Carbonyl glycoside compound, preparation method thereof and application in antitumor drugs

Abstract

The present invention discloses a carbon glycoside compound, a preparation method thereof and an application in anti-tumor drugs, and belongs to the field of carbohydrate drug synthesis. The structure of the carbon glycoside compound is shown in general formula (I) or (II). The present invention uses fully acetylated rhamnose, glucose, mannose and the like as raw materials, and can efficiently obtain unprotected rhamnose, glucose, mannose and other free radical precursors with excellent reactivity and stability by preparing them into benzyl glucosinolates and removing the ester group in two steps. Under the conditions of visible light, photocatalyst, phosphine reagent, alkali and solvent, they undergo Giese reaction with olefin receptors connected to different drugs, and can directly obtain α-carbon glycosides with novel structure and single configuration. The carbon glycoside compound showed good activity in the inhibitory activity assay on human ovarian teratoma cells (PA-1) and digestive tract tumor cells (KYSE-510), and is expected to be further developed into an anti-tumor drug.

Description

Technical Field

[0001] The invention belongs to the field of carbohydrate drug synthesis, and relates to a type of carbonyl glycoside compound, a preparation method thereof, and application thereof in anti-tumor drugs. Background Art

[0002] Carbonyl glycosides are a class of compounds formed by connecting sugars or sugar derivatives to non-sugar components through carbon-carbon (CC) bonds via the anomeric carbon atom. This type of compound is widely distributed in the plant kingdom and has important research value and application prospects in the fields of biochemistry and medicinal chemistry. From the perspective of medicinal chemistry, C-glycosylation modification is an effective structural modification method that can significantly improve the pharmacokinetic properties of compounds, including enhancing water solubility and improving membrane permeability. More importantly, carbonyl glycosides show excellent stability to the acidic environment and enzymatic hydrolysis in the body. This feature makes it an alternative to traditional methods in drug development. O - Trends in glycoside drugs. For example, glycoside-modified paclitaxel retains the parent drug's efficacy and improves solubility, but the susceptibility of the glycoside bond to enzymatic hydrolysis limits its application. Therefore, in modern drug development, introducing glycoside structures into bioactive molecules via C-C bonds has become a key strategy for improving drug therapeutic efficacy. This strategy has been successfully applied in a variety of drugs, including SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) for the treatment of diabetes, as well as analogs of the immunomodulator KRN7000, and other glycosides.

[0003]

[0004] In recent years, researchers have developed a variety of free radical reactions using photoredox catalysis strategies, stereoselectively completing the synthesis of various types of carbonyl glycosides, including alkyl, aryl, alkenyl, and alkynyl groups. In addition to traditional brominated glycosides as glycosyl free radical precursors, Professor Niu Dawen used glycosyl sulfoxides as free radical precursors (Niu, D et al. Angew. Chem. Int. Ed. 2022, 61 , e202204922.) and glycosyl allyl sulfone (Niu, D et al. Angew. Chem. Int. Ed. 2023, 62 ,e202309887.) completed the synthesis of carbonyl glycoside compounds under photoredox catalysis. Subsequently, Professor Xu Minyu (Koh, Met al. J. Nature 2024, 631 , 319–328.), Professor Zhang Xiaheng (Zhang, X. H et al. Angew. Chem. Int. Ed. 2024, 63 , e202412436.), Professor Sun Zhankui (Sun, Z. K et al.Sci. China Chem. 2023, 66, 1788−1794.) and Professor Li Ming and Professor Liu Xuewei (Li, M.; Liu, X. W et al. ACS Catal . 2024, 14 , 17727−17738.) and others have successively used 4-tetrafluoropyridine glucosinolate as a glycosyl radical precursor, reacting it with electron-deficient alkenes or enol silyl ethers under visible light irradiation to prepare alkyl glucosides and glycosyl ketone glucosides. These thioglycosyl radical precursors are also suitable for the synthesis of hydroxyl-unprotected glucosides, including glucosides peptides and proteins. In addition, Professor Zhu Feng (Zhu, F et al.) Angew. Chem. Int. Ed . 2025,e202504504.), Professor Shu Xingzhong (Shu, XZ et al. J. Am. Chem. Soc . 2024, 146 , 32269–32275.) and Professor Wang Liming (Wang, L et al. Org. Lett . 2025, 27 , 3994–3999.) Recently, free radical reactions of glycosyl benzoate, glycosyl hemiacetal, and glycosyl xanthate donors have been developed to complete the synthesis of alkyl and aryl carbonyl glycosides.

[0005]

[0006] Although some progress has been made in the synthesis of carbonyl glycosides through free radicals, key challenges remain in drug development and application. In particular, the development of high-performance glycoside precursors is crucial for the screening of clinically valuable glycosides for antiviral and antitumor applications. These precursors must simultaneously meet the following key properties: 1) high efficiency and affordability, suitable for industrial production; 2) excellent reactivity and stability; 3) the development of glycoside precursors with few or no protecting groups to directly form stable carbonyl glycoside drugs; and 4) good regio- and stereoselectivity. Summary of the Invention

[0007] In view of the above problems, the purpose of the present invention is to provide a class of carbon glycoside compounds and their preparation methods and applications, wherein the carbon glycoside compounds have good high water solubility and anti-tumor activity.

[0008] The first object of the present invention is to provide a class of carbonyl glycoside compounds with high water solubility and good anti-tumor activity, the structure of which is shown in general formula (I) or (II):

[0009] .

[0010] The curved saccharide moiety in the general formula (I) or (II) represents the general structure of a five-membered ring furanose or a six-membered ring pyranose.

[0011] Furthermore, the carbon glycoside compound is any of the following structures:

[0012] .

[0013] A second object of the present invention is to provide a method for preparing the aforementioned carbon glycoside compound (I) or (II) by photocatalytic free radical desulfurization, wherein the raw materials are inexpensive, the glycosyl free radical precursor has excellent reactivity and stability, and the product maintains good regio- and stereoselectivity. The glycosyl free radical precursor is a 2-substituted and unprotected benzyl glucosinolate having the general formula (V). The benzyl glucosinolate compound (V) undergoes a Giese reaction with an olefin receptor (VI) linked to an anticancer drug under the conditions of visible light, a photocatalyst, a phosphine reagent, a base, and a solvent, directly synthesizing a series of activated carbon glycosides with high stereoselectivity and high water solubility, thereby achieving ideal cancer cell inhibitory activity.

[0014] To achieve the above object, the reaction of the preparation method of the present invention is as follows:

[0015] ;

[0016] in,

[0017] R 1 :H or benzyl (Bn), substituted benzyl, 1-naphthylmethyl (Nap), alkyl or acetyl (Ac), benzoyl (Bz), silicon, benzaldehyde dimethyl acetal or isopropylidene acetal and other acetal protecting groups, R in the same molecule 1 can be the same or different groups, preferably: Ac;

[0018] R 2 : is a halogen atom Cl, Br, I, methoxycarbonyl (COOMe), ethoxycarbonyl (COOEt), aldehyde group (CHO), hydroxymethyl group, preferably COOMe;

[0019] R 3 : is a halogen atom Cl, Br, I, carboxyl (COOH), aldehyde (CHO), preferably COOH;

[0020] Furthermore, the compound of formula (V) is selected from any of the following structures:

[0021] .

[0022] R 4 : Select from any of the following structures:

[0023] .

[0024] Specifically, the preparation method of the compounds represented by general formula (I) and (II) comprises the following steps:

[0025] Step 1: First, react the compound of formula (III) with the compound of formula (VII) under acidic conditions at 60°C–100°C for 10–30 minutes, then cool to room temperature, add the compound of formula (VIII) and a base, and react at 20°C–40°C for 4–8 hours to obtain the target compound of formula (IV);

[0026] .

[0027] The acid in the acidic conditions is one of boron trifluoride etherate (BF3·OEt2), HClO4, trimethylsilyl trifluoromethanesulfonate (TMSOTf), and TMSClO4; preferably, BF3·OEt2; the base is one of triethylamine (Et3N), sodium bicarbonate, and sodium carbonate; preferably, Et3N; the molar ratio of the compound of formula (III), the compound of formula (VII), and the compound of formula (VIII) to the base is 1.0:1.0:1.0:1.0:1.0:~1.0:3.0:3.0:3.0:3.0; the solvent is: N, N - one of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dioxane, 1, 2-dichloroethane or tetrahydrofuran, preferably acetonitrile; the concentration of the compound of formula (III) in the solvent is: 0.1-0.5 mmol / mL;

[0028] Step 2: removing the acetyl group from the compound of formula (IV) under alkaline conditions and hydrolyzing the ester group to obtain the target compound of formula (V);

[0029] .

[0030] The base in the alkaline conditions is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, and sodium methoxide; preferably, lithium hydroxide; the molar ratio of the compound of formula (IV) to the base is 1.0:1.0 to 1.0:20.0; the solvent is one or more of tetrahydrofuran, water, acetonitrile, dioxane, and acetone; preferably, a mixed solvent of tetrahydrofuran and water in a volume ratio of 1:1; the concentration of the compound of formula (IV) in the solvent is 0.05 to 0.5 mmol / mL;

[0031] Step 3: Dissolve the compound of formula (V), the compound of formula (VI), a photocatalyst, a phosphine reagent and a base in a solvent, and react at 20°C–45°C for 10–36 hours under visible light to obtain the target compound of formula (I) or (II):

[0032] .

[0033] The photocatalyst is: Ir[dFCF3ppy]2(bpy)PF6, [Ir(dFCF3ppy)2dtbbpy]PF6, [lr(ppy)2(dtbbpy)]BF4, 4CzIPN, [Ru(bpy)3](PF6)2, fac -[Ir(ppy)3], one of Hantzsch ester and [Ru(bpy)3]Cl2; preferably: Ir[dF(CF3)ppy]2(dtbbpy)PF6; the phosphine reagent is: triphenylphosphine, Ph2OEtP, Ph2MeP, Bu3P, bis(diphenylphosphino)methane, tri(2,4,6-trimethoxyphenyl)phosphine, tri(4-chlorophenyl)phosphine, tri(pentafluorophenyl)phosphine, tri(4-fluorophenyl)phosphine, tri(4-bromophenyl)phosphine and diphenyl(2-pyridyl)phosphine; preferably: triphenylphosphine; the base is: one of K3PO4, KH2PO4, NaHCO3, 2,6-lutidine, K2CO3, Na2HPO4, Cs2CO3, Et3N; preferably: NaHCO3; the wavelength of the visible light source is: 365 nm, 390 nm, 427 nm, 456 nm or broad spectrum; preferably: 427 nm; the molar ratio of the compound of formula (V), the compound of formula (VI), the photocatalyst, the phosphine reagent and the base is: 1.0:1.0:0.01:1.0:1.0~1.0:5.0:0.1:5.0:5.0; the solvent is: one of DMF, DMSO, acetonitrile, dioxane, 1,2-dichloroethane or tetrahydrofuran; preferably: DMF; the concentration of the compound of formula (V) in the solvent is: 0.005~0.10 mmol / mL.

[0034] A third object of the present invention is to provide the use of the aforementioned carbonyl glycoside compounds in the preparation of anti-tumor drugs. The aforementioned carbonyl glycoside compounds (I)-1, (I)-2, (I)-3, and (I)-4, which exhibit anti-tumor activity, were evaluated for their inhibitory activity against human ovarian teratoma cells (PA-1) and digestive tract tumor cells (KYSE-510). The results revealed that these compounds exhibited significant inhibitory effects against both types of tumor cells and are therefore useful in the preparation of drugs for the treatment of human ovarian teratoma or digestive tract tumors.

[0035] Beneficial effects of the present invention:

[0036] The present invention uses cheap and readily available fully acetylated rhamnose, glucose, mannose, and the like as raw materials. Through a two-step reaction of preparing benzyl glucosinolates and removing the ester group, unprotected rhamnose, glucose, mannose, and other free radical precursors with excellent reactivity and stability can be efficiently obtained. These free radical precursors undergo a Giese reaction with olefin acceptors linked to various drugs, such as paclitaxel, to directly obtain α-carbonyl glycosides with a novel structure and a single configuration in a yield exceeding 50%. The solubility of the prepared carbonyl glycoside compounds (I)-1, (I)-2, (I)-3, and (I)-4 is significantly improved compared to paclitaxel, being 7.2 times, 10.2 times, 3.6 times, and 12 times, respectively. In an assay of inhibitory activity against human ovarian teratoma (PA-1) cell lines, the activities (IC 50 16.200 nm, 18.860 nm, 19.990 nm, 19.830 nm) and paclitaxel (IC 50 8.996 nm); in the inhibitory activity assay against digestive tract tumor cells (KYSE-510), the activities of (I)-1, (I)-2, (I)-3 and (I)-4 (IC 50 4.848 nm, 6.880 nm, 4.087 nm, 2.584 nm) and also compared with paclitaxel (IC 50 0.781 nm) and is expected to be further developed into an anti-tumor drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The IC values ​​of four carbonyl glycoside compounds for inhibiting PA-1 in vitro 50 Evaluation curve. DETAILED DESCRIPTION

[0038] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the specific examples are only used to illustrate the present invention and should not and will not limit the scope of protection claimed in the claims of the present invention.

[0039] Example 1:

[0040] Step 1:

[0041]

[0042] Under argon, compound (III)-1 (680 mg, 1.73 mmol, 1.0 equiv.) and thiourea (264 mg, 3.45 mmol, 2.0 equiv.) were dissolved in acetonitrile (9 mL). BF3·OEt2 (900 μL, 3.46 mmol, 2.0 equiv.) was added at room temperature, and the temperature was gradually increased to 80°C with stirring for 15 minutes. TLC monitoring indicated complete reaction of the starting materials. The reaction solution was cooled to room temperature, and Et3N (480 μL, 3.45 mmol, 2.0 equiv.) and methyl 2-bromomethylbenzoate (790 mg, 3.45 mmol, 2.0 equiv.) were added. The reaction was continued at room temperature for 5 hours. TLC monitoring showed that the reaction of the raw material was complete. The reaction solution was concentrated under reduced pressure, diluted with DCM, and washed with 1 M HCl solution and saturated NaHCO3 solution in sequence. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 3:1) to obtain the target compound (IV)-1 (810 mg, 1.58 mmol, 91%).

[0043] The analysis data are as follows: = +40.54 ( c 0.9, CHCl3);

[0044] 1 H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 7.7, 1.2 Hz, 1H), 7.46–7.43(m, 1H), 7.38–7.30 (m, 2H), 5.34–5.28 (m, 2H), 5.24 (dd, J = 10.0, 3.3 Hz,1H), 5.15 (d, J = 1.1 Hz, 1H), 4.39–4.27 (m, 3H), 4.05 (d, J = 13.2 Hz, 1H), 3.98–3.94 (m, 1H), 3.92 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.96 (s, 3H).

[0045] 13 C NMR (101 MHz, CDCl3) δ.2, 52.2, 33.4, 20.9, 20.8, 20.7, 20.6.

[0046] RMS (ESI) m / z : [M+Na] + calcd for C 23 H 28 O 11 SNa 535.1245; found 535.1237.

[0047] Step 2:

[0048]

[0049] Under argon, compound (IV)-1 (260 mg, 0.50 mmol, 1.0 equiv.) was dissolved in THF / H₂O (v / v 1 / 1, 2.5 mL) and lithium hydroxide (120 mg, 5.01 mmol, 10.0 equiv.) was added. The mixture was allowed to react at room temperature for 5 hours. TLC monitoring indicated that the reaction was complete. The reaction was quenched by addition of a cation exchange resin, filtered, and the filtrate was concentrated under reduced pressure without purification to afford the target compound (V)-1 (153 mg, 0.46 mmol, 93%).

[0050] The analysis data are as follows: = +39.67 ( c 0.3, MeOH);

[0051] 1 H NMR (400 MHz, D2O) δ 7.46 (d, J = 6.9 Hz, 1H), 7.42–7.27 (m, 3H), 5.13 (s, 1H), 4.14–3.99 (m, 2H), 3.95–3.90 (m, 2H), 3.80–3.71 (m, 3H), 3.65(t, J = 9.7 Hz, 1H).

[0052] 13 C NMR (101 MHz, D2O) δ177.8, 139.1, 134.8, 130.3, 128.8, 127.7,127.3, 84.3, 73.0, 71.6, 71.2, 67.1, 60.7, 33.8, 32.6.

[0053] RMS (ESI) m / z : [MH] - calcd for C 14 H 17 O7S 329.0700; found 329.0696.

[0054] Step 3:

[0055]

[0056] Under argon protection, compound (V)-1 (34 mg, 0.10 mmol, 1.0 equiv.), compound (VI)-1 (210 mg, 0.2 mmol, 2.0 equiv.), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4 mg, 0.004mmol, 0.04 equiv.), NaHCO3 (12 mg, 0.15 mmol, 1.5 equiv.) and triphenylphosphine (53 mg, 0.2mmol, 2.0 equiv.) were dissolved in dry DMF (2.0 mL) and placed under a light source with a wavelength of 427 nm for reaction at room temperature for 20 hours. TLC monitoring showed that the reaction of the raw material was complete. The reaction solution was quenched with water and concentrated in vacuo. It was then purified by column chromatography (DCM:MeOH = 9:1) to obtain the target compound (I)-1 (67 mg, 55.1 μmol, 55%).

[0057] The analysis data are as follows: = -25.90 ( c = 0.1, MeOH);

[0058] 1 H NMR (400 MHz, CD3OD) δ8.13–8.09 (m, 2H), 7.80–7.76 (m, 2H), 7.67–7.65 (m, 1H), 7.60–7.55 (m, 4H), 7.52–7.50 (m, 1H), 7.49–7.45 (m, 2H), 7.46–7.41 (m, 4H), 7.35–7.30 (m, 2H), 7.27 (t, J = 7.3 Hz, 1H), 6.44 (s, 1H), 6.06(t, J = 8.6 Hz, 1H), 5.83 (d, J = 6.4 Hz, 1H), 5.64 (d, J = 7.2 Hz, 1H), 5.49(d, J = 6.6 Hz, 1H), 5.23–5.10 (m, 2H), 5.05–4.99 (m, 1H), 4.35 (dd, J =10.9, 6.6 Hz, 1H), 4.21–4.17 (m, 2H), 3.98–3.95 (m, 1H), 3.92 (t, J = 7.1 Hz,2H), 3.85–3.80 (m, 2H), 3.75–3.71 (m, 1H), 3.68–3.66 (m, 2H), 2.50–2.45 (m,3H), 2.41 (s, 3H), 2.18–2.15 (m, 4H), 2.09–1.98 (m, 2H), 1.88 (s, 3H), 1.86–1.77 (m, 2H), 1.66 (s, 3H), 1.14 (s, 3H), 1.13 (s, 3H)。

[0059] 13 C NMR NMR (151 MHz, CD3OD) δ.3, 79.0,78.5, 77.6, 77.5, 76.8, 76.2, 73.2, 72.9, 72.8, 72.3, 71.3, 72.7, 73.1, 73.7, 73.9, 73.8, 73.9, 73.4, 73.6, 73.7, 73.8, 73.9, 73.8, 73.9, 73.6, 73.8, 73.9, 69.5, 62.9, 59.2,55.3, 47.9, 44.6, 37.6, 36.4, 34.2, 26.9, 25.8, 23.2, 22.4, 20.8, 14.9, 10.5.

[0060] HRMS (ESI) m / z : [M+Na] + calcd for C 64 H 72 O 22 N2Na 1243.4469; found1243.4452.

[0061] Example 2:

[0062] Step 1:

[0063]

[0064] Under argon, compound (III)-2 (840 mg, 2.15 mmol, 1.0 equiv.) and thiourea (330 mg, 4.30 mmol, 2.0 equiv.) were dissolved in acetonitrile (13 mL). BF₃·OEt₂ (1.1 mL, 4.30 mmol, 2.0 equiv.) was added at room temperature, and the temperature was gradually increased to 80°C with stirring for 15 minutes. TLC monitoring indicated complete reaction of the starting materials. The reaction solution was cooled to room temperature, and Et₃N (600 μL, 4.30 mmol, 2.0 equiv.) and methyl 2-bromomethylbenzoate (980 mg, 4.30 mmol, 2.0 equiv.) were added. The reaction was continued at room temperature for 5 hours. TLC monitoring showed that the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure, diluted with DCM, and washed with 1 M HCl solution and saturated NaHCO3 solution in sequence. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 2.5:1) to obtain the target compound (IV)-2 (1.05 g, 2.05 mmol, 95%).

[0065] The analysis data are as follows: = -37.69 ( c 1.2, CHCl3);

[0066] 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 6.8 Hz, 1H), 7.47–7.44 (m, 1H), 7.38–7.30 (m, 2H), 5.16–5.04 (m, 2H), 5.04–4.98 (m, 1H), 4.38 (d, J = 10.1Hz, 1H), 4.31 (d, J = 13.3 Hz, 1H), 4.26–4.19 (m, 2H), 4.09 (dd, J = 12.3,2.3 Hz, 1H), 3.90 (s, 3H), 3.63–3.58 (m, 1H), 2.11 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.98 (s, 3H).

[0067] 13 C NMR (101 MHz, CDCl3) δ.2, 32.8, 20.8, 20.6, 20.6.

[0068] RMS (ESI) m / z : [M+Na] + calcd for C 23 H 28 O 11 SNa 535.1245; found 535.1243.

[0069] Step 2:

[0070]

[0071] Under argon, compound (IV)-2 (237 mg, 0.46 mmol, 1.0 equiv.) was dissolved in THF / H₂O (v / v 1 / 1, 2.5 mL) and lithium hydroxide (110 mg, 4.65 mmol, 10.0 equiv.) was added. The mixture was allowed to react at room temperature for 4 hours. TLC monitoring indicated that the reaction was complete. The reaction was quenched by addition of a cation exchange resin, filtered, and the filtrate was concentrated under reduced pressure without purification to yield the target compound (V)-2 (138 mg, 0.42 mmol, 90%).

[0072] The analysis data are as follows: = -37.51 ( c 0.5, MeOH);

[0073] 1 H NMR (400 MHz, CD3OD) δ 7.93 (dd, J = 7.9, 1.4 Hz, 1H), 7.48–7.42(m, 2H), 7.35–7.30 (m, 1H), 4.43 (d, J = 12.9 Hz, 1H), 4.29 (d, J = 13.0 Hz,1H), 4.16 (d, J = 9.1 Hz, 1H), 3.87 (dd, J= 12.1, 2.2 Hz, 1H), 3.66 (dd, J =12.1, 5.9 Hz, 1H), 3.30–3.17 (m, 4H).

[0074] 13 C NMR (101 MHz, CD3OD) δ 169.2, 140.4, 131.4, 131.1, 129.7, 126.8,84.2, 72.9, 72.1, 71.7, 68.7, 32.5, 16.5.

[0075] RMS (ESI) m / z : [MH] - calcd for C 14 H 17 O7S 329.0700; found 329.0700.

[0076] Step 3:

[0077]

[0078] Under argon protection, compound (V)-2 (33 mg, 0.10 mmol, 1.0 equiv.), compound (VI)-1 (208 mg, 0.2 mmol, 2.0 equiv.), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4 mg, 0.004mmol, 0.04 equiv.), NaHCO3 (12 mg, 0.15 mmol, 1.5 equiv.) and triphenylphosphine (51 mg, 0.2mmol, 2.0 equiv.) were dissolved in dry DMF (2.0 mL) and placed under a light source with a wavelength of 427 nm for reaction at room temperature for 20 hours. TLC monitoring showed that the reaction of the raw material was complete. The reaction solution was quenched with water and concentrated in vacuo. It was then purified by column chromatography (DCM:MeOH = 9:1) to obtain the target compound (I)-2 (72 mg, 59 μmol, 59%).

[0079] The analysis data are as follows: = -48.15 ( c = 0.10, MeOH);

[0080] 1 H NMR (400 MHz, CD3OD) δ8.13–8.08 (m, 2H), 7.78–7.70 (m, 2H), 7.67(t, J = 7.4 Hz, 1H), 7.60–7.54 (m, 4H), 7.53–7.47 (m, 3H), 7.43–7.40 (m, 4H),7.36–7.30 (m, 2H), 7.27 (t, J = 7.3 Hz, 1H), 6.44 (s, 1H), 6.05 (t, J = 8.6Hz, 1H), 5.82 (d, J = 6.5 Hz, 1H), 5.63 (d, J = 7.2 Hz, 1H), 5.48 (d, J = 6.3Hz, 1H), 5.21–5.12 (m, 2H), 5.03–4.98 (m, 1H), 4.34 (dd, J = 10.9, 6.7 Hz,1H), 4.18–4.15 (m, 2H), 3.93–3.90 (m, 1H), 3.83–3.76 (m, 2H), 3.65–3.59 (m,2H), 3.58–3.52 (m, 1H), 3.45–3.42 (m, 1H), 3.27–3.21 (m, 1H), 2.57–2.42 (m,3H), 2.41 (s, 3H), 2.24–2.15 (m, 4H), 2.04–2.00 (m, 2H), 1.87 (s, 3H), 1.85–1.75 (m, 2H), 1.65 (s, 3H), 1.14 (s, 3H), 1.12 (s, 3H)。

[0081] 13 C NMR (151 MHz, CD3OD) δ.2, 79.0, 78.5,77.5, 76.8, 76.7, 76.2, 75.2, 74.6, 73.2, 73.0, 72.3, 74.6, 73.2, 73.0, 72.3, 74.7, 75.9, 78.5, 77.7, 78.6, 78.7, 78.8, 78.7, 78.2, 75.2, 74.6, 73.2, 73.0, 72.3, 71.3, 63.2, 59.2, 55.3,47.9, 44.6, 36.4, 34.2, 26.9, 23.2, 22.4, 22.1, 20.8, 14.9, 10.5.

[0082] HRMS (ESI) m / z : [M+Na] + calcd for C 64 H 72 O 22 N2Na 1243.4469; found1243.4486.

[0083] Example 3:

[0084] Step 1:

[0085]

[0086] Under argon, compound (III)-3 (1.0 g, 3.01 mmol, 1.0 equiv.) and thiourea (460 mg, 6.00 mmol, 2.0 equiv.) were dissolved in acetonitrile (18 mL). BF₃·OEt₂ (1.5 mL, 6.00 mmol, 2.0 equiv.) was added at room temperature, and the temperature was gradually increased to 80°C with stirring for 15 minutes. TLC monitoring indicated complete reaction. The reaction solution was cooled to room temperature, and Et₃N (840 μL, 6.00 mmol, 2.0 equiv.) and methyl 2-bromomethylbenzoate (1.36 g, 6.00 mmol, 2.0 equiv.) were added. The reaction was continued at room temperature for 5 hours. TLC monitoring showed that the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure, diluted with DCM, and washed with 1 M HCl solution and saturated NaHCO3 solution in sequence. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 3:1) to obtain the target compound (IV)-3 (1.20 g, 2.64 mmol, 88%).

[0087] The analysis data are as follows: = -37.69 ( c 1.2, CHCl3);

[0088] 1 H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.1, 1.4 Hz, 1H), 7.47–7.43(m, 1H), 7.38–7.29 (m, 2H), 5.28 (dd, J = 3.4, 1.4 Hz, 1H), 5.19 (dd, J =10.1, 3.4 Hz, 1H), 5.10–5.00 (m, 2H), 4.31 (d, J = 13.3 Hz, 1H), 4.19–4.11(m, 1H), 4.08 (d, J = 13.3 Hz, 1H), 3.92 (s, 3H), 2.12 (s, 3H), 2.04 (s, 3H), 1.95 (s, 3H), 1.15 (d, J = 6.2 Hz, 3H).

[0089] 13 C NMR (101 MHz, CDCl3)δ 170.0, 169.9, 169.8, 167.5, 139.7, 132.1,131.5, 131.2, 129.1, 127.5, 81.7, 71.3, 71.0, 69.7, 66.9, 52.2, 33.6, 20.9,20.8, 20.6, 17.3.

[0090] RMS (ESI) m / z : [M+Na] + calcd for C 21 H 26 O9SNa 477.1190; found 477.1184.

[0091] Step 2:

[0092]

[0093] Under argon, compound (IV)-3 (225 mg, 0.67 mmol, 1.0 equiv.) was dissolved in THF / H₂O (v / v 1 / 1, 3.5 mL) and lithium hydroxide (160 mg, 6.71 mmol, 10.0 equiv.) was added. The mixture was allowed to react at room temperature for 5 hours. TLC monitoring indicated that the reaction was complete. The reaction was quenched by addition of a cation exchange resin, filtered, and the filtrate was concentrated under reduced pressure without purification to yield the target compound (V)-3 (200 mg, 0.63 mmol, 94%).

[0094] The analysis data are as follows: = -105.96 ( c 0.5, MeOH);

[0095] 1 H NMR (400 MHz, CD3OD) δ 7.95 (dd, J = 7.7, 1.5 Hz, 1H), 7.48–7.44(m, 1H), 7.42–7.29 (m, 2H), 5.02 (d, J = 1.4 Hz, 1H), 4.35 (d, J = 13.1 Hz,1H), 4.06 (d, J = 13.0 Hz, 1H), 3.88–3.84 (m, 1H), 3.79 (dd, J= 3.3, 1.5 Hz,1H), 3.56 (dd, J = 9.5, 3.4 Hz, 1H), 3.38 (t, J = 9.5 Hz, 1H), 1.21 (d, J =6.2 Hz, 3H).

[0096] 13 C NMR (101 MHz, CD3OD) δ 169.2, 140.4, 131.4, 131.1, 129.7, 126.8,84.2, 72.9, 72.1, 71.7, 68.7, 47.0, 32.5, 16.5.

[0097] RMS (ESI) m / z : [MH] - calcd for C 14 H 17 O6S 313.0751; found 313.0757.

[0098] Step 3:

[0099]

[0100] Under argon protection, compound (V)-3 (31 mg, 0.10 mmol, 1.0 equiv.), compound (VI)-1 (210 mg, 0.2 mmol, 2.0 equiv.), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4 mg, 0.004mmol, 0.04 equiv.), NaHCO3 (12 mg, 0.15 mmol, 1.5 equiv.) and triphenylphosphine (53 mg, 0.2mmol, 2.0 equiv.) were dissolved in dry DMF (2.0 mL) and placed under a light source with a wavelength of 427 nm for reaction at room temperature for 20 hours. TLC monitoring showed that the reaction of the raw material was complete. The reaction solution was quenched with water and concentrated in vacuo. It was then purified by column chromatography (DCM:MeOH = 10:1) to obtain the target compound (I)-3 (61 mg, 51 μmol, 51%).

[0101] The analysis data are as follows: = -90.33 ( c = 0.10, MeOH);

[0102] 1H NMR (400 MHz, CD3OD) δ 8.15–8.05 (m, 2H), 7.81–7.74 (m, 2H), 7.67(t, J = 7.4 Hz, 1H), 7.57–7.50 (m, 4H), 7.53–7.46 (m, 3H), 7.48–7.40 (m, 4H),7.36–7.30 (m, 2H), 7.27 (t, J = 7.3 Hz, 1H), 6.44 (s, 1H), 6.05 (t, J = 8.7Hz, 1H), 5.82 (d, J = 6.4 Hz, 1H), 5.63 (d, J = 7.2 Hz, 1H), 5.49–5.47 (m,1H), 5.21–5.11 (m, 2H), 5.00 (d, J = 9.5 Hz, 1H), 4.34 (dd, J = 10.9, 6.7 Hz,1H), 4.20–4.15 (m, 2H), 3.88–3.83 (m, 2H), 3.78–3.74 (m, 1H), 3.65 (dd, J =8.7, 3.3 Hz, 1H), 3.51 (dd, J = 8.4, 6.1 Hz, 1H), 3.40 (t, J = 8.7 Hz, 1H),2.56–2.42 (m, 3H), 2.41 (s, 3H), 2.22–2.10 (m, 4H), 1.87 (s, 3H), 1.85–1.75(m, 3H), 1.65 (s, 3H), 1.22–1.18 (m, 3H), 1.14 (s, 3H), 1.12 (s, 3H)。

[0103] 13 C NMR NMR (151 MHz, CD3OD) δ.3, 79.0,78.5, 77.5, 76.8, 76.2, 74.4, 73.2, 72.8, 72.3, 71.3, 71.1, 72.7, 73.7, 74.8, 75.9, 76.1, 77.7, 78.8, 78.9, 79.8, 79.9, 79.1 59.2, 55.3, 49.9,47.9, 44.6, 37.6, 36.4, 34.5, 26.9, 25.5, 23.2, 22.4, 20.8, 18.3, 14.9, 10.5.

[0104] HRMS (ESI) m / z : [M+Na] + calcd for C 64 H 72 O 21 N2Na 1227.4520; found1227.4536.

[0105] Example 4:

[0106] Step 1:

[0107]

[0108] Under argon, compound (III)-4 (465 mg, 1.19 mmol, 1.0 equiv.) and thiourea (185 mg, 2.38 mmol, 2.0 equiv.) were dissolved in acetonitrile (10 mL). BF₃·OEt₂ (0.6 mL, 2.38 mmol, 2.0 equiv.) was added at room temperature, and the temperature was gradually increased to 80°C with stirring for 15 minutes. TLC monitoring indicated complete reaction of the starting materials. The reaction solution was cooled to room temperature, and Et₃N (330 μL, 2.38 mmol, 2.0 equiv.) and methyl 2-bromomethylbenzoate (540 mg, 2.38 mmol, 2.0 equiv.) were added. The reaction was continued at room temperature for 5 hours. TLC monitoring showed that the reaction of the raw material was complete. The reaction solution was concentrated under reduced pressure, diluted with DCM, and washed with 1 M HCl solution and saturated NaHCO3 solution in sequence. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 3:1) to obtain the target compound (IV)-4 (550 mg, 1.07 mmol, 90%).

[0109] The analysis data are as follows: = -29.17 ( c 0.9, CHCl3);

[0110] 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.7 Hz, 1H), 7.41–7.34 (m, 1H), 7.26 (t, J = 7.5 Hz, 2H), 5.32 (d, J = 2.6 Hz, 1H), 5.14 (t, J = 10.0 Hz,1H), 4.88 (dd, J = 10.0, 3.4 Hz, 1H), 4.31–4.23 (m, 2H), 4.15 (d, J = 13.3Hz, 1H), 4.05–3.99 (m, 2H), 3.82 (s, 3H), 3.75 (t, J = 6.6 Hz, 1H), 2.07 (s, 3H), 1.99 (s, 3H), 1.98 (s, 3H) 1.97 (s, 3H).

[0111] 13C NMR (101 MHz, CDCl3) δ 170.4, 170.3, 170.1, 169.6, 167.6, 139.7,131.9, 131.3, 131.2, 129.5, 127.5, 83.4, 74.3, 71.9, 67.3, 67.2, 61.4, 52.2,32.9, 20.7, 20.6.

[0112] RMS (ESI) m / z : [M+Na] + calcd for C 23 H 28 O 11 SNa 535.1245; found 535.1230.

[0113] Step 2:

[0114]

[0115] Under argon, compound (IV)-4 (255 mg, 0.49 mmol, 1.0 equiv.) was dissolved in THF / H₂O (v / v 1 / 1, 3.0 mL) and lithium hydroxide (120 mg, 4.90 mmol, 10.0 equiv.) was added. The mixture was allowed to react at room temperature for 5 hours. TLC monitoring indicated that the reaction was complete. The reaction was quenched by addition of a cation exchange resin, filtered, and the filtrate was concentrated under reduced pressure without purification to afford the target compound (V)-4 (152 mg, 0.46 mmol, 93%).

[0116] The analysis data are as follows: = -9.26 ( c 0.5, MeOH);

[0117] 1 H NMR (400 MHz, D2O) δ 7.78 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz,1H), 7.37–7.33 (m, 2H), 4.25–4.17 (m, 2H), 4.15 (s, 1H), 3.85 (s, 1H), 3.64–3.58 (m, 2H), 3.52–3.47 (m, 1H), 3.46–3.42 (m, 2H).

[0118] 13 C NMR (101 MHz, D2O) δ 182.6, 138.7, 132.0, 131.2, 130.4, 127.6,84.8, 78.7, 73.9, 69.5, 68.7, 60.8, 32.3.

[0119] RMS (ESI) m / z : [MH] - calcd for C 14 H 17 O7S 329.0700; found 329.0701.

[0120] Step 3:

[0121]

[0122] Under argon protection, compound (V)-4 (33 mg, 0.10 mmol, 1.0 equiv.), compound (VI)-1 (211 mg, 0.2 mmol, 2.0 equiv.), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4 mg, 0.004mmol, 0.04 equiv.), NaHCO3 (13 mg, 0.15 mmol, 1.5 equiv.) and triphenylphosphine (54 mg, 0.2mmol, 2.0 equiv.) were dissolved in dry DMF (2.0 mL) and placed under a light source with a wavelength of 427 nm for reaction at room temperature for 22 hours. TLC monitoring showed that the reaction of the raw material was complete. The reaction solution was quenched with water and concentrated in vacuo. It was then purified by column chromatography (DCM:MeOH = 12:1) to obtain the target compound (I)-4 (65 mg, 59 μmol, 53%).

[0123] The analysis data are as follows: = -38.11 ( c = 0.10, MeOH);

[0124] 1 H NMR (400 MHz, CD3OD) δ8.13–8.09 (m, 2H), 7.80–7.76 (m, 2H), 7.67–7.65 (m, 1H), 7.60–7.55 (m, 4H), 7.52–7.50 (m, 1H), 7.51–7.47 (m, 2H), 7.46–7.41 (m, 4H), 7.35–7.30 (m, 2H), 7.27 (t, J = 7.3 Hz, 1H), 6.44 (s, 1H), 6.06(t, J = 8.6 Hz, 1H), 5.83 (d, J = 6.4 Hz, 1H), 5.64 (d, J = 7.2 Hz, 1H), 5.49(d, J = 6.6 Hz, 1H), 5.23–5.10 (m, 2H), 5.05–4.99 (m, 1H), 4.35 (dd, J =10.9, 6.6 Hz, 1H), 4.21–4.17 (m, 2H), 3.98–3.95 (m, 1H), 3.95–3.90 (m, 2H),3.84–3.78 (m, 2H), 3.75–3.71 (m, 1H), 3.68–3.65 (m, 2H), 2.50–2.47 (m, 3H),2.41 (s, 3H), 2.18–2.15 (m, 3H), 2.09–1.98 (m, 2H), 1.88 (s, 3H), 1.86–1.77(m, 2H), 1.66 (s, 3H), 1.14 (s, 3H), 1.13 (s, 3H)。

[0125] 13 C NMR (151 MHz, CD3OD) δ.8, 128.4, 128.2, 127.3, 119.8, 84.6, 80.9, 77.7, 77.2,76.1, 75.5, 74.9, 74.0, 72.8, 71.9, 71.0, 70.6, 70.0, 61.1, 57.9, 54.0, 46.6,43.2, 36.2, 35.1, 33.1, 25.6, 21.9, 21.2, 21.0, 19.5, 13.6, 9.1.

[0126] HRMS (ESI) m / z : [M+Na] + calcd for C 64 H 72 O 22 N2Na 1243.4469; found1243.4480.

[0127] Example 5:

[0128] Step 1 and step 2: the same as step 1 and step 2 of Example 1;

[0129] Step 3:

[0130]

[0131] Under argon, compound (V)-1 (33 mg, 0.10 mmol, 1.0 equiv.), compound (VI)-2 (62 mg, 0.2 mmol, 2.0 equiv.), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4 mg, 0.004 mmol, 0.04 equiv.), NaHCO3 (13 mg, 0.15 mmol, 1.5 equiv.), and triphenylphosphine (54 mg, 0.2 mmol, 2.0 equiv.) were dissolved in dry DMF (2.0 mL) and reacted under 427 nm light at room temperature for 24 hours. TLC monitoring indicated complete reaction. The reaction solution was quenched with water and concentrated in vacuo. The product was then purified by column chromatography (DCM:MeOH = 8:1) to afford the target compound (II)-1 (31 mg, 65 μmol, 65%).

[0132] The analysis data are as follows: = +20.08 ( c = 0.10, MeOH);

[0133] 1 H NMR (400 MHz, CD3OD) δ 7.75–7.72 (m, 1H), 7.66–7.63 (m, 1H), 7.51(t, J = 7.7 Hz, 1H), 5.16–5.13 (m, 1H), 4.51–4.48 (m, 2H), 3.93–3.87 (m, 1H), 3.75–3.70 (m, 3H), 3.71 (dd, J = 8.2, 3.2 Hz, 1H), 3.62 (t, J = 8.2 Hz, 1H),3.53–3.46 (m, 1H), 2.91–2.90 (m, 1H), 2.77–2.75 (m, 1H), 2.61–2.53 (m, 2H),2.47–2.45 (m, 1H), 2.22–2.06 (m, 1H), 2.00–1.86 (m, 2H).

[0134] 13 C NMR (101 MHz, CD3OD) δ174.7, 174.2, 172.1, 171.1, 136.4, 134.6,133.9, 130.1, 127.8, 121.4, 77.3, 77.2, 76.4, 72.7, 69.5, 62.8, 53.6, 33.5,32.4, 25.8, 24.1.

[0135] HRMS (ESI) m / z : [M+Na] + calcd for C 22 H 27 O9N3Na 500.1640; found500.1628.

[0136] Example 6:

[0137] Step 1 and step 2: the same as step 1 and step 2 of Example 2;

[0138] Step 3:

[0139]

[0140] Under argon, compound (V)-2 (34 mg, 0.10 mmol, 1.0 equiv.), compound (VI)-2 (64 mg, 0.2 mmol, 2.0 equiv.), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4 mg, 0.004 mmol, 0.04 equiv.), NaHCO3 (14 mg, 0.15 mmol, 1.5 equiv.), and triphenylphosphine (55 mg, 0.2 mmol, 2.0 equiv.) were dissolved in dry DMF (2.0 mL) and reacted under 427 nm light at room temperature for 20 hours. TLC monitoring indicated complete reaction. The reaction solution was quenched with water and concentrated in vacuo. The product was then purified by column chromatography (DCM:MeOH = 8:1) to afford the target compound (II)-2 (27 mg, 57 μmol, 57%).

[0141] The analysis data are as follows: = -70.05 ( c = 0.10, MeOH);

[0142] 1 H NMR (400 MHz, CD3OD) δ 7.75 (dd, J= 8.0, 1.0 Hz, 1H), 7.65 (dd, J = 7.6, 1.0 Hz, 1H), 7.57–7.43 (m, 1H), 5.17 (dd, J = 13.3, 5.1 Hz, 1H), 4.55–4.41 (m, 2H), 4.00–3.92 (m, 1H), 3.81–3.75 (m, 1H), 3.67–3.62 (m, 1H), 3.61(d, J = 5.7 Hz, 1H), 3.55 (t, J = 8.9 Hz, 1H), 3.49–3.42 (m, 1H), 3.28–3.22(m, 1H), 2.97–2.86 (m, 1H), 2.82–2.74 (m, 1H), 2.65–2.55 (m, 1H), 2.54–2.43(m, 2H), 2.23–2.14 (m, 1H), 2.12–2.01 (m, 2H).

[0143] 13 C NMR (101 MHz, CD3OD) δ 174.7, 174.5, 172.1, 171.1, 136.3, 134.6,133.9, 130.1, 127.8, 121.4, 76.5, 75.2, 74.7, 73.0, 63.1, 53.6, 33.5, 32.4,24.1, 22.1.

[0144] HRMS (ESI) m / z : [M+H] + calcd for C 22 H 28 O9N3 478.1820; found 478.1813.

[0145] Example 7:

[0146] Step 1 and step 2: the same as step 1 and step 2 of Example 3;

[0147] Step 3:

[0148]

[0149] Under argon, compound (V)-3 (32 mg, 0.10 mmol, 1.0 equiv.), compound (VI)-2 (64 mg, 0.2 mmol, 2.0 equiv.), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4 mg, 0.004 mmol, 0.04 equiv.), NaHCO3 (12 mg, 0.15 mmol, 1.5 equiv.), and triphenylphosphine (53 mg, 0.2 mmol, 2.0 equiv.) were dissolved in dry DMF (2.0 mL) and exposed to a 427 nm light source. The reaction was allowed to proceed at room temperature for 21 hours. TLC monitoring indicated the reaction was complete. The reaction solution was quenched with water and concentrated in vacuo. The product was then purified by column chromatography (DCM:MeOH = 8:1) to afford the target compound (II)-3 (28 mg, 60 μmol, 60%).

[0150] The analysis data are as follows: = +15.65 ( c = 0.08, MeOH);

[0151] 1 H NMR (400 MHz, CD3OD) δ 7.74 (dd, J = 7.9, 1.0 Hz, 1H), 7.64 (dd, J = 7.5, 1.0 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 5.17 (dd, J = 13.4, 5.1 Hz,1H), 4.54–4.42 (m, 2H), 3.86–3.84 (m, 1H), 3.77 (t, J = 2.9 Hz, 1H), 3.65(dd, J = 8.6, 3.4 Hz, 1H), 3.51–3.50 (m, 1H), 3.41 (t, J = 8.6 Hz, 1H), 2.91–2.88 (m, 1H), 2.77–2.74 (m, 1H), 2.61–2.41 (m, 3H), 2.21–2.09 (m, 2H), 1.86–1.84 (m, 1H), 1.23–1.20 (m, 3H).

[0152] 13C NMR (101 MHz, CD3OD) δ 174.7, 174.0, 172.1, 171.1, 136.3, 134.6,133.9, 130.1, 127.7, 121.4, 78.3, 74.3, 73.1, 72.7, 71.2, 53.6, 33.8, 32.4,25.5, 24.1, 18.4.

[0153] HRMS (ESI) m / z : [M+H] + calcd for C 22 H 28 O8N3 462.1871; found 462.1864.

[0154] Example 8:

[0155] Step 1 and step 2: same as step 1 and step 2 of Example 4;

[0156] Step 3:

[0157]

[0158] Under argon, compound (V)-4 (34 mg, 0.10 mmol, 1.0 equiv.), compound (VI)-2 (60 mg, 0.2 mmol, 2.0 equiv.), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4 mg, 0.004 mmol, 0.04 equiv.), NaHCO3 (14 mg, 0.15 mmol, 1.5 equiv.), and triphenylphosphine (51 mg, 0.2 mmol, 2.0 equiv.) were dissolved in dry DMF (2.0 mL) and exposed to a 427 nm light source. The reaction was allowed to proceed at room temperature for 21 hours. TLC monitoring indicated the reaction was complete. The reaction solution was quenched with water and concentrated in vacuo. The product was then purified by column chromatography (DCM:MeOH = 9:1) to afford the target compound (II)-4 (33 mg, 69 μmol, 69%).

[0159] The analysis data are as follows: = +41.48 ( c = 0.10, MeOH);

[0160] 1 H NMR (400 MHz, CD3OD) δ7.74–7.70 (m, 1H), 7.65 (d, J = 7.5 Hz, 1H),7.52 (t, J = 7.7 Hz, 1H), 5.17 (dd, J = 13.4, 5.1 Hz, 1H), 4.52–4.48 (m, 2H), 4.03–3.99 (m, 1H), 3.96–3.89 (m, 2H), 3.79–3.75 (m, 1H), 3.75–3.65 (m, 3H), 2.91–2.90 (m, 1H), 2.78–2.75 (m, 1H), 2.63–2.43 (m, 3H), 2.18–2.15 (m, 1H), 2.13–1.96 (m, 2H).

[0161] 13 C NMR (101 MHz, CD3OD) δ 174.7, 172.1, 171.1, 136.4, 134.6, 133.9,130.1, 127.8, 121.4, 75.0, 74.3, 71.9, 70.3, 70.2, 62.3, 53.6, 33.8, 32.4,24.1, 22.7.

[0162] HRMS (ESI) m / z : [M+H] + calcd for C 22 H 28 O9N3 478.1820; found 478.1812.

[0163] Example 9: Activity Evaluation

[0164] 1. Evaluation of inhibitory activity against human ovarian teratoma cells (PA-1)

[0165] Some of the aforementioned carbonyl glycoside compounds (I)-1, (I)-2, (I)-3, and (I)-4 were subjected to in vitro activity assays. Human ovarian teratoma cells (PA-1) were used in the experiments to examine the inhibitory activity of the four α-glycosylpaclitaxel carbonyl glycoside compounds against PA-1, with paclitaxel (PTX) serving as a positive control. The assay method is as follows:

[0166] (1) Seed board:

[0167] PA-1 cells in the logarithmic growth phase were harvested after digestion, resuspended in culture medium, and counted using a hemocytometer. The cell density was adjusted to 60,000 cells / mL and seeded into 96-well plates at 100 μL / well (6,000 cells). The seeded 96-well plates were incubated at 37°C for 24 hours until the cells were fully attached.

[0168] (2) Dosing:

[0169] Compounds (I)-1, (I)-2, (I)-3, (I)-4, and PTX were each dissolved in DMSO to a 20 mM solution. The compounds were then serially diluted to the corresponding concentrations in complete culture medium and added to a 96-well plate at a rate of 100 μL / well, resulting in final concentrations of 200 nM, 100 nM, 50 nM, 25 nM, 12.5 nM, and 6.25 nM. Three parallel groups were set up for each concentration. After drug addition, the 96-well plate was placed in an incubator and incubated for 48 hours.

[0170] (3) Data determination:

[0171] Add 20 μL of CCK-8 to each well and incubate at 37°C for 30 minutes. Remove the 96-well plate and measure the absorbance at 490 nm using a microplate reader. Calculate cell viability using the following formula: Cell viability (%) = 100% - [(OD control - OD experimental) / (OD control - blank)]. GraphPad Prism 8.0 was used to calculate the half-maximal inhibitory concentration (IC) of the compound. 50 ).

[0172] (4) Test results:

[0173] Table 1 In vitro PA-1 inhibitory activity of four carbonyl glycosides

[0174]

[0175] The experimental results are as follows Figure 1 As shown in Table 1: The activities of compounds (I)-1, (I)-2, (I)-3 and (I)-4 (IC 50 16.200 nm, 18.860 nm, 19.990 nm, 19.830 nm ) and paclitaxel (IC 50 8.996 nm).

[0176] 2. Evaluation of the inhibitory activity of KYSE-510 on digestive tract tumor cells

[0177] Some of the aforementioned carbonyl glycoside compounds (I)-1, (I)-2, (I)-3, and (I)-4 were subjected to in vitro activity assays. The experiments used digestive tract tumor cells (KYSE-510) to examine the inhibitory activity of the four aforementioned α-glycosylpaclitaxel carbonyl glycoside compounds against KYSE-510, using PTX as a positive control drug. The assay method is as follows:

[0178] (1) Seed board:

[0179] KYSE-510 cells in the logarithmic growth phase were harvested after digestion, resuspended in culture medium, and counted using a hemocytometer. The cell density was adjusted to 60,000 cells / mL and seeded into a 96-well plate at 100 μL / well (6,000 cells). The seeded 96-well plate was incubated at 37°C for 24 hours until the cells were fully attached.

[0180] (2) Dosing:

[0181] Compounds (I)-1, (I)-2, (I)-3, (I)-4, and PTX were each dissolved in DMSO to a 20 mM solution. The compounds were then serially diluted to the corresponding concentrations in complete culture medium and added to a 96-well plate at a rate of 100 μL / well, resulting in final concentrations of 200 nM, 100 nM, 50 nM, 25 nM, 12.5 nM, 6.25 nM, 3.12 nM, 1.56 nM, and 0.78 nM. Three parallel groups were set up for each concentration. After drug addition, the 96-well plate was placed in an incubator and incubated for 48 hours.

[0182] (3) Data determination:

[0183] Add 20 μL of CCK-8 to each well and incubate at 37°C for 30 minutes. Remove the 96-well plate and measure the absorbance at 490 nm using a microplate reader. Calculate cell viability using the following formula: Cell viability (%) = 100% - [(OD control - OD experimental) / (OD control - blank)]. GraphPad Prism 8.0 was used to calculate the half-maximal inhibitory concentration (IC) of the compound. 50 ).

[0184] (4) Test results:

[0185] Table 2 In vitro inhibitory activity of KYSE-510 by four carbonyl glycoside compounds

[0186]

[0187] The experimental results are shown in Table 2: The activities of compounds (I)-1, (I)-2, (I)-3 and (I)-4 (IC 504.848 nm, 6.880 nm, 4.087 nm, 2.584 nm) and paclitaxel (IC 50 0.781 nm), and is expected to be further developed into an anti-gastrointestinal tumor drug.

[0188] Example 10: Solubility Evaluation

[0189] 5 mg each of paclitaxel, compounds (I)-1, (I)-2, (I)-3 and (I)-4 were dissolved in PBS and then placed in a 25°C water bath. After 1 hour, the supernatant was centrifuged and freeze-dried. The weighing results are shown in the table.

[0190] Table 3 Solubility data of four carbonyl glycoside compounds

[0191]

[0192] As shown in Table 3, the solubility of paclitaxel in water at room temperature is 50 μg / mL. The solubilities of compounds (I)-1, (I)-2, (I)-3, and (I)-4 are 360 ​​μg / mL, 510 μg / mL, 180 μg / mL, and 600 μg / mL, respectively. These solubilities are 7.2 times, 10.2 times, 3.6 times, and 12 times that of paclitaxel, respectively. These results demonstrate that monosaccharide modification significantly increases the solubility of paclitaxel, thereby significantly improving the pharmacokinetic properties of the compounds.

[0193] Example 11: In vivo anti-tumor activity evaluation

[0194] Based on the good solubility and anti-tumor cell activity of compounds (I)-1 and (I)-4, further in vivo tumor inhibition activity studies were carried out.

[0195] Experimental methods:

[0196] (1) Establishment of tumor-bearing mouse model: 19-22 g female KM mice were selected as experimental subjects. MCF-7 cells were prepared to a density of 1×10 7 0.1 mL of the cell suspension with a concentration of 10 cells / mL was inoculated into the right axilla of each mouse.

[0197] (2) Tumor-bearing mice were randomly divided into 4 groups, with 6 mice in each group, namely, normal saline control group (PBS group), paclitaxel injection group (PTX group), (I)-1 experimental group and (I)-4 experimental group. 3Around 20 mg / kg of paclitaxel and equivalent amounts of (I)-1 and (I)-4 were administered via tail vein injection. The PBS group received a corresponding volume of normal saline intravenously. Dosing was performed once every four days for a total of three doses. On day 4 after the third dose, the mice were sacrificed (cervical dislocation) and the tumors were removed.

[0198] (3) The tumor volume obtained in step (2) was measured. The changes in the measured tumor volume are shown in Table 4.

[0199] Table 4 Tumor volume changes (mm 3 , ± s , n=6)

[0200]

[0201] The above results demonstrated that paclitaxel (PTX group), (I)-1 and (I)-4 all exhibited tumor growth inhibitory activity compared with the control PBS group.

Claims

1. A carbon glycoside compound, characterized in that The structure is shown in general formula (I): ； The curved glycosyl moiety in the general formula (I) represents the general structure of a five-membered ring furanose or a six-membered ring pyranose.

2. The carbon glycoside compound according to claim 1, wherein Is any of the following structures: 。 3. A method for preparing the carbon glycoside compound according to claim 1, characterized in that: The following steps are involved: Step 1: First, react the compound of formula (III) with the compound of formula (VII) under acidic conditions at 60°C–100°C for 10–30 minutes, then cool to room temperature, add the compound of formula (VIII) and a base, and react at 20°C–40°C for 4–8 hours to obtain the target compound of formula (IV); ; R 1 is acetyl, R 2 is methoxycarbonyl or ethoxycarbonyl; Step 2: removing the acetyl group from the compound of formula (IV) under alkaline conditions and hydrolyzing the ester group to obtain the target compound of formula (V); ; R 3 is a carboxyl group; Step 3: Dissolve the compound of formula (V), the compound of formula (VI), a photocatalyst, a phosphine reagent and a base in a solvent, and react at 20°C–45°C for 10–36 hours under visible light to obtain the target compound of formula (I): ； R 4 For the following structure: 。 4. The method for preparing a carbon glycoside compound according to claim 3, wherein The acid in the acidic conditions in step 1 is one of boron trifluoride etherate, HClO4, trimethylsilyl trifluoromethanesulfonate, and TMSClO4; the base is one of triethylamine, sodium bicarbonate, and sodium carbonate; and the solvent is: N, N - one of dimethylformamide, dimethyl sulfoxide, acetonitrile, dioxane, 1,2-dichloroethane or tetrahydrofuran.

5. The method for preparing a carbon glycoside compound according to claim 3, wherein The base in the alkaline condition in step 2 is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, and sodium methoxide; and the solvent is one or more of tetrahydrofuran, water, acetonitrile, dioxane, and acetone.

6. The method for preparing a carbon glycoside compound according to claim 3, wherein: The photocatalyst in step 3 is: Ir[dFCF3ppy]2(bpy)PF6, [Ir(dFCF3ppy)2dtbbpy]PF6, [lr(ppy)2(dtbbpy)]BF4, 4CzIPN, [Ru(bpy)3](PF6)2, fac -One of [Ir(ppy)3], Hantzsch ester and [Ru(bpy)3]Cl2.

7. The method for preparing the glycosyl carbon glycoside compound according to claim 3, wherein: The phosphine reagent in step 3 is one of triphenylphosphine, Ph2OEtP, Ph2MeP, Bu3P, bis(diphenylphosphino)methane, tri(2,4,6-trimethoxyphenyl)phosphine, tri(4-chlorophenyl)phosphine, tri(pentafluorophenyl)phosphine, tri(4-fluorophenyl)phosphine, tri(4-bromophenyl)phosphine and diphenyl(2-pyridyl)phosphine.

8. The method for preparing a carbon glycoside compound according to claim 3, wherein The base in step 3 is one of K3PO4, KH2PO4, NaHCO3, 2,6-lutidine, K2CO3, Na2HPO4, Cs2CO3, and Et3N; the wavelength of the visible light source is 365 nm, 390 nm, 427 nm, 456 nm, or a broad spectrum; and the solvent is one of DMF, DMSO, acetonitrile, dioxane, 1,2-dichloroethane, or tetrahydrofuran.

9. Use of the carbon glycoside compound according to claim 1 or 2 for preparing antitumor drugs.

10. Use of the carbon glycoside compound according to claim 1 or 2 for preparing drugs for treating human ovarian teratoma or digestive tract tumors.

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