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CN-122011069-A - Antitumor 1,2, 3-triazole-alpha-L-threose nucleoside phosphonate analogue and preparation method and application thereof

CN122011069ACN 122011069 ACN122011069 ACN 122011069ACN-122011069-A

Abstract

The invention discloses an anti-tumor 1,2, 3-triazole-alpha-L-threose phosphonic acid nucleoside compound, a preparation method and application thereof, wherein the 1,2, 3-triazole-alpha-L-threose phosphonic acid nucleoside analogue has a chemical structure shown in a general formula 1: Wherein R 1 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 3-fluorophenyl, 3-nitrophenyl, 4-methoxyphenyl, 4-cyanophenyl, 3, 4-dimethoxyphenyl, 2-pyridyl, 2-naphthyl, 2-thienyl, 3-thienyl, phenylthiomethyl, cyclohexyl, methoxyethyl, n-pentyl and the like, and the preparation method of the 1,2, 3-triazole-alpha-L-threose nucleoside compound has the advantages of simple operation, simple route, high yield, suitability for large-scale preparation, and good antitumor activity by in vitro antitumor activity research, and is expected to be used as an antitumor drug or a lead of the antitumor drug.

Inventors

  • XU WENKE
  • WANG ZHIFANG
  • HUANG XUEWEI
  • TIAN SEN
  • ZHANG XUSHAN
  • SHAO MINGZHE
  • Liang Xingran

Assignees

  • 河南警察学院

Dates

Publication Date
20260512
Application Date
20260202

Claims (9)

  1. 1. An anti-tumor 1,2, 3-triazole-alpha-L-threose phosphonic acid nucleoside compound is characterized by having a chemical structure of formula (1): wherein the substituent R 1 is one of aryl, heteroaryl, arylthio and aliphatic group.
  2. 2. The antitumor nucleoside 1,2, 3-triazole-alpha-L-threose phosphonate compound of claim 1, wherein the aryl is phenyl, 2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 3-fluorophenyl, 3-nitrophenyl, 4-methoxyphenyl, 4-cyanophenyl, 3, 4-dimethoxyphenyl, 2-naphthyl; the heteroaryl is 2-pyridyl, 2-thienyl, 3-thienyl; The arylthio is a phenylthio; the aliphatic group is cyclohexyl, methoxyethyl and n-amyl.
  3. 3. The anti-tumor 1,2, 3-triazole-alpha-L-threose phosphonic acid nucleoside compound according to claim 2, wherein the 1,2, 3-triazole-alpha-L-threose phosphonic acid nucleoside compound has the following 22 structures, and specific numbers are 1a-1v in sequence: 。
  4. 4. A process for the preparation of an antitumor nucleoside 1,2, 3-triazole- α -L-threose phosphonate analogue according to any one of claims 1-3, characterized in that it is prepared by the following reaction scheme: wherein the substituent R 1 is one of phenyl, non-phenyl aryl, heteroaryl, arylthio and aliphatic group.
  5. 5. The preparation process of antitumor nucleoside 1,2, 3-triazole-alpha-L-threose analogue, as claimed in claim 4, characterized in that the step (1) is to dissolve compound I in organic solvent at room temperature and to react with azido trimethyl silane under the catalysis of Lewis acid to obtain compound II; dissolving an intermediate II in water and a tertiary butanol solvent at room temperature, sequentially adding a Lewis acid, a ligand, a stabilizer and a terminal alkyne analogue, and separating by column chromatography after the reaction is finished to obtain a compound III; dissolving 1,2, 3-triazole nucleoside phosphonate III in an organic solvent, acidolyzing the ester group under the protection of nitrogen, and purifying by reverse phase column chromatography after the reaction is finished to obtain the target compound 1.
  6. 6. The method for preparing the antitumor nucleoside 1,2, 3-triazole-alpha-L-threose phosphonate analogue, according to claim 5, wherein in the step (1), one Lewis acid refers to stannic chloride or trimethyl silyl triflate, and one organic solvent refers to dichloromethane, 1, 2-dichloroethane, acetonitrile and tetrahydrofuran.
  7. 7. The method for preparing the antitumor nucleoside 1,2, 3-triazole-alpha-L-threose phosphonate analogue, according to claim 5, wherein in the step (2), one Lewis acid refers to cuprous iodide, cuprous bromide, cupric sulfate and cupric sulfate pentahydrate, one ligand refers to one or two of sodium ascorbate, potassium carbonate, triethylamine and diisopropylethylamine, and one stabilizer refers to tetrabutylammonium bisulfate and acetic acid.
  8. 8. The method for preparing an antitumor nucleoside 1,2, 3-triazole-alpha-L-threose phosphonate analogue according to claim 5, wherein in the step (3), the reagent in the acidolysis reaction is one of trimethyliodosilane, trimethylbromosilane, trimethyliodosilane/2, 4, 6-collidine, trimethylbromosilane/2, 4, 6-collidine, trimethyliodosilane/2, 6-lutidine, trimethylbromosilane/2, 6-lutidine, one organic solvent is one of acetonitrile, tetrahydrofuran and dichloromethane, the ester group is ethyl ester or isopropyl ester, and the mixed solution of methanol: water=1:4 is used as an eluent in the reversed-phase column chromatography purification process.
  9. 9. The use of the antitumor 1,2, 3-triazole-alpha-L-threose nucleoside analogues in preparation of medicaments, according to any one of claims 1 to 3, characterized in that the antitumor 1,2, 3-triazole-alpha-L-threose nucleoside analogues are used as active ingredients for preparing antitumor medicaments for prostatic cancer cells or as intermediates for preparing antitumor medicaments.

Description

Antitumor 1,2, 3-triazole-alpha-L-threose nucleoside phosphonate analogue and preparation method and application thereof Technical Field The invention relates to the technical fields of nucleotide chemistry and pharmaceutical chemistry, in particular to an antitumor 1,2, 3-triazole-alpha-L-threose phosphonic acid nucleoside analogue, and a preparation method and application thereof. Background Nucleosides and their derivatives have an irreplaceable role in the treatment of diseases such as antiviral, antitumor, etc. Unnatural nucleosides are often activated as an important class of small molecule drugs by stepwise phosphorylation within cells to form the corresponding nucleoside triphosphates. The activated nucleoside triphosphates can be involved in the synthesis of viral RNA, DNA, or interfere with cellular nucleic acid synthesis, thereby exhibiting antiviral or antitumor activity. In nucleoside design, sugar ring modification and base modification are effective means for obtaining novel nucleosides. The threose phosphonate nucleoside is used as an isostere of mononucleotide, so that not only can the stability of the compound in vivo be improved, but also partial initial enzymatic phosphorylation steps can be avoided, and the nucleoside compound can keep higher bioavailability under the condition of low dependence on metabolic activation, thereby being widely favored by nucleic acid chemists. Among these structural optimizations, 1,2, 3-triazole nucleosides have been of great interest for their unique chemical and biological advantages. Firstly, the 1,2, 3-triazole ring belongs to an aromatic heterocyclic structure, has excellent chemical stability and metabolic stability, and secondly, the ribavirin generally has the capability of improving solubility, membrane permeability and pharmacokinetics, so that the ribavirin shows better absorption and distribution performance in vivo. Third, the triazole ring has good electron donating and accepting properties, can be used as a bioisostere of purine or pyrimidine, and can change the interaction with polymerase while maintaining the function of a nucleoside skeleton. Based on the above, if the metabolic advantage of threose phosphonate is combined with the electronic effect, stability and conformational adjustability of 1,2, 3-triazole heterocycle, the shortcomings of the traditional nucleoside in stability, bioavailability and drug resistance can be improved, and a new structural basis is provided for finding a lead compound with antitumor potential, so that the combination of the two is a problem to be solved urgently. Disclosure of Invention In order to solve the technical problems, the invention provides an antitumor 1,2, 3-triazole-alpha-L-threose nucleoside phosphonate analogue, a preparation method and application thereof, and the compound can inhibit the activity of prostate cancer cells, has simple synthesis reaction conditions and wide application range, and can be prepared in a large amount. In order to solve the technical problems, the invention provides an anti-tumor 1,2, 3-triazole-alpha-L-threose phosphonic acid nucleoside compound, which is characterized by having a chemical structure shown in a formula (1): wherein the substituent R 1 is one of aryl, heteroaryl, arylthio and aliphatic group. Further, the aryl is phenyl, 2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 3-fluorophenyl, 3-nitrophenyl, 4-methoxyphenyl, 4-cyanophenyl, 3, 4-dimethoxyphenyl, 2-naphthyl; the heteroaryl is 2-pyridyl, 2-thienyl, 3-thienyl; The arylthio is a phenylthio; the aliphatic group is cyclohexyl, methoxyethyl and n-amyl. Further, the 1,2, 3-triazole-alpha-L-threose phosphonic acid nucleoside compound has the following 22 structures, and specific numbers are 1a-1v in sequence: 。 in order to solve the technical problems, the invention provides another technical scheme that the preparation method of the antitumor 1,2, 3-triazole-alpha-L-threose nucleoside phosphonate analogue is characterized by adopting the following reaction route: wherein the substituent R 1 is one of phenyl, non-phenyl aryl, heteroaryl, arylthio and aliphatic group. Further, the step (1) is to dissolve the compound I in an organic solvent at room temperature, and to react with azido trimethylsilane under the catalysis of a Lewis acid through nucleophilic substitution to obtain a compound II; dissolving an intermediate II in water and a tertiary butanol solvent at room temperature, sequentially adding a Lewis acid, a ligand, a stabilizer and a terminal alkyne analogue, and separating by column chromatography after the reaction is finished to obtain a compound III; dissolving 1,2, 3-triazole nucleoside phosphonate III in an organic solvent, acidolyzing the ester group under the protection of nitrogen, and purifying by reverse phase column chromatography after the reaction is finished to obtain the target compound 1. Further, in the step (1