkylphosphoramidate internucleoside linkage in which there is an aminoalkyl having a protected terminal amine group, thereby producing a modified oligodeoxynucleotide;
c) extending the nucleotide sequence of the modified oligodeoxynucleotide produced in step (b) as needed to produce the selected nucleotide sequence; d) deprotecting the protected terminal amino group present on the
aminoalkylphosphoramidate internucleoside linkage, thereby producing a
functionalized oligodeoxynucleotide; and e) combining the functionalized oligodeoxynucleotide produced in step (d) with a selected non-radioactive label, under conditions appropriate for joining of the functionalized oligodeoxynucleotide and the non-radioactive label.
4. The method of Claim 3 wherein step (a), (b) and (c) are repeated as needed to produce a
modified oligodeoxynucleotide having more than one aminoalkylphosphoramidate linkage in which there is a primary aminoalkyl having a
protected terminal amino group.
5. A synthetic oligodeoxynucleotide of selected nucleotide sequence which is internally
labelled at at least one selected
internucleoside linkage, produced by the method of Claim 4.
6. The method of Claim 3 wherein the appropriately protected diamine has a base labile protecting group; the appropriate solvent is carbon tetrachloride; and the selected non-radioactive label is selected from the group consisting of: fluorophores, spin labels, drug derivatives, antigens and intercalators. The method of Claim 2 wherein the appropriately protected diamine is N-1-trifluoroacetylhexane- diamine; the appropriate solvent is carbon tetrachloride; and the selected non-radioactive label is a fluorophore selected from the group consisting of: biotin, fluorescein and
rhodamine.
8. A synthetic oligodeoxynucleotide of selected nucleotide sequence which is internally
labelled at at least one selected
internucleoside linkage, produced by the method of Claim 7.
9. A protected diamine of the formula:
XCONH(CH2)nNH2, wherein X is a base labile protecting group and n is at least two.
10. The protected diamine of Claim 9 wherein X is.
CF3 and n is 6.
11. A protected amino alcohol of the formula: XNH(CH2)nOH, wherein X is a base labile protecting group and n is at least two.
12. The protected amino alcohol of Claim 11 wherein X is F-MOC and n is 6.
PCT/US1991/001531 1990-03-08 1991-03-06 Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling WO1991013902A2 (en)

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