JP2006248987A - Nucleoside, nucleoside derivative, oligonucleotide, and oligonucleotide association product - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To associate a non-natural oligonucleotide by chemical bonds different from hydrogen bonds or bonds by stacking or hydrophobic interactions. <P>SOLUTION: Halogen bonds are noticed as one of bonds causing the associations of non-natural oligonucleotides, and a non-natural nucleoside containing a halogen bond donor or a halogen bond receptor and its nucleoside derivative is synthesized. An oligonucleotide having a nucleoside residue functioning as a halogen bond donor or a halogen bond receptor is synthesized from the nucleoside derivative and a commercially available phosphoroamidite unit for synthesizing DNA. An association product is formed by associating an oligonucleotide having a nucleoside residue functioning as a halogen bond donor or a halogen bond receptor with a halogen bond donor or a halogen bond receptor through halogen bonds. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a nucleoside containing a halogen bond donor and a halogen bond acceptor, a nucleoside derivative which is a substitute for this nucleoside, an oligonucleotide synthesized containing the nucleoside, and a halogen bond donor in these oligonucleotides. The present invention relates to a non-natural oligonucleotide aggregate formed by associating with a halogen bond receptor by a halogen bond.

  The technology for associating non-natural oligonucleotide compounds (hereinafter referred to as artificial oligonucleotides as necessary) is an important basic technology for developing new materials. In the conventional association technique, a nucleoside having a heterocyclic compound capable of forming a hydrogen bond with each other at the base site is used as a nucleotide constituting an artificial oligonucleotide. Between these nucleotides, base pairs are formed by hydrogen bonding, and by this base pair formation, artificial oligonucleotides associate to form a double-stranded structure.

  However, the method of associating non-natural oligonucleotides by hydrogen bonding is based on the fact that a hydrogen atom donating site such as NH or OH is present at the base site of the oligonucleotide chain, and an unshared electron pair having a high electron donating property within the oligonucleotide chain. It is necessary that oxygen atoms and nitrogen atoms having the above are blended in a balanced manner. Therefore, the chemical structure of the base site that can be introduced into the oligonucleotide chain has been limited.

  Examples of techniques that do not use hydrogen bonding for oligonucleotide association include techniques for introducing residues that can be chemically bonded to each other by stacking, hydrophobic interaction, and the like into the oligonucleotide chain. However, the association of oligonucleotides utilizing these interactions has limited combinations of base sites that can specifically bind as compared to the association using hydrogen bonding.

  Therefore, a method for synthesizing a non-natural oligonucleotide in which a hydrogen atom donating site such as NH or OH and an oxygen atom or nitrogen atom having an unshared electron pair having a high electron donating property can be blended in a balanced manner, or a base that can be paired A method for synthesizing non-natural oligonucleotides whose sites are not limited to a specific combination, and a method for synthesizing non-natural oligonucleotides that can form an aggregate with a bond different from that due to hydrogen bonding, stacking, hydrophobic interaction, etc. Expected.

  By the way, among chemical bonds such as hydrogen bonds, stacking, and hydrophobic interactions, halogen bonds are C—X bond (where X is a halogen atom) σ * orbital and nitrogen or oxygen atoms are not shared. It is a non-covalent bond resulting from the overlap with the electron pair, and the binding energy of the halogen bond is estimated to be about 2 to 50 kcal / mol from the result of quantum chemical calculation (see, for example, Non-Patent Document 1). . This bond energy corresponds to a bond strength comparable to or higher than hydrogen bonds.

  Therefore, the present inventors paid attention to the halogen bond. If a non-natural nucleoside containing a halogen bond donor is introduced into one non-natural oligonucleotide chain and a nucleoside containing a halogen bond acceptor is introduced into the other non-natural oligonucleotide chain, It has been found that nucleotides can form aggregates by halogen bonds.

Uhlman.E.; Peyman, A,; Breipohl, G.; Will, D.W.Angrew.Chem.Int.Ed.1998,37,2796

  The present invention relates to a non-natural oligonucleotide aggregate formed by association with each other by a chemical bond different from the bond by hydrogen bonding, stacking, and hydrophobic interaction, and a halogen bond acceptor or a halogen bond donor forming the aggregate. It aims at providing the non-natural oligonucleotide containing the nucleoside derivative which functions as.

  In the present invention, first, nucleosides represented by the following general formula (1) and general formula (2) are synthesized.

  In the formula, R 1 is an aromatic ring or a heteroaromatic ring containing a C—X bond (where X is a halogen element) as a halogen bond donor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group.

  In the formula, R2 is an aromatic ring or heteroaromatic ring having a lone pair as a halogen bond acceptor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group.

  From the nucleoside represented by the general formula (1), a nucleoside derivative represented by the following general formula (3) in which any or all of the 3'-position hydroxyl group or the 5'-position hydroxyl group is protected with a protecting group is synthesized. Further, a nucleoside derivative represented by the following general formula (4) in which either or all of the 3′-position hydroxyl group or the 5′-position hydroxyl group is protected with a protecting group is synthesized from the nucleoside represented by the general formula (2). To do.

  In particular, an aromatic ring or heteroaromatic ring in which at least one of the same atom or a plurality of different atoms is introduced among the halogen elements fluorine, chlorine, bromine, and iodine is applicable as the compound of R1 in the formula. . In addition, as the compound of R2 in the formula, an aromatic ring or a heteroaromatic ring containing a nitrogen atom or an oxygen atom is applicable. Further, in the nucleoside derivatives described above, there are cases where R3 is an H atom and R4 is a substituent other than an H atom, and R3 is a substituent other than an H atom and R4 is an H atom, depending on the purpose. Substituents can be appropriately introduced into R3 or R4.

  Further, in the present invention, a plurality of nucleosides selected from the nucleoside represented by the following general formula (5) and the nucleoside bound to the nucleobase using the nucleotide derivatives represented by the above general formula (3) and general formula (4). An oligonucleotide in which the oxygen at the 3 ′ position and the oxygen at the 5 ′ position are bonded to a phosphodiester bond is synthesized. In addition, an oligonucleotide in which a 3′-position oxygen and a 5′-position oxygen of a plurality of nucleosides selected from a nucleoside represented by the following general formula (6) and a nucleoside bound to a nucleobase are phosphodiester-bonded is synthesized. To do.

  In the formula, R 1 is an aromatic ring or a heteroaromatic ring containing a C—X bond (where X is a halogen element) as a halogen bond donor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group.

  In the formula, R2 is an aromatic ring or heteroaromatic ring having a lone pair as a halogen bond acceptor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group.

  The nucleotide according to the present invention is a phosphodiester wherein the 3′-position oxygen and the 5′-position oxygen of a plurality of nucleosides selected from a nucleoside represented by the general formula (5) and a nucleoside bound to a nucleobase are phosphodiester A combination of a nucleoside represented by the general formula (6) and a nucleoside to which a nucleobase is bonded, wherein the 3′-position oxygen and the 5′-position oxygen are phosphodiester-bonded. In addition, a nucleoside represented by the general formula (5), a nucleoside represented by the general formula (6), and a nucleobase are mixed, and these are phosphodiester-bonded by oxygen at the 3 ′ position and oxygen at the 5 ′ position. It may also be an oligonucleotide.

  In the present invention, the oligonucleotide having a nucleoside residue that functions as a halogen bond donor and the oligonucleotide having a nucleoside residue that functions as a halogen bond acceptor are associated by halogen bonds.

  The oligonucleotide aggregate according to the present invention is a phosphoric acid diester wherein the 3′-position oxygen and the 5′-position oxygen of a plurality of nucleosides selected from a nucleoside represented by the general formula (5) and a nucleoside bound to a nucleobase A 3'-position oxygen and a 5'-position oxygen of a plurality of nucleosides selected from a ligated oligonucleotide, a nucleoside represented by the general formula (6) and a nucleoside bound to a nucleobase are linked by a phosphodiester bond. Is an oligonucleotide aggregate in which at least one halogen bond is formed between a halogen bond donor and a halogen bond acceptor.

  In addition, the 3′-position oxygen and the 5′-position oxygen of a plurality of nucleosides selected from the nucleoside represented by the general formula (5), the nucleoside represented by the general formula (6), and the nucleoside bound to the nucleobase are phosphorous. It may be an oligonucleotide aggregate in which at least one halogen bond is formed between a halogen bond donor and a halogen bond acceptor between oligonucleotides formed by acid diester bonds.

  According to the present invention, it is possible to form a non-natural oligonucleotide aggregate by a halogen bond.

  The present invention provides an unnatural oligonucleotide aggregate formed by association with each other by a chemical bond different from that by hydrogen bonding, stacking, or hydrophobic interaction, and an oligonucleotide containing a nucleoside derivative that contributes to the formation of the aggregate. Therefore, the present inventors focused on the halogen bond as one of the bonds that cause the association of non-natural oligonucleotides.

  In the present invention, first, a non-natural nucleoside containing a halogen bond donor or a halogen bond acceptor and a derivative of this nucleoside are synthesized. Then, an oligonucleotide having a nucleoside residue that functions as a halogen bond donor or a halogen bond acceptor is synthesized from this nucleoside derivative and a commercially available phosphoramidite unit for DNA synthesis. An oligonucleotide having a nucleoside residue that functions as a halogen bond donor or a halogen bond acceptor can associate with a halogen bond donor and a halogen bond acceptor to form an aggregate. In the following description, an unnatural oligonucleotide is referred to as an artificial oligonucleotide, and an unnatural nucleoside derivative is referred to as an artificial nucleoside derivative, as necessary.

  In the present invention, an artificial nucleoside derivative containing a halogen bond donor is an artificial nucleoside derivative containing a C—X bond (where X is a halogen element), among fluorine, chlorine, bromine and iodine which are halogen elements. It refers to a compound in which an aromatic ring or heteroaromatic ring in which at least one of the same atom or a plurality of different atoms is introduced is bonded to a ribose-1-yl moiety and derivatives thereof. Alternatively, an aromatic or heteroaromatic ring in which at least one of the same atom or a plurality of different atoms is introduced among the halogen elements fluorine, chlorine, bromine and iodine is substituted with a substituent at the 2-position excluding H or a hydroxyl group The compound and its derivative couple | bonded with the 2-deoxyribose-1-yl site | part made.

  The aromatic ring or heteroaromatic ring that can be incorporated three-dimensionally into the double helix structure of nucleic acid includes those having a five-membered ring such as imidazole, those having a six-membered ring such as benzene, pyrene, A group having three benzene rings such as anthracene or a group having four benzene rings such as naphthacene is suitable, and halogen atoms are introduced into these aromatic rings or heteroaromatic rings as much as possible. Can do. The number of halogen atoms that can be introduced into an aromatic ring or heteroaromatic ring is, for example, a maximum of 3 for imidazole, 5 for benzene, 9 for anthracene, and 11 for naphthacene.

  Examples of the substituent other than a hydrogen atom or a hydroxyl group that can be bonded to the 2-position in the aromatic ring or heteroaromatic ring include, for example, an alkoxy group that may have a substituent, preferably methoxy, 2-cyanoethoxy, etc. Can be given.

  Here, some hydroxyl groups or all hydroxyl groups bonded to the ribose-1-yl moiety or 2-deoxyribose-1-yl moiety may be protected with an appropriate protecting group.

  Examples of the aromatic ring or heteroaromatic ring in which one or more of the same atom or a plurality of different atoms are introduced among the halogen elements fluorine, chlorine, bromine, and iodine include 3-iodophenyl, 3-bromophenyl, 3 -Chlorophenyl, 2,4-difluoro-3-iodophenyl, 2,4,5-trifluorophenyl, 2,4,5,6-tetrafluorophenyl, 4-nitro-3-iodophenyl, 3-iodopyrrole- Examples include 1-yl, 4-iodoimidazol-1-yl, 2-fluoro-4-iodoimidazol-1-yl, 4,5-diiodoimidazol-1-yl, and the like. Any aromatic ring or heteroaromatic ring into which one or more halogen elements are introduced can be used without being limited to the above examples. From the viewpoint that iodine has the highest binding energy, iodine is used as a halogen element in the examples of the present invention.

  In the present invention, an artificial nucleoside derivative containing a halogen bond acceptor is an aromatic ring or heteroaromatic ring that can be a halogen bond acceptor such as a nitrogen atom or oxygen atom having an unshared electron pair at the ribose-1-yl moiety. Refers to bound compounds and derivatives thereof. Or the 2nd-position refers to the compound couple | bonded with the 2-deoxyribose-1-yl site | part substituted by substituents other than H or a hydroxyl group, and its derivative (s). Examples of the aromatic ring or heteroaromatic ring that can be a halogen bond acceptor include imidazol-1-yl, pyridin-3-yl, pyrimidin-5-yl, 2-pyrimidone-1-yl, and 2-aminopyridine-5- Yl, 4-iodoimidazol-1-yl and the like.

  An artificial oligonucleotide synthesized in a specific example of the present invention is a molecule in which a plurality of nucleosides selected from the above-described artificial nucleosides and nucleosides bound to nucleobases are phosphodiester-bonded with 3′-position oxygen and 5′-position oxygen. It is. Further, an artificial nucleoside containing the halogen bond donor, an artificial nucleoside containing a halogen bond acceptor, and any other nucleoside may be mixed in one oligonucleotide molecule.

  In addition, an aggregate of an artificial oligonucleotide is a halogen bond donor in a complex among complexes formed by associating an artificial oligonucleotide including the halogen bond donor with an artificial oligonucleotide including a halogen bond acceptor. In which at least one halogen bond is formed between and a halogen bond acceptor.

  Hereinafter, an example in which iodine is used as a halogen element will be described with reference to the drawings for a synthetic scheme of an artificial nucleoside containing a halogen bond donor or a halogen bond acceptor and a synthetic scheme of a derivative of this artificial nucleoside. FIG. 1 shows a synthetic scheme for synthesizing an artificial nucleoside derivative as a halogen-bonded acceptor as a preliminary step for synthesizing an artificial oligonucleotide, and FIG. 2 shows an artificial nucleoside derivative as a halogen-bonded donor as a preliminary step for synthesizing an artificial oligonucleotide. A synthesis scheme for synthesizing is shown. Hereinafter, specific examples of the synthesis method for synthesizing the nucleoside, the intermediate, and the nucleoside derivative described using the synthesis schemes of FIGS. 1 and 2 will be described. The numbers in parentheses in the title correspond to the compound numbers in FIGS.

  The synthesis of an artificial nucleoside derivative that functions as a halogen-bonded receptor will be described with reference to FIG. First, as an example of an aromatic ring or heteroaromatic ring into which at least one atom of a halogen element is introduced, 4,5-diiodoimidazole is used, and 1- (2-deoxy-3, 5-di-0-p-trioyl-β-D-ribofuranose-1-yl) -4,5-diiodoimidazole was synthesized, and then 1- (2 shown in the structural formula (14) from this nucleoside derivative. -Deoxy-β-D-ribofuranose-1-yl) -4,5-diiodoimidazole is synthesized. Subsequently, 1- (2-deoxy-5-O- (4) represented by structural formula (15) from 1- (2-deoxy-β-D-ribofuranose-1-yl) -4,5-diiodoimidazole. , 4′-dimethoxytrityl) -β-D-ribofuranose-1-yl) -4,5-diiodoimidazole is synthesized from the compound represented by the structural formula (15) and represented by the structural formula (16). -(2-Deoxy-5-O- (4,4′-dimethoxytrityl) -β-D-ribofuranose-1-yl) -4-iodoimidazole is obtained. Then, the nucleoside derivative of the structural formula (16) is deprotected to obtain 1- (2-deoxy-β-D-ribofuranose-1-yl) -4-iodoimidazole of the structural formula (17). Further, 1- (2-deoxy-5-O- (4,4′-dimethoxytrityl) -β-D-ribofuranose-1-yl) -4- represented by Structural Formula (16) to Structural Formula (18) Derived iodoimidazole-3 ′-(cyanoethyldiisopropyl phosphoramidite).

  Similarly, as shown in FIG. 2, an artificial nucleoside derivative that functions as a halogen bond donor is synthesized. As an example of an aromatic ring or heteroaromatic ring into which one or more halogen atoms are introduced, 1,3-diiodobenzene and 3 ′, 5′-O — ((1,1,3,3-tetraisopropyl) Using disiloxanediyl) -2'-deoxy-D-ribono-1 ', 4'-lactone, 3', 5'-O-((1,1,3,3- An α, β mixture of tetraisopropyl) disiloxanediyl) -1 ′, 2′-dideoxy-1 ′-(3-iodophenyl) -D-ribofuranose was synthesized, and the structural formula (19) The α, β mixture of 1 ′, 2′-dideoxy-1 ′-(3-iodophenyl) -D-ribofuranose shown in 20) is synthesized.

  And 5′-O- (4,4′-dimethoxytrityl) -1 ′, 2′-dideoxy-β-1 ′-(3-iodophenyl)-represented by Structural Formula (21) synthesized from β-form 5′-O- (4,4′-dimethoxytrityl) -1 ′, 2′-dideoxy-α-1 ′-(3-iodophenyl represented by Structural Formula (22) synthesized from D-ribofuranose α-form ) -D-ribofuranose is used as a β-form, and 5′-O- (4,4′-dimethoxytrityl) -1 ′, 2′-dideoxy-β-1′- represented by the structural formula (23) (3-Iodophenyl) -D-ribofuranose 3 ′-(cyanoethyldiisopropyl phosphoramidite) is obtained.

  An artificial compound having a nucleoside residue that functions as a halogen bond donor using a DNA automatic synthesizer from the compound represented by Structural Formula (18) and the compound represented by Structural Formula (23) and a commercially available phosphoramidite unit for DNA synthesis. Oligonucleotides and artificial oligonucleotides having nucleoside residues that function as halogen-bonded receptors are respectively synthesized.

(13): Synthesis of 1- (2-deoxy-3,5-di-0-p-trioyl-β-D-ribofuranose-1-yl) -4,5-diiodimidazole 4,5-diiodo Imidazole (2.22 mg, 6.95 mmol) was dissolved in dehydrated acetonitrile (70 ml), sodium hydride (166.9 mg, 6.95 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. In addition, 1-chloro-2-deoxy-3,5-di-O-para-trioyl-α-D-erythro-pentofuranose (500 mg, 6.32 mmol) was added four times every 15 minutes. After the reaction system was stirred at room temperature for 2 hours, the reaction residue was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous sodium hydrogen sulfate. The organic layer was concentrated and isolated and purified using silica gel chromatography (C-200) with hexane-chloroform 0 → 12% to obtain a compound (3.80 g, yield 89%). The structure of the obtained compound was measured by ¹ H-NMR (CDCl ₃ 500 MHz) and ¹³ C-NMR (CDCl ₃ 126 MHz). The results are shown below. ^{As a result of 1} H-NMR measurement and ¹³ C-NMR measurement, 1- (2-deoxy-3,5-di-0-p-trioyl-β-D-ribofuranose-1 represented by the following structural formula (13) -Yl) -4,5-diiodoimidazole could be identified.

¹ H-NMR (CDCl ₃ 500 MHz)
δ: 7.95-7.85 (5H, m, Tol, imi 2H), 7.29-7.23 (4H, m, Tol), 6.78 (1H, dd, 1′H, J = 5) .62, 7.81), 5.64 (1H, m, 4′H), 4.67 (2H, t, 5′H × 2, J = 2.69, 3.42), 4.61 ( 1H, m, 3′H), 2.81-2.80 (1H, m, 2′H), 2.58-2.53 (1H, m, 2′H), 2.44 (3H, s) , Tol CH ₃ ), 2.41 (3H, s, Tol CH ₃ )

¹³ C-NMR (CDCl ₃ 126 MHz)
δ: 166.28, 166.02, 144.83, 144.54, 139.05, 129.95, 129.73, 129.59, 129.49, 126.56, 126.37, 97.26, 89.57, 83.27, 79.83, 74.74, 63.89, 39.91, 21.91, 21.86

(14): Synthesis of 1- (2-deoxy-β-D-ribofuranose-1-yl) -4,5-diiodoimidazole Next, synthesized 1- (2-deoxy-3,5-di -0-p-toluyl-β-D-ribofuranose-1-yl) -4,5-diiodoimidazole (3.79 g, 5.64 mmol) was dissolved in methanol (56 ml) and sodium methoxide (305 mg, 5.64 mmol) was added and stirred at room temperature for 1 hour. The residue was isolated and purified using dry silica gel chromatography (C-200) with chloroform-methanol 0 → 3% to obtain a compound (2.21 g, yield 90%). The structure of the obtained compound was measured by ¹ H-NMR (CDCl ₃ 500 MHz) and ¹³ C-NMR (CDCl ₃ 126 MHz). The results are shown below. ^{As a result of 1} H-NMR measurement and ¹³ C-NMR measurement, it was possible to identify 1- (2-deoxy-β-D-ribofuranose-1-yl) represented by the following structural formula (14).

¹ H-NMR (CDCl ₃ 500 MHz)
δ: 8.08 (1H, s, imi 2H), 5.60 (1H, t, 1′H, J = 6.10), 4.65-4.64 (1H, m, 4′H), 4.05-4.03 (1H, m, 3′H), 3.89 (2H, dd, 5′H × 2, J = 12.24, 56.03), 3.05 (1H, br, OH), 2.61 (1H, br, OH), 2.53-2, 43 (2H, m, 2′H × 2)

¹³ C-NMR (CDCl ₃ 126 MHz)
δ: 139.53, 88.93, 86.95, 80, 12, 70.69, 61.55, 41.70, 29.60

(15): Synthesis of 1- (2-deoxy-5-O- (4,4′-dimethoxytrityl) -β-D-ribofuranose-1-yl) -4,5-diiodimidazole 1- (2 -Deoxy-β-D-ribofuranose-1-yl) -4,5-diiodoimidazole (2.18 g, 5.00 mmol) was dehydrated and azeotroped about 3 times with anhydrous pyridine and dissolved in anhydrous pyridine (50 ml) 4,4′-dimethoxytrityl chloride (1.86 g, 5.50 mmol) was added and stirred at room temperature for 6 hours. Methanol (5 ml) was added thereto to stop the reaction, and the solvent was concentrated. The reaction residue was extracted with ethyl acetate-water, and the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated and isolated and purified using silica gel chromatography (C-200) with chloroform-methanol 0 → 2% to obtain the following compound (3.17 g, yield 86%). The structure of the obtained compound was measured by ¹ H-NMR (CDCl ₃ 500 MHz) and ¹³ C-NMR (CDCl ₃ 126 MHz). The results are shown below. ^{As a result of 1} H-NMR measurement and ¹³ C-NMR measurement, 1- (2-deoxy-5-O- (4,4′-dimethoxytrityl) -β-D-ribofuranose represented by the following structural formula (15) -1-yl) -4,5-diiodoimidazole.

¹ H-NMR (CDCl ₃ 500 MHz)
δ: 7.77 (1H, s, imi 2H), 7.42-7.20 (9H, m, DMTr), 6.84-6.82 (4H, m, DMTr), 5.97 (1H, t, 1′H, J = 6.35), 4.50 (1H, m, 4′H), 3.79 (6H, s, DMTr), 3.41-3.30 (2H, m, 5 'H × 2), 2.53-2.48 (1H, m, 2'H), 2.39-2.34 (1H, m, 2'H), 2.09 (1H, br, OH)

¹³ C-NMR (CDCl ₃ 126 MHz)
δ: 158.76, 144.44, 139.28, 135.63, 135.55, 130.10, 130.10, 128.18, 128.15, 127.20, 113.44, 96.93, 89.15, 86.90, 86.12, 79.90, 72.17, 63.59, 55.41, 41.67

(16): Synthesis of 1- (2-deoxy-5-O- (4,4′-dimethoxytrityl) -β-D-ribofuranose-1-yl) -4-iodoimidazole 1- (2-deoxy- 5- (4,4′-dimethoxytrityl) -β-D-ribofuranose-1-yl) -4,5-iodoimidazole (738 mg, 1.0 mmol) was dissolved in dehydrated tetrahydrofuran (10 ml), and the reaction system was The atmosphere was replaced with argon and cooled to -78 ° C. Ethyl magnesium bromide (1M in THF, 1.0 mL, 1.0 mmol) was added thereto, and the mixture was stirred at −78 ° C. for 5 minutes, and then stirred at 0 ° C. for 5 minutes. Thereto was added ethylmagnesium bromide (1M in THF, 1.0 mL, 1.0 mmol) again, and the mixture was stirred at 0 ° C. for 15 minutes. Subsequently, water (3 mL) was added to the reaction system to stop the reaction, followed by extraction with ethyl acetate-saturated aqueous sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was isolated and purified using silica gel chromatography (C-200) with chloroform-methanol 0 → 1% to obtain a compound (334 mg, yield 56%). The structure of the obtained compound was measured by ¹ H-NMR (CDCl ₃ 500 MHz) and ¹³ C-NMR (CDCl ₃ 126 MHz). The results are shown below. ^{As a result of 1} H-NMR measurement and ¹³ C-NMR measurement, 1- (2-deoxy-5-O- (4,4′-dimethoxytrityl) -β-D-ribofuranose represented by the following structural formula (16) -1-yl) -4-iodoimidazole.

¹ H-NMR (CDCl ₃ 500 MHz)
δ: 7.50 (1H, s, imi 2H), 7.40-7.22 (9H, m, DMTr), 7.11 (1H, s, imi 5H), 6.85-6.83 (4H) , M, DMTr), 5.97 (1H, t, J = 6.59, 1′H), 4.50 (1H, m, 3′H), 4.05 (1H, dd, J = 4. 40, 8.06, 4′H), 3.80 (6H, s, DMTr), 3.39-3.26 (2H, m, 5′H, 5 ″ H), 2.41 (2H, dd) , 2'H, 2 "H), 2.18 (1H, br, OH)

¹³ C-NMR (CDCl ₃ 126 MHz)
δ: 158.78, 144.48, 137.47, 135.70, 135.59, 130.17, 130.14, 128.24, 128.17, 127.20, 122.44, 133.44, 86.89, 86.13, 82.76, 72.53, 63.87, 55.44, 41.66

(17): Synthesis of 1- (2-deoxy-β-D-ribofuranose-1-yl) -4-iodoimidazole 1- (2-deoxy-5- (4,4′-dimethoxytrityl) -β- 80% acetic acid (3.3 mL) was added to D-ribofuranose-1-yl) -4,5-diiodimidazole (200 mg, 0.327 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated and extracted with water-chloroform. The aqueous layer was washed 3 times with chloroform, and the organic layer was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the reaction residue was isolated and purified with chloroform-methanol (4: 1 v / v) using recycle preparative HPLC to obtain the compound (84 mg, 83% yield). The structure of the obtained compound was measured by ¹ H-NMR (acetone-d ₆ 500 MHz) and ¹³ C-NMR (CDCl ₃ 126 MHz). The results are shown below. ^{As a result of 1} H-NMR measurement and ¹³ C-NMR measurement, it was identified as 1- (2-deoxy-β-D-ribofuranose-1-yl) -4-iodoimidazole represented by the following structural formula (17). did it.

¹ H-NMR (acetone-d ₆ 500 MHz)
δ: 7.77 (1H, s, imi 2H), 7.52 (1H, s, imi 5H), 6.11 (1H, dd, J = 6.10, 7.08 Hz, 1′H), 4 .55-4.51 (2H, m, OH, 3′H), 4.18 (1H, br, OH), 3.98 (1H, dd, J = 3.91, 6.84, 4′H) ), 3.75-3.69 (2H, m, 5′H, 5 ″ H), 2.50-2.45 (1H, m, 2 ″ H), 2.42-2.37 (1H, m, 2 "H)

¹³ C-NMR (CDCl ₃ 126 MHz)
δ: 18. ESIMS calcd. C ₈ H ₁₂ IN ₂ O ₃ ⁺ [M + N] ⁺ 310.9893, found 310.9898

(18): 1- (2-Deoxy-5-O- (4,4′-dimethoxytrityl) -β-D-ribofuranose-1-yl) -4-iodoimidazole-3 ′-(cyanoethyldiisopropylphosphoro) Synthesis of amidite) 1- (2-deoxy-5- (4,4′-dimethoxytrityl) -β-D-ribofuranose-1-yl) -4,5-iodoimidazole was dissolved in dehydrated dichloromethane (5 mL). It was. Diisopropylethyl emine (327 μL, 1.96 mmol) and chloro (2-cyanoethoxy) (N, N-diisopropylamino) phosphine (131 μL, 0.588 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction system was extracted with ethyl acetate-saturated aqueous sodium hydrogen carbonate, and the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated, and the reaction residue was isolated and purified with hexane-ethyl acetate-triethylamine (10: 10: 1) using column chromatography to obtain the compound (59 mg, 15% yield). The structure of the obtained compound was measured by ¹ H-NMR (CDCl ₃ 500 MHz) and ³¹ P-NMR (CDCl ₃ 202 MHz). The results are shown below. ^{As a result of 1} H-NMR measurement and ¹³ C-NMR measurement, 1- (2-deoxy-5-O- (4,4′-dimethoxytrityl) -β-D-ribofuranose represented by the following structural formula (18) -1-yl) -4-iodoimidazole-3 ′-(cyanoethyldiisopropyl phosphoramidite).

¹ H-NMR (CDCl ₃ 500 MHz)
δ: 7.57 (1H, m), 7.43-7.24 (9H, m), 7.18 (1H, m), 6.88-6.85 (4H, m), 6.01 ( 1H, m), 4.61 (1H, m), 4.28-4.24 (1H, m), 3.89-3.58 (10H, m), 3.35-3.27 (2H, m), 2.64 (1H, m), 2.61-2.44 (2H, m), 1.22-1.12 (12H, m)

³¹ P-NMR (CDCl ₃ 202 MHz)
δ: 149.51, 149.48

(19): 3 ', 5'-O-((1,1,3,3-tetraisopropyl) disiloxanediyl) -1', 2'-dideoxy-1 '-(3-iodophenyl) -D- Synthesis of α, β mixture of ribofuranose 1,3-iodobenzene (4.95 mg, 15.0 mmol) was dissolved in dehydrated tetrahydrofuran (30 mL), stirred at −78 ° C. under an argon stream, and n-butyllithium ( 1.54M in hexane, 9.74 mL, 15.0 mmol) was added slowly. After stirring at −78 ° C. for 30 minutes, 3 ′, 5′-O — ((1,1,3,3-tetraisopropyl) disiloxanediyl) -2′-deoxy-dissolved in dehydrated tetrahydrofuran (30 mL) D-ribono-1 ′, 4′-lactone (3.74 mg, 10.0 mmol) was added to the reaction system using a syringe. After 1 hour, a saturated aqueous ammonium chloride solution (20 mL) was added at −78 ° C. to stop the reaction, and the temperature was raised to room temperature. The reaction system was extracted with ethyl acetate-saturated aqueous ammonium solution, and the organic layer was washed with water and saturated aqueous sodium chloride solution. The organic layer was collected and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Dehydrated dichloromethane (35 mL) was added to the residue, and the mixture was stirred at −78 ° C. under a stream of argon. Trifluoroborane / diethyl ether complex (3.80 mL, 30.0 mmol), triethylsilane (4.79 mL, 30.0 mmol) Was added. Six hours later, extraction was performed with saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with water and a saturated aqueous sodium chloride solution. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated. The residue was isolated and purified using silica gel chromatography (C-200) with hexane-ethyl acetate 0 → 1% to obtain a compound (1.80 g, yield 32%, α: β = 1: 5). .6). The structure of the obtained compound was measured by ¹ H-NMR (CDCl ₃ 500 MHz) and ¹³ C-NMR (CDCl ₃ 126 MHz). The results are shown below. ^{As a result of 1} H-NMR measurement and ¹³ C-NMR measurement, 3 ′, 5′-O — ((1,1,3,3-tetraisopropyl) disiloxanediyl) -1 represented by the following structural formula (19) It was identified as an α, β mixture of ', 2'-dideoxy-1'-(3-iodophenyl) -D-ribofuranose.

¹ H-NMR (CDCl ₃ 500 MHz)
δ: 7.73 (0.15H, s, α-Ph 2H), 7.68 (0.85H, s, β-Ph 2H), 7.60-7.58 (1H, m, αβ-Ph 4H) ), 7.30-7.29 (1H, m, αβ-Ph 6H), 7.07-7.04 (1H, m, αβ-Ph 5H), 5.02 (0.85H, t, J = 7.33 Hz, β-1′H), 4.96 (0.15H, dd, J = 6.10, 9.77 Hz, α-1′H), 4.59-4.54 (0.15H, m, α-3′H), 4.52-4.48 (0.85H, m, β-3′H), 4.14-4.10 (0.85H, m, β-4′H) 4.07-4.03 (0.15H, m, α-4′H), 3.93-3.86 (2H, m, αβ-5′H, 5 ″ H), 2.67-2 .62 (0.15H, m, α-2′H), 2.39-2.34 (0 .85H, m, β-2′H), 2.12-2.00 (1H, m, αβ-2′H), 1.12-0.95 (28H, m, αβ-i-PrSi)

¹³ C-NMR (CDCl ₃ 126 MHz, βisomer)
δ: 144.84, 136.74, 134.93, 130.33, 125.32, 94.65, 86.66, 78.31, 73.17, 63.67, 43.29, 17.82, 17.73, 17.67, 17.48, 17.33, 17.30, 17.20, 13.73, 13.61, 13.23, 12.78 ESIMS calcd. _{C 23 H 43 INO 4 Si 2} + [M + NH 4] + 580.1770, found 580.2539

(20): Synthesis of α, β mixture of 1 ′, 2′-dideoxy-1 ′-(3-iodophenyl) -D-ribofuranose 3 ′, 5′-O — ((1,1,3,3 -Tetraisopropyl) disiloxanediyl) -1 ', 2'-dideoxy-1'-(3-iodophenyl) -D-ribofuranose α, β mixture (1.68 mg, 3.18 mmol) in tetrahydrofuran (16 mL) Triethylamine (1.81 mL, 5.73 mmol) and triethylamine-3 hydrofluorin (1.81 mL, 11.2 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction system was extracted with chloroform-water, the aqueous layer was washed with chloroform, the organic layer was collected and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was isolated and purified using silica gel chromatography (C-200) with chloroform-methanol 0 → 3% to obtain a compound (yield 951 mg, α: β = 1: 5. 6). The structure of the obtained compound was measured by ¹ H-NMR (CDCl ₃ 500 MHz) and ¹³ C-NMR (CDCl ₃ 126 MHz). The results are shown below. ^{As a result of 1} H-NMR measurement and ¹³ C-NMR measurement, α, β mixture of 1 ′, 2′-dideoxy-1 ′-(3-iodophenyl) -D-ribofuranose represented by the following structural formula (20) Was identified.

¹ H-NMR (CDCl ₃ 500 MHz)
δ: 7.74 (0.15H, s, α-Ph 2H), 7.70 (0.85H, s, β-Ph 2H), 7.63-7.60 (1H, m, αβ-Ph 4H ), 7.33-7.29 (1H, m, αβ-Ph 6H), 7.10-7.05 (1H, m, αβ-Ph 5H), 5.10 (0.85H, dd, J = 5.62, 10.26 Hz, β-1′H), 5.38 (0.15 H, t, J = 7.81 Hz, α-1′H), 4.47-4.42 (1H, m, αβ-3′H), 4.07 (0.15H, dd, J = 4.88, 9.28 Hz, α-4′H), 4.02-4.00 (0.85H, m, β− 4′H), 3.85-3.81 (1H, m, αβ-5′H), 3.78-3.71 (1H, m, αβ-5 ″ H), 2.70-2.65. (0.15H, m, α-2′H), 2.28-2.6 5 (0.85H, m, β-2′H), 2.04-1.94 (3H, m, αβ-2 ″ H, OH × 2)

¹³ C-NMR (CDCl ₃ 126 MHz, βisomer)
δ: 143.73, 136.94, 135.01, 130.37, 125.40, 94.62, 87.50, 79.34, 73.64, 63.42, 43.92

(21): 5′-O- (4,4′-dimethoxytrityl) -1 ′, 2′-dideoxy-β-1 ′-(3-iodophenyl) -D-ribofuranose; (22): 5 Synthesis of '-O- (4,4'-dimethoxytrityl) -1', 2'-dideoxy-α-1 '-(3-iodophenyl) -D-ribofuranose 1,2-dideoxy-1'-( An α, β mixture (421 mg, 1.32 mmol) of 3-iodophenyl) -D-ribofuranose was dehydrated azeotropically with dehydrated pyridine three times, dissolved in dehydrated pyridine (13 mL), and 4,4′-dimethoxytrityl. Chloride (490 mg, 1.45 mmol) was added. The mixture was stirred at room temperature for 1 hour, and methanol (3.0 mL) was added to stop the reaction. The reaction system was concentrated to some extent, the residue was extracted with ethyl acetate-saturated aqueous sodium bicarbonate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was collected and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was isolated and purified with hexane-ethyl acetate 0 → 40% using silica gel chromatography (C-200) to obtain a compound (βisomer: 467 mg, yield). 57%, α isomer: 71 mg, 9% yield). The structure of the obtained compound was measured by ¹ H-NMR (CDCl ₃ 500 MHz) and ¹³ C-NMR (CDCl ₃ 126 MHz). The results are shown below. ^{As a result of 1} H-NMR measurement and ¹³ C-NMR measurement, 5′-O- (4,4′-dimethoxytrityl) -1 ′, 2′-dideoxy-β-1 ′ represented by the following structural formula (21) -(3-iodophenyl) -D-ribofuranose, and 5′-O- (4,4′-dimethoxytrityl) -1 ′, 2′-dideoxy-α-1 ′-( It was identified as 3-iodophenyl) -D-ribofuranose.

・ Βisomer
¹ H-NMR (CDCl ₃ 500 MHz)
δ: 7.92 (1H, s, Ph 2H), 7.61 (1H, s, Ph 4H), 7.47-7.26 (9H, m, DMTr), 7.23-7.20 (1H) , M, Ph 6H), 7.06 (1H, t, J = 7.81 Hz Ph 5H), 6.86-6.83 (4H, m, DMTr), 5.11 (1H, dd, J = 5 .62, 10.25 Hz, 1′H), 4.41-4.40 (1H, m, 3′H), 4.07-4.05 (1H, m, 4′H), 3.79 ( 6H, s, DMTr), 3.36-3.28 (2H, m, 5'H, 5 "H), 2.6-2.22 (1H, m, 2'H), 2.06-2 .00 (1H, m, 2 "H), 1.94 (1H, br, OH)
¹³ C-NMR (CDCl ₃ 126 MHz, βisomer)
δ: 158.61, 144.92, 144.50, 136.24, 136.09, 134.97, 130.23, 130.20, 128.30, 128.01, 126.94, 125.38, 113.32, 94.55, 86.61, 86.43, 79.21, 74.67, 64.51, 55.37, 44.01

・ Α isomer
¹ H-NMR (CDCl ₃ 500 MHz)
δ: 7.76 (1H, s, Ph 2H), 7.65-7.59 (1H, m, Ph 4H), 7.45-7.21 (10H, m, DMTr, 6H), 7.08 (1H, t, J = 7.81 Hz Ph 5H), 6.86-6.83 (4H, m, DMTr), 5.06 (1H, t, J = 7.33 Hz, 1′H), 4. 42 (1H, m, 3′H), 4.17-4.14 (1H, dd, J = 4.64, 10.50 Hz, 4′H), 3.80 (6H, s, DMTr), 3 .38-3.35 (1H, m, 5'H), 3.24-3.21 (1H, m, 5 "H), 2.72-2.66 (1H, m, 2'H), 2.00-1.95 (1H, m, 2 "H), 1.86 (1H, br, OH)
¹³ C-NMR (CDCl ₃ 126 MHz, βisomer)
δ: 158.69, 145.67, 144.89, 136.59, 136.07, 136.02, 134.87, 130.35, 130.20, 128.26, 128.07, 127.03, 125.09, 113.35, 94.67, 86.58, 84.71, 79.054, 75.21, 64.80, 55.38, 43.24

(23) 5′-O- (4,4′-dimethoxytrityl) -1 ′, 2′-dideoxy-β-1 ′-(3-iodophenyl) -D-ribofuranose 3 ′-(cyanoethyldiisopropylphosphoro Synthesis of amidite) 5′-O- (4,4′-dimethoxytrityl) -1 ′, 2′-dideoxy-β-1 ′-(3-iodophenyl) -D-ribofuranose (300 mg, 0.482 mmol) Was dissolved in dehydrated dichloromethane (5 mL). Diisopropylethylamine (322 μL, 1.93 mmol) and chloro (2-cyanoethoxy) (N, N-diisopropylamino) phosphine (129 μL, 0.578 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction system was extracted with ethyl acetate-saturated aqueous sodium hydrogen carbonate, and the organic layer was collected and dried over anhydrous sodium sulfate. The organic layer was aggregated, and the residue was isolated and purified with hexane-ethyl acetate-triethylamine (10: 10: 1) using column chromatography to obtain the compound (316 mg, yield 81%). The structure of the obtained compound was measured by ¹ H-NMR (CDCl ₃ 500 MHz) and ³¹ P-NMR (CDCl ₃ 202 MHz). The results are shown below. ^{As a result of 1} H-NMR measurement and ³¹ P-NMR measurement, 5′-O- (4,4′-dimethoxytrityl) -1 ′, 2′-dideoxy-β-1 ′ represented by the following structural formula (23) It could be identified as-(3-iodophenyl) -D-ribofuranose 3 '-(cyanoethyldiisopropyl phosphoramidite).

¹ H-NMR (CDCl ₃ 500 MHz)
δ: 7.83 (1H, m), 7.61 (1H, m), 7.36-7.27 (9H, m), 7.21 (1H, m), 7.06 (1H, m) 6.85-6.81 (4H, m), 5.10 (1H, m), 4.49 (1H, m), 4.22 (1H, m), 3.86-3.54 (10H) M), 3.35-3.21 (2H, m), 2.61 (1H, m), 2.46-2.31 (2H, m), 2.01 (1H, m), 1. 18-1.07 (12H, m)

³¹ P-NMR (CDCl ₃ 202 MHz)
δ: 148.70, 148.51

Synthesis of oligonucleotide containing halogen bond donor and halogen bond acceptor Synthesis of oligonucleotide using the above phosphoramidite (18), (23) and a commercially available phosphoramidite unit for DNA synthesis and a DNA automatic synthesizer. went. Deprotection and cut-out were performed by a standard method using aqueous ammonia. The nucleoside residue introduced by phosphoramidite (18) is described as imi, and the nucleoside residue introduced by (23) is described as iph. The sequence of the oligonucleotide obtained by synthesis is
A: 5′-CGCAGTXTAGTCCC-3 ′ (X = imi, iph)
B: 5′-GGACTAYACTGCG-3 ′ (Y = A, T, G, C, imimi)
Met. The structures of A and B were confirmed by MALDI TOF Mass spectrum.
A (X = imimi): calculated value 3990.5, measured value 3990.1
A (X = iph): calculated value 4000.6, actual value 3997.8
B (Y = imimi): calculated value 4039.6, actually measured value 4038.8

Confirmation of association by halogen bond Each of the oligo DNAs represented by the above A (X = iph) and B (X = A, T, G, C, imimi) is 10 mM phosphate buffer (100 mM sodium chloride, 0.1 mM). Dissolved in EDTA pH 7.0) to prepare 2 μM solution and mixed them. The change in absorbance at 260 nm with respect to the temperature change of the mixed solution was measured, and the temperature at which the differential curve was maximum was defined as Tm. The result is shown in FIG. When X and Y are a combination of iph which is a halogen bond donor and imi which is an acceptor, Tm is higher than other bonds. Thereby, in the oligonucleotide chain A and the oligonucleotide chain B, the nucleoside derivative iph (structural formula (23)) functions as a halogen bond donor, and imimi (structural formula (18)) functions as a halogen bond acceptor. Thus, it can be said that iph and imi specifically pair through a halogen bond to form an aggregate.

It is a figure which shows the synthetic scheme which synthesize | combines the artificial nucleoside derivative as a halogen bond acceptor as a pre-step which synthesize | combines the artificial oligonucleotide shown as a specific example of this invention. It is a figure which shows the synthetic scheme which synthesize | combines the non-natural nucleoside derivative as a halogen bond donor as a pre-step which synthesize | combines the artificial oligonucleotide shown as a specific example of this invention. The figure showing the measurement result which mixed the oligo-DNA solution represented by A (X = iph) and B (X = A, T, G, C, imimi), and measured the light-absorbency change in 260 nm with respect to the temperature change of a liquid mixture. It is.

Claims (16)

A nucleoside represented by the following general formula (1).

(In the formula, R1 is an aromatic ring or a heteroaromatic ring containing a C—X bond (where X is a halogen element) as a halogen bond donor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group. .)   2. In the above formula, R1 is an aromatic ring or heteroaromatic ring into which at least one of the same atom or a plurality of different atoms is introduced among the halogen elements fluorine, chlorine, bromine and iodine. The nucleoside described. A nucleoside represented by the following general formula (2).

(In the formula, R2 is an aromatic ring or heteroaromatic ring having a lone pair as a halogen bond acceptor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group.)   4. The nucleoside according to claim 3, wherein R2 in the formula is an aromatic ring or a heteroaromatic ring containing a nitrogen atom or an oxygen atom. A nucleoside derivative represented by the following general formula (3), wherein either or all of the 3′-position hydroxyl group and the 5′-position hydroxyl group are protected with a protecting group.

(In the formula, R1 is an aromatic ring or a heteroaromatic ring containing a C—X bond (where X is a halogen element) as a halogen bond donor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group. R3 is an H atom and R4 is a substituent other than an H atom, or R3 is a substituent other than an H atom, and R4 is an H atom.)   6. In the above formula, R1 is an aromatic ring or heteroaromatic ring into which at least one of the same atom or a plurality of different atoms is introduced among the halogen elements fluorine, chlorine, bromine and iodine. The described nucleoside derivative. A nucleoside derivative represented by the following general formula (4), wherein either or all of the hydroxyl group at the 3 ′ position and the hydroxyl group at the 5 ′ position are protected with a protecting group.

(Wherein R2 is an aromatic ring or heteroaromatic ring having a lone pair as a halogen bond acceptor, Y is a hydrogen atom, a hydroxyl group or an alkoxy group. R3 is an H atom and R4 is (It is a substituent other than an H atom, or R3 is a substituent other than an H atom, and R4 is an H atom.)   8. The nucleoside derivative according to claim 7, wherein R2 in the formula is an aromatic ring or a heteroaromatic ring containing a nitrogen atom or an oxygen atom. An oligonucleotide formed by phosphodiester bonding of 3′-position oxygen and 5′-position oxygen of a plurality of nucleosides selected from a nucleoside represented by the following general formula (5) and a nucleoside bound to a nucleobase.

(In the formula, R1 is an aromatic ring or a heteroaromatic ring containing a C—X bond (where X is a halogen element) as a halogen bond donor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group. .)   10. In the above formula, R1 is an aromatic ring or heteroaromatic ring into which at least one of the same atom or a plurality of different atoms is introduced among the halogen elements fluorine, chlorine, bromine and iodine. The described oligonucleotide. An oligonucleotide formed by phosphodiester bonding of 3′-position oxygen and 5′-position oxygen of a plurality of nucleosides selected from a nucleoside represented by the following general formula (6) and a nucleoside bound to a nucleobase.

(In the formula, R2 is an aromatic ring or heteroaromatic ring having a lone pair as a halogen bond acceptor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group.)   12. The oligonucleotide according to claim 11, wherein R2 is an aromatic ring or a heteroaromatic ring containing a nitrogen atom or an oxygen atom. 3'-position oxygen and 5'-position oxygen of a plurality of nucleosides selected from a nucleoside represented by the following general formula (7), a nucleoside represented by the following general formula (8), and a nucleoside to which a nucleobase is bound. Is an oligonucleotide formed by binding a phosphodiester bond.

(In the formula, R1 is an aromatic ring or a heteroaromatic ring containing a C—X bond (where X is a halogen element) as a halogen bond donor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group. .)

(In the formula, R2 is an aromatic ring or heteroaromatic ring having a lone pair as a halogen bond acceptor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group.) An oligonucleotide formed by phosphodiester bonding of 3′-position oxygen and 5′-position oxygen of a plurality of nucleosides selected from a nucleoside represented by the following general formula (9) and a nucleoside bound to a nucleobase;
An oligonucleotide formed by phosphodiester bond between 3′-position oxygen and 5′-position oxygen of a plurality of nucleosides selected from a nucleoside represented by the following general formula (10) and a nucleoside bound to a nucleobase:
An oligonucleotide aggregate in which at least one halogen bond is formed between a halogen bond donor and a halogen bond acceptor.

(In the formula, R1 is an aromatic ring or a heteroaromatic ring containing a C—X bond (where X is a halogen element) as a halogen bond donor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group. .)

(In the formula, R2 is an aromatic ring or heteroaromatic ring having a lone pair as a halogen bond acceptor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group.)   In the above formula, R1 is an aromatic ring or heteroaromatic ring in which at least one of the same atom or a plurality of different atoms is introduced among the halogen elements fluorine, chlorine, bromine, and iodine. In the above formula, R2 is nitrogen. The oligonucleotide aggregate according to claim 14, which is an aromatic ring or a heteroaromatic ring containing an atom or an oxygen atom. 3'-position oxygen and 5'-position oxygen of a plurality of nucleosides selected from a nucleoside represented by the following general formula (11), a nucleoside represented by the following general formula (12) and a nucleoside to which a nucleobase is bound. An oligonucleotide aggregate in which at least one halogen bond is formed between a halogen bond donor and a halogen bond acceptor between oligonucleotides formed by phosphodiester bonds.

(In the formula, R1 is an aromatic ring or a heteroaromatic ring containing a C—X bond (where X is a halogen element) as a halogen bond donor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group. .)

(In the formula, R2 is an aromatic ring or heteroaromatic ring having a lone pair as a halogen bond acceptor, and Y is a hydrogen atom, a hydroxyl group or an alkoxy group.)

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