Cross-linking oligonucleotides

a cross-linking oligonucleotide and oligonucleotide technology, applied in the field of nucleoside cross-linking agents, can solve the problems of host toxicity, potential problems that must be circumvented,

Inactive Publication Date: 2004-02-03
DRUG ROYALTY TRUST 9
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention relates to new types of nucleotides (the building blocks of DNA) that can be used as probes in genetic testing. These nucleotides contain a special chemical group called a covalent crosslinking arm, which makes them very effective at attaching to their specific targets in the genome. This allows researchers to accurately identify and locate these targets without mistakenly detecting other parts of the genomic material. Additionally, the invention introduces some interesting new compounds that can serve as precursors for making certain components of DNA molecules. Overall, this technology helps improve the accuracy and precision of genetic tests while providing more insights about how our genes function.

Problems solved by technology

This patent discusses how researchers have been utilizing oligonucleotides with crosslinking arms to study the interactions between different molecules like DNA and RNA. These crosslinking oligonucleotides can help regulate gene expressions and act as chemotherapy against harmful organisms. However, there are challenges associated with creating these types of probes including issues with mismatching and finding optimal balance between speed and accuracy when trying to crosslink at the right time. Therefore, the technical problem presented in this patent is developing probe oligonucleotides that contain crosslinking arms that can easily form covalent bonds with specific complementary bases while avoiding mismatching and improving the efficacy of hybridformation.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

6-(Tritylamino)caproic Acid

6-Aminocaproic acid (26 g, 0.2 mole) was dissolved in dichloromethane (200 mL) by the addition of triethylamine (100 mL). Trityl chloride (120 g, 0.45 mol) was added and the solution stirred for 36 hr. The resulting solution was extracted with 1N HCl and the organic layer evaporated to dryness. The residue was suspended in 2-propanol / 1N NaOH (300 mL / 100 mL) and refluxed for 3 hr. The solution was evaporated to a thick syrup and added to dichloromethane (500 mL). Water was added and acidified. The phases were separated, and the organic layer dried over sodium sulfate and evaporated to dryness. The residue was suspended in hot 2-propanol, cooled, and filtered to give 43.5 g (58%) of 6-(trityl-amino)caproic acid, useful as an intermediate compound.

example 2

5-(Tritylamino) pentylhydroxymethylenemalononitrile

To a dichloromethane solution of 6-(tritylamino)-caproic acid (20.0 g, 53 mmole) and triethylamine (20 mL) in an ice bath was added dropwise over 30 min isobutylchloroformate (8.3 mL, 64 mmole). After the mixture was stirred for 2 hr in an ice bath, freshly distilled malononitrile (4.2 g, 64 mmole) was added all at once. The solution was stirred for 2 hr in an ice bath and for 2 hr at RT. The dichloromethane solution was washed with ice cold 2N HCl (300 mL) and the biphasic mixture was filtered to remove product that precipitated (13.2 g). The phases were separated and the organic layer dried and evaporated to a thick syrup. The syrup was covered with dichloromethane and on standing deposited fine crystals of product. The crystals were filtered and dried to give 6.3 g for a total yield of 19.5 g (87%) of the product, which is useful as an intermediate.

example 3

5-(Tritylamino) pentylmethoxymethylenemalononitrile

A suspension of the malononitrile of Example 2 (13 g, 31 mmole) in ether / dichloromethane (900 mL / 100 mL), cooled in an ice bath, was treated with a freshly prepared ethereal solution of diazomethane (from 50 mmole of Diazald.RTM. (Aldrich Chemical Company)). The solution was stirred for 6 hr and then neutralized with acetic acid (10 mL). The solution was evaporated to dryness and the residue chromatographed on silica gel using dichloromethane / acetone (4 / 1) as the eluent. Fractions containing product were pooled and evaporated to a syrup. The syrup was triturated with dichloromethane to induce crystallization. The crystals were filtered and dried to give 8.3 g (61%) of chromatographically pure product, useful as an intermediate compound.

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Abstract

This invention is directed to novel substituted nucleotide bases with a crosslinking arm which accomplish crosslinking between specific sites on adjoining strands of oligonucleotides a oligodeoxynucleotides. The invention is also directed to oligonucleotides comprising at least one of these crosslinking agents and to the use of the resulting novel oligonucleotides for diagnostic and therapeutic purposes. The crosslinking agents of the invention are of the following formula (.GAMMA.): wherein, R.sub.1 is hydrogen, or a sugar moiety or analog thereof optionally substituted at its 3' or its 5' position with a phosphorus derivative attached to the sugar moiety by an oxygen and including groups Q.sub.1 Q.sub.2 and Q.sub.3 or with a reactive precursor thereof suitable for nucleotide bond formation; Q.sub.1 is hydroxy phosphate a diphosphate; Q.sub.2 .dbd.of or .dbd.S; Q.sub.3 is CH.sub.2 --R', S--R', O--R', or N--R'R"; each of R' and R" is independently hydrogen or C.sub.1-6 alkyl; B is a nucleic acid base or analog thereof that is a component of an oligonucleotide; Y is a functional linking group; each of to and q is independently 0 to 8, inclusive; r is 0 or 1; and A' is a leaving group. This invention is also directed to novel 3,4-disubstituted and 3,4,-trisubstituted pyrazolo[3,4-d]-pyrimidines and to the use of these nucleic acid bases in the preparation of oligonucleotides. The invention includes nucleosides and mono- and oligonucleotides comprising at least one of these pyrazolopyrimidines, and to the use of the resulting novel oligonucleotides for diagnostic purposes.

Description

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Claims

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Application Information

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Owner DRUG ROYALTY TRUST 9
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