Anti-tumor 1, 2, 3-triazole-alpha-L-threose nucleoside phosphonate analogue as well as preparation method and application thereof

Abstract

The invention discloses an anti-tumor 1, 2, 3-triazole-alpha-L-threose nucleoside phosphonate compound as well as a preparation method and application thereof, and the 1, 2, 3-triazole-alpha-L-threose nucleoside phosphonate analogue has a chemical structure as shown in a general formula 1, r1 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 4-bromophenyl, 3-fluorophenyl, 3-nitrophenyl, 4-methoxyphenyl, 4-cyanophenyl, 3, 4-dichlorophenyl, 3, 4-dichlorophenyl, 3, 4-dichlorophenyl, 3, 4-dichlorophenyl, 3, 4-dichlorophenyl, 3, 4-dichlorophenyl, 3, 4-dichlorophenyl, 3, 4-dichlorophenyl, 3, 4-dichlorophenyl, 3, 4-dichlorophenyl, 3, 4-dichlorophenyl R1, R2, R3, R4, R5, R6, R7, R7, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, R8, the technical route for preparing the 1, 2, 3-triazole-alpha-L-threose nucleoside phosphonate compound is simple to operate, concise in route and relatively high in yield, the used reagents are common reagents and suitable for large-scale preparation, and in-vitro antitumor activity research finds that the compound has good antitumor activity and can be used for preparing the 1, 2, 3-triazole-alpha-L-threose nucleoside phosphonate compound. The compound is expected to be used as an anti-tumor drug or a primer of the anti-tumor drug.

Description

Technical Field

[0001] This invention relates to the fields of nucleotide chemistry and medicinal chemistry, specifically to antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside analogs, their preparation methods, and applications. Background Technology

[0002] Nucleosides and their derivatives play an irreplaceable role in the treatment of diseases such as antiviral and antitumor infections. Non-natural nucleosides, as an important class of small molecule drugs, are often activated through stepwise phosphorylation within cells to generate corresponding nucleoside triphosphates. Activated nucleoside triphosphates can participate in the synthesis of viral RNA and DNA or interfere with cellular nucleic acid synthesis, thus exhibiting antiviral or antitumor activity. In nucleoside design, sugar ring modification and base modification are effective means to obtain novel nucleosides. Threonophosphonate nucleosides, as isosteres of mononucleotides, not only improve the stability of compounds in vivo but also avoid some initial enzymatic phosphorylation steps, allowing nucleoside compounds to maintain high bioavailability under conditions of low dependence on metabolic activation, thus gaining widespread favor among nucleic acid chemists.

[0003] Among these structural optimizations, 1,2,3-triazole nucleosides have attracted significant attention due to their unique chemical and biological advantages. First, the 1,2,3-triazole ring belongs to the aromatic heterocyclic structure, exhibiting excellent chemical and metabolic stability. Second, triazole nucleosides typically possess the ability to improve solubility, membrane permeability, and pharmacokinetics, resulting in superior absorption and distribution in vivo. Third, the triazole ring exhibits excellent electron-donating and accepting properties, serving as a bioisostere for purines or pyrimidines, thus altering interactions with polymerases while maintaining the function of the nucleoside skeleton.

[0004] Based on this, if the metabolic advantages of threophosphonates are combined with the electronic effects, stability and conformational tunability of 1,2,3-triazole heterocycles, it can not only improve the shortcomings of traditional nucleosides in terms of stability, bioavailability and drug resistance, but also provide a new structural basis for the discovery of lead compounds with anti-tumor potential. Therefore, combining the two has become an urgent problem to be solved. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside analogs, their preparation methods, and applications. These compounds can inhibit the activity of prostate cancer cells, and their synthesis reaction conditions are simple, they have a wide range of applications, and they can be prepared in large quantities.

[0006] To solve the above-mentioned technical problems, the present invention provides a technical solution as follows: an antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside compound, characterized in that it has the chemical structure of formula (1):

[0007]

[0008] Among them, substituent R 1 It refers to one of the following groups: aryl, heteroaryl, arylthio, and aliphatic group.

[0009] Furthermore, the aryl group is phenyl, 2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-fluorophenyl, 3-nitrophenyl, 4-methoxyphenyl, 4-cyanophenyl, 3,4-dimethoxyphenyl, or 2-naphthyl;

[0010] The heteroaryl group is 2-pyridyl, 2-thienyl, or 3-thienyl;

[0011] The arylthyl group is an anisole sulfide group;

[0012] The aliphatic groups are cyclohexyl, methoxyethyl, and n-pentyl.

[0013] Furthermore, the 1,2,3-triazole-α-L-threophosphonic acid nucleoside compounds have the following 22 structures, specifically numbered 1a-1v:

[0014]

[0015] .

[0016] To solve the above-mentioned technical problems, another technical solution provided by the present invention is: according to the above-described method for preparing antitumor 1,2,3-triazole-α-L-threonophosphonic acid nucleoside analogs, characterized by the following reaction route:

[0017]

[0018] Among them, substituent R 1 It refers to one of the following groups: phenyl, non-phenyl aryl, heteroaryl, arylthio, and aliphatic group.

[0019] Further, step (1) is as follows: at room temperature, compound I is dissolved in an organic solvent and reacted with azidotrimethylsilane in a Lewis acid via a nucleophilic substitution reaction to obtain compound II;

[0020] Step (2) is as follows: at room temperature, intermediate II is dissolved in water and tert-butanol solvent, and a Lewis acid, a ligand, a stabilizer, and a terminal alkyne analog are added in sequence. After the reaction is completed, compound III is obtained by column chromatography.

[0021] Step (3) is as follows: 1,2,3-triazole nucleophosphonate III is dissolved in an organic solvent, the ester group is acidified under nitrogen protection, and after the reaction is completed, it is purified by reversed-phase column chromatography to obtain target compound 1.

[0022] Furthermore, in step (1), a Lewis acid refers to tin tetrachloride or trimethylsilyl trifluoromethanesulfonate; an organic solvent refers to dichloromethane, 1,2-dichloroethane, acetonitrile, or tetrahydrofuran.

[0023] Furthermore, in step (2), a Lewis acid refers to cuprous iodide, cuprous bromide, copper sulfate, or copper sulfate pentahydrate; a ligand refers to one or two of sodium ascorbate, potassium carbonate, triethylamine, or diisopropylethylamine; and a stabilizer refers to tetrabutylammonium hydrogen sulfate or acetic acid.

[0024] Furthermore, in step (3), the reagent in the acid hydrolysis reaction refers to one of trimethyliodosilane, trimethylbromosilane, trimethyliodosilane / 2,4,6-coridine, trimethylbromosilane / 2,4,6-coridine, trimethyliodosilane / 2,6-rutidine, and trimethylbromosilane / 2,6-rutidine; the organic solvent refers to one of acetonitrile, tetrahydrofuran, and dichloromethane; the ester group refers to ethyl ester or isopropyl ester; and a methanol:water = 1:4 mixture is used as the eluent in the reversed-phase column chromatography purification process.

[0025] To solve the above-mentioned technical problems, another technical solution provided by the present invention is: based on the application of the antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside analog in drug preparation, characterized in that: 1,2,3-triazole-α-L-threophosphonic acid nucleoside analog is used as the active ingredient to prepare anti-prostate cancer cell drugs or as an intermediate for preparing antitumor drugs.

[0026] The beneficial effects of this invention are as follows:

[0027] The technical route for preparing 1,2,3-triazole-α-L-threophosphonic acid nucleoside compounds described in this application is simple to operate, concise, and has a high yield. All reagents used are commonly used and suitable for large-scale preparation. In vitro antitumor activity studies have revealed that some compounds have good antitumor activity, especially outstanding activity against prostate cancer cells. Therefore, these compounds are expected to be used as anti-prostate cancer cell drugs or as lead compounds for antitumor drugs.

[0028] To make the above and other objects, features and advantages of the present invention more apparent and understandable, preferred embodiments are described in detail below. Detailed Implementation

[0029] Embodiments of the present invention will now be described in detail. The present invention can be implemented in various forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided to provide a more thorough and complete understanding of the invention. It should be understood that the embodiments of the present invention are for illustrative purposes only and are not intended to limit the scope of protection of the present invention.

[0030] Example

[0031] An antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside compound having the chemical structure of formula (1):

[0032]

[0033] Among them, substituent R 1 It refers to one of the following groups: aryl, heteroaryl, arylthio, and aliphatic group.

[0034] The aryl group is phenyl, 2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-fluorophenyl, 3-nitrophenyl, 4-methoxyphenyl, 4-cyanophenyl, 3,4-dimethoxyphenyl, or 2-naphthyl;

[0035] The heteroaryl group is 2-pyridyl, 2-thienyl, or 3-thienyl;

[0036] The arylthyl group is an anisole sulfide group;

[0037] The aliphatic groups are cyclohexyl, methoxyethyl, and n-pentyl.

[0038] The antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside compounds have the following 22 structures, specifically numbered 1a-1v:

[0039]

[0040] .

[0041] The preparation method of the above-mentioned antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside analog is another technical solution disclosed in this application. The technical solution is as follows: using 4-methyl-3-O-diethoxyphosphonomethyl-2-O-benzoyl-1-O-acetyl-L-threoyl I as the starting material, the target 1,2,3-triazole-α-L-threophosphonic acid nucleoside compounds 1a-1v are finally obtained through azidation reaction, alkyne and azidocycloaddition reaction, removal of protecting group.

[0042] The reaction route is shown below:

[0043]

[0044] Among them, substituent R 1 It refers to one of the following groups: phenyl, non-phenyl aryl, heteroaryl, arylthio, and aliphatic group.

[0045] Compound I was prepared based on the inventors’ previous research, as detailed in the literature (Eur. J. Med. Chem., 2021, 221, 113513-113527), and is used directly in this application.

[0046] Step (1) in the above reaction route is as follows: Compound I is dissolved in an organic solvent at room temperature and reacted with trimethyl azidosilane in the presence of a Lewis acid via a nucleophilic substitution reaction to obtain compound II; the Lewis acid refers to tin tetrachloride or trimethyl silyl trifluoromethanesulfonate; preferably, the Lewis acid is tin tetrachloride; the organic solvent refers to dichloromethane, 1,2-dichloroethane, acetonitrile, or tetrahydrofuran.

[0047] Step (2) in the above reaction route is as follows: Intermediate II is dissolved in water and tert-butanol at room temperature. A Lewis acid, a ligand, a stabilizer, and a terminal alkyne analog are added sequentially. After the reaction is complete, compound III is obtained by column chromatography. The Lewis acid refers to cuprous iodide, cuprous bromide, copper sulfate, or copper sulfate pentahydrate; preferably, copper sulfate pentahydrate is preferred. The ligand refers to one or two of sodium ascorbate, potassium carbonate, triethylamine, and diisopropylethylamine; preferably, sodium ascorbate / potassium carbonate is selected as the ligand. The stabilizer refers to tetrabutylammonium hydrogen sulfate or acetic acid.

[0048] Step (3) in the above reaction route is as follows: 1,2,3-triazole nucleophosphonate III is dissolved in an organic solvent, and the ester group is acid-hydrolyzed under nitrogen protection. After the reaction is completed, the target compound 1 is obtained by reversed-phase column chromatography. The reagent in the acid hydrolysis reaction refers to one of trimethyliodosilane, trimethylbromosilane, trimethyliodosilane / 2,4,6-coridin, trimethylbromosilane / 2,4,6-coridin, trimethyliodosilane / 2,6-rutidin, or trimethylbromosilane / 2,6-rutidin. The organic solvent refers to one of acetonitrile, tetrahydrofuran, or dichloromethane. The ester group refers to ethyl ester or isopropyl ester. In the reversed-phase column chromatography purification process, a mixture of methanol and water in a ratio of 1:4 is used as the eluent.

[0049] The synthesis of compound 1a-1v is as follows:

[0050] Synthetic compound 1a

[0051] Under argon protection, compound I (5.0 g, 11.6 mmol) was dissolved in anhydrous dichloromethane. Azide-trimethylsilane (3.7 mL, 34.9 mmol) was added to the system, and tin tetrachloride (1.4 mL, 12.8 mmol) was added dropwise under ice bath conditions. The reaction was then brought to room temperature for 6 hours until the reactants were completely reacted. Saturated sodium bicarbonate solution was slowly added to the system until no more bubbles were produced. The mixture was transferred to a separatory funnel, and the aqueous phase was extracted three times with dichloromethane. The combined dichloromethane layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound II (4.5 g, 94.1%).

[0052] Compound II (4.5 g, 10.9 mmol) was added to a solution of water and tert-butanol (1:1, 200 mL), followed by the addition of potassium carbonate (1.5 g, 10.9 mmol), sodium ascorbate (6.5 g, 32.7 mmol), copper sulfate pentahydrate (5.5 g, 21.8 mmol), tetrabutylammonium hydrogen sulfate (3.7 g, 10.9 mmol), and phenylacetylene (2.4 mL, 21.8 mmol). After reacting at room temperature for 8 hours, the reaction was quenched with brine and ammonia. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration, compound III (3.9 g, 87%) was purified by column chromatography.

[0053] Under argon protection, compound III (3.9 g, 9.5 mmol) was dissolved in dry acetonitrile (100 mL). 2,6-Dimethylpyridine (8.9 mL, 76.0 mmol) and trimethylbromosilane (10.1 mL, 76.0 mmol) were added sequentially in an ice bath. The reaction was carried out at 0 °C for 1 hour. The reaction was monitored by TLC until complete. The reaction was quenched with water, and the mixture was extracted three times with ethyl acetate. The aqueous phases were combined, concentrated under reduced pressure, and the crude product 1a was purified by reversed-phase column chromatography (methanol:water = 1:4). Methanol was removed under reduced pressure, and the aqueous phase was freeze-dried to obtain a colorless oil 1a (2.8 g, 82%). 1 H NMR (400 MHz, CDCl3) δ 8.41 (s,1H), 7.77-7.72 (m, 2H), 7.47-7.72 (m, 2H), 7.40-7.35 (m, 1H), 6.07 (d, J =2.0 Hz, 1H), 4.72-4.69 (m, 1H), 4.64-4.57 (m, 1H), 4.02-3.97 (m, 1H), 3.77-3.61 (m, 2H), 1.44 (d, J = 6.4 Hz, 3H) ppm.

[0054] Synthetic compound 1b

[0055] Using the same method as compound 1a (replacing phenylacetylene with 2-methylphenylacetylene), a colorless oily substance 1b was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(s, 1H), 7.55-7.50 (m, 1H), 7.34-7.25 (m,1H), 6.09 (d, J = 2.4 Hz, 1H), 4.77-4.75 (m, 1H), 4.67-4.57 (m, 1H), 4.07-4.03 (m, 1H), 3.70-3.60 (m, 2H), 2.3 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H) ppm.

[0056] Synthetic compound 1c

[0057] Using the same method as compound 1a (replacing phenylacetylene with 3-methylphenylacetylene), a colorless oily substance 1c was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.54-7.47 (m, 2H), 7.34-7.26 (m,1H), 7.19-7.13 (m, 1H), 6.03 (d, J = 2.0 Hz, 1H), 4.74-4.69 (m, 1H), 4.65-4.56 (m, 1H), 4.09-4.01 (m, 1H), 3.75-3.58 (m, 2H), 2.30 (s, 3H), 1.42 (d, J= 6.4 Hz, 3H) ppm.

[0058] Synthetic compound 1d

[0059] Using the same method as compound 1a (replacing phenylacetylene with 4-ethylphenylacetylene), a colorless oily substance 1d was obtained. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.64-7.58 (m, 2H), 7.25-7.20 (m,2H), 6.03 (d, J = 2.0 Hz, 1H), 4.72-4.69 (m, 1H), 4.63-4.56 (m, 1H), 4.04-3.99 (m, 1H), 3.77-3.62 (m, 2H), 2.61-2.51 (m, 2H), 1.42 (d, J = 6.4 Hz, 3H), 1.13 (t, J = 7.6 Hz, 3H) ppm.

[0060] Synthetic compound 1e

[0061] Using the same method as compound 1a (replacing phenylacetylene with 4-propylphenylacetylene), a colorless oily substance 1e was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.69-7.63 (m, 2H), 7.28-7.20 (m,2H), 6.06 (d, J = 2.0 Hz, 1H), 4.76-4.69 (m, 1H), 4.65-4.55 (m, 1H), 4.07-3.97 (m, 1H), 3.76-3.62 (m, 2H), 2.57-2.46 (m, 2H), 1.60-1.48 (m, 2H), 1.42(d, J = 6.8 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H) ppm.

[0062] Synthetic compound 1f

[0063] Using the same method as compound 1a (replacing phenylacetylene with 2-chlorophenylacetylene), a colorless oily substance 1f was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.73-7.67 (m, 1H), 7.49-7.43 (m, 1H), 7.37-7.30 (m, 1H), 6.08 (d, J = 2.0 Hz, 1H), 4.78-4.76 (m, 1H), 4.67-4.58 (m,1H), 4.12-4.04 (m, 1H), 3.74-3.60 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H) ppm.

[0064] 1g of synthesized compound

[0065] Using the same method as compound 1a (replacing phenylacetylene with 3-chlorophenylacetylene), 1 g of a colorless oil was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.63-7.54 (m, 2H), 7.36-7.25 (m, 2H), 6.10 (d, J = 2.0 Hz, 1H), 4.77-4.73 (m, 1H), 4.69-4.62 (m, 1H), 4.08-4.04 (m,1H), 3.81-3.65 (m, 2H), 1.48 (d, J = 6.4 Hz, 3H) ppm.

[0066] Synthesize compound 1h

[0067] Using the same method as compound 1a (replacing phenylacetylene with 4-chlorophenylacetylene), a colorless oily substance 1h was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.61-7.53 (m, 2H), 7.35-7.25 (m, 2H), 6.06 (d, J = 2.0 Hz, 1H), 4.72-4.66 (m, 1H), 4.65-4.53 (m, 1H), 4.04-3.96 (m,1H), 3.77-3.61 (m, 2H), 1.42 (d, J = 6.4 Hz, 3H) ppm.

[0068] Synthetic compound 1i

[0069] Using the same method as compound 1a (replacing phenylacetylene with 4-bromophenylacetylene), a colorless oily substance 1i was obtained. 1 H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.04-7.95 (m, 2H), 7.58-7.53 (m, 2H), 5.90-5.85 (m, 1H), 4.68-4.62 (m, 1H), 4.36-4.30 (m, 1H), 3.86-3.81 (m, 1H), 3.61-3.51 (m, 2H), 1.24 (d, J = 6.0 Hz, 3H) ppm.

[0070] Synthetic compound 1j

[0071] Using the same method as compound 1a (replacing phenylacetylene with 3-fluorophenylacetylene), a colorless oily substance 1j was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.53-7.49 (m, 1H), 7.45-7.36 (m, 2H), 7.10-7.36 (m, 1H), 6.08 (d, J = 2.0 Hz, 1H), 4.72-4.69 (m, 1H), 4.64-4.57 (m,1H), 4.03-3.98 (m, 1H), 3.76-3.61 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H) ppm.

[0072] Synthetic compound 1k

[0073] Using the same method as compound 1a (replacing phenylacetylene with 3-nitrophenylacetylene), a colorless oily substance 1k was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.24-8.20 (m, 1H), 7.98-7.92 (m,1H), 7.90-7.85 (m, 1H), 7.50-7.43 (m, 1H), 6.05 (d, J = 2.0 Hz, 1H), 4.70-4.67 (m, 1H), 4.66-4.58 (m, 1H), 4.04-3.99 (m, 1H), 3.77-3.60 (m, 2H), 1.45(d, J = 6.4 Hz, 3H) ppm.

[0074] Synthetic compound 1l

[0075] Using the same method as compound 1a (replacing phenylacetylene with 4-methoxyphenylacetylene), a colorless oily substance 1l was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.48-7.43 (m, 2H), 6.81-6.75 (m,2H), 5.88 (d, J = 2.0 Hz, 1H), 4.56-4.52 (m, 1H), 3.88-3.84 (m, 1H), 3.62 (s,3H), 3.60-3.46 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H) ppm.

[0076] Synthetic compound 1m

[0077] Using the same method as compound 1a (replacing phenylacetylene with 4-cyanophenylacetylene), a colorless oily substance 1m was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.75-7.71 (m, 2H), 7.65-7.61 (m,2H), 6.10 (d, J = 1.5 Hz, 1H), 4.71-4.69 (m, 1H), 4.66-4.60 (m, 1H), 4.03-3.97 (m, 1H), 3.79-3.63 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H) ppm.

[0078] Synthetic compound 1n

[0079] Using the same method as compound 1a (replacing phenylacetylene with 3,4-dimethoxyphenylacetylene), a colorless oily substance 1n was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.16-7.10 (m, 1H), 7.09-7.05(m, 1H), 6.83-6.78 (m, 1H), 6.01 (d, J = 2.0 Hz, 1H), 4.71-4.67 (m, 1H), 4.62-4.55 (m, 1H), 4.04-3.98 (m, 1H), 3.78-3.64 (m, 8H), 1.42 (d, J = 6.4 Hz, 3H) ppm.

[0080] Synthetic compound 1o

[0081] Using the same method as compound 1a (replacing phenylacetylene with 2-alkynylpyridine), a colorless oily substance 1o was obtained. 1 H NMR (400 MHz, CDCl3) δ 9.05-9.02 (m, 1H), 8.71 (s, 1H), 8.66-8.62 (m, 1H), 8.60-8.52 (m, 1H), 7.88-7.83 (m, 1H), 6.16 (d, J = 2.0 Hz, 1H), 4.70-4.68 (m,1H), 4.64-4.59 (m, 1H), 3.95-3.93 (m, 1H), 3.76-3.64 (m, 2H), 2.61-2.51 (m,2H), 1.44 (d, J = 6.4 Hz, 3H) ppm.

[0082] Synthetic compound 1p

[0083] Using the same method as compound 1a (replacing phenylacetylene with 1-ynylnaphthalene), a colorless oily substance 1p was obtained. 1 HNMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.92-7.85 (m, 1H), 7.78-7.72 (m, 1H), 7.46-7.33 (m, 4H), 6.02 (d, J = 2.0 Hz, 1H), 4.76-4.73 (m, 1H), 4.63-4.55 (m,1H), 4.10-4.02 (m, 1H), 3.72-3.59 (m, 2H), 2.61-2.51 (m, 2H), 1.39 (d, J =6.4 Hz, 3H) ppm.

[0084] Synthetic compound 1q

[0085] Using the same method as compound 1a (replacing phenylacetylene with 2-ynylthiophene), a colorless oily substance 1q was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.48-7.43 (m, 2H), 7.16-7.11 (m, 1H), 6.10 (d, J = 2.0 Hz, 1H), 4.74-4.71 (m, 1H), 4.65-4.59 (m, 1H), 4.02-3.98 (m,1H), 3.76-3.66 (m, 2H), 1.44 (d, J = 6.4 Hz, 3H) ppm.

[0086] Synthetic compound 1r

[0087] Using the same method as compound 1a (replacing phenylacetylene with 3-ynylthiophene), a colorless oily substance 1r was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.75-7.72 (m, 1H), 7.51-7.47 (m, 1H), 7.46-7.42 (m, 1H), 6.07 (d, J = 2.0 Hz, 1H), 4.71-4.68 (m, 1H), 4.64-4.57 (m,1H), 4.01-3.97 (m, 1H), 3.77-3.62 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H) ppm.

[0088] Synthetic compound 1s

[0089] Using the same method as compound 1a (replacing phenylacetylene with phenylpropynyl sulfide), a colorless oily substance 1s was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(s, 1H), 7.41-7.36 (m, 2H), 7.32-7.27 (m,2H), 7.18-7.13 (m, 1H), 5.80 (d, J = 2.4 Hz, 1H), 4.48-4.43 (m, 1H), 4.34-4.30 (m, 1H), 4.28-4.20 (m, 2H), 4.03-3.95 (m, 1H), 3.58-3.44 (m, 1H), 1.21(d, J = 6.4 Hz, 3H) ppm.

[0090] Synthesize 1t of compound

[0091] Using the same method as compound 1a (replacing phenylacetylene with cyclohexylacetylene), a colorless oily substance 1t was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 6.07 (d, J = 2.8 Hz, 1H), 4.75-4.73(m, 1H), 4.67-4.60 (m, 1H), 4.13-4.06 (m, 1H), 3.77-3.67 (m, 2H), 2.82-2.74 (m, 1H), 2.04-1.93 (m, 2H), 1.83-1.75 (m, 2H), 1.48-1.24 (m, 9H) ppm.

[0092] Synthetic compound 1u

[0093] Using the same method as compound 1a (replacing phenylacetylene with methylbutynyl ether), a colorless oily substance 1u was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 6.16 (d, J = 2.0 Hz, 1H), 4.75-4.74(m, 1H), 4.67-4.63 (m, 3H), 4.05-4.01 (m, 1H), 3.72-3.65 (m, 2H), 3.45-3.39 (m, 4H), 1.45 (d, J = 6.4 Hz, 3H) ppm.

[0094] Synthetic compound 1v

[0095] Using the same method as compound 1a (replacing phenylacetylene with 1-heptyne), a colorless oily substance 1v was obtained. 1 HNMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 6.10 (d, J = 2.8 Hz, 1H), 4.75-4.73 (m,1H), 4.68-4.62 (m, 1H), 4.10-4.06 (m, 1H), 3.80-3.66 (m, 2H), 2.76-2.70 (m,2H), 1.72-1.64 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.36-1.26 (m, 4H), 0.88 (t,J = 7.2 Hz, 3H) ppm.

[0096] The in vitro anti-prostate cancer cell activity of compound 1a-1v prepared in this invention was then tested:

[0097] Experimental materials: 1,2,3-triazole-α-L-threophosphonic acid nucleoside analog, prepared by the method described in the above examples; human prostate cancer cells PC-3 were selected from authorized surrogate cells of the Chinese Academy of Sciences Type Culture Collection / Stem Cell Bank catalog number SCSP-532.

[0098] Experimental Results: The antitumor activity of the compounds of this invention was preliminarily screened using the MTT assay. Compound 1r showed strong inhibitory activity against the proliferation of human prostate cancer cells PC-3, with different concentrations and treatment times showing significant inhibitory effects. 50 (uM) is shown in Table 1:

[0099] Time(h) 24 48 72 PC-3 50.688±0.020 25.937±0.018 1.893±0.044

[0100] Other compounds inhibited the proliferation of human prostate cancer cells PC-3 for 72 hours (IC50). 50 (uM) See Table 2:

[0101] 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k PC-3 ＞8 ＞8 ＞8 ＞8 ＞8 ＞8 ＞8 ＞8 ＞8 ＞8 ＞8 1l 1m 1n 1o 1p 1q 1s 1t 1u 1v PC-3 ＞8 ＞8 ＞8 ＞8 6.282±0.04 ＞8 ＞8 ＞8 ＞8 ＞8

[0102] Therefore, it can be concluded that 1,2,3-triazole-α-L-threophosphonic acid nucleoside analogs can be used as active ingredients to prepare drugs against prostate cancer cells or as intermediates for the preparation of antitumor drugs.

[0103] The description of the various embodiments above tends to emphasize the differences between the various embodiments. The similarities or similarities can be referred to each other. For the sake of brevity, this application will not repeat them.

[0104] Note that the above description is merely a preferred embodiment of the present invention and the technical principles employed. Those skilled in the art will understand that the present invention is not limited to the specific embodiments described herein, and various obvious changes, readjustments, and substitutions can be made without departing from the scope of protection of the present invention. Therefore, although the present invention has been described in detail through the above embodiments, the present invention is not limited to the above embodiments, and may include many other equivalent embodiments without departing from the concept of the present invention, the scope of which is determined by the scope of the appended claims.

Claims

1. An antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside compound, characterized in that: It has the chemical structure of formula (1): Among them, substituent R 1 It refers to one of the following groups: aryl, heteroaryl, arylthio, and aliphatic group.

2. The antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside compound according to claim 1, characterized in that: The aryl group is phenyl, 2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-fluorophenyl, 3-nitrophenyl, 4-methoxyphenyl, 4-cyanophenyl, 3,4-dimethoxyphenyl, or 2-naphthyl; The heteroaryl group is 2-pyridyl, 2-thienyl, or 3-thienyl; The arylthyl group is an anisole sulfide group; The aliphatic groups are cyclohexyl, methoxyethyl, and n-pentyl.

3. The antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside compound according to claim 2, characterized in that: The 1,2,3-triazole-α-L-threophosphonic acid nucleoside compounds have the following 22 structures, specifically numbered 1a-1v: 。 4. The method for preparing the antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside analog according to any one of claims 1-3, characterized in that... Prepared using the following reaction route: Among them, substituent R 1 It refers to one of the following groups: phenyl, non-phenyl aryl, heteroaryl, arylthio, and aliphatic group.

5. The method for preparing the antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside analog according to claim 4, characterized in that: Step (1) is as follows: Compound I is dissolved in an organic solvent at room temperature and reacted with azidetrimethylsilane in a Lewis acid via a nucleophilic substitution reaction to obtain compound II; Step (2) is as follows: at room temperature, intermediate II is dissolved in water and tert-butanol solvent, and a Lewis acid, a ligand, a stabilizer, and a terminal alkyne analog are added in sequence. After the reaction is completed, compound III is obtained by column chromatography. Step (3) is as follows: 1,2,3-triazole nucleophosphonate III is dissolved in an organic solvent, and the ester group is acidified under nitrogen protection. After the reaction is completed, the target compound 1 is obtained by reversed-phase column chromatography.

6. The method for preparing the antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside analog according to claim 5, characterized in that: In step (1), a Lewis acid refers to tin tetrachloride or trimethylsilyl trifluoromethanesulfonate; an organic solvent refers to dichloromethane, 1,2-dichloroethane, acetonitrile, or tetrahydrofuran.

7. The method for preparing the antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside analog according to claim 5, characterized in that: In step (2), a Lewis acid refers to cuprous iodide, cuprous bromide, copper sulfate, or copper sulfate pentahydrate; a ligand refers to one or two of sodium ascorbate, potassium carbonate, triethylamine, or diisopropylethylamine; and a stabilizer refers to tetrabutylammonium hydrogen sulfate or acetic acid.

8. The method for preparing the antitumor 1,2,3-triazole-α-L-threophosphonic acid nucleoside analog according to claim 5, characterized in that: In step (3), the reagent in the acid hydrolysis reaction refers to one of trimethyliodosilane, trimethylbromosilane, trimethyliodosilane / 2,4,6-coridine, trimethylbromosilane / 2,4,6-coridine, trimethyliodosilane / 2,6-rutidine, and trimethylbromosilane / 2,6-rutidine; the organic solvent refers to one of acetonitrile, tetrahydrofuran, and dichloromethane; the ester group refers to ethyl ester or isopropyl ester; and the methanol:water = 1:4 mixture is used as the eluent in the reversed-phase column chromatography purification process.

9. The use of the antitumor 1,2,3-triazole-α-L-threophosphonate nucleoside analog according to any one of claims 1-3 in the preparation of a drug, characterized in that: Using 1,2,3-triazole-α-L-threophosphonate nucleoside analogue as the active ingredient, it can be used to prepare anti-prostate cancer cell drugs or as an intermediate in the preparation of anti-tumor drugs.

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