A kind of indole sugar carbon glycoside macrocyclic compound and its preparation method and application

Abstract

The present invention relates to the field of pharmaceutical technology, specifically to an indole sugar glycoside macrocyclic compound, its preparation method, and application. The specific technical scheme comprises adding a catalyst to a 6-azide-substituted 1-indole glycoside or a 6-azide-substituted 1,3-bisindole glycoside, and stirring in an organic solvent for 0 to 24 hours to form the indole sugar glycoside macrocyclic compound. The entire synthesis process has the advantages of mild conditions, good selectivity, and simple operation. Furthermore, the indole sugar glycoside macrocyclic compound exhibits broad anti-tumor activity.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to an indole sugar carbon glycoside macrocyclic compound and a preparation method and application thereof. Background Art

[0002] Macrocyclic compounds typically have structural characteristics such as a larger molecular weight, a polar backbone structure, and more hydrogen donor acceptors. The structural characteristics of macrocyclic compounds give them a semi-rigid molecular conformation, which ensures the necessary flexibility to better adapt to the spatial structure of the binding site. Compared with traditional small molecules, they can better bind to targets with large and featureless binding sites. These characteristics are crucial for mimicking the structural domains of protein-protein interactions (PPIs), and it is precisely because of these structural characteristics that macrocyclic compounds have advantages that traditional small molecule drugs lack. Therefore, macrocyclic substances are increasingly used in the drug development of PPIs. However, macrocyclic compounds are often underrepresented in screening molecular collection libraries, limiting their use in lead compound discovery. For example, the AstraZeneca molecular collection library contains a total of 3.8 million compounds, but contains less than 17,000 macrocyclic compounds.

[0003] On the other hand, indole carbonyl glycosides have excellent antiviral, anti-inflammatory, analgesic and anti-tumor biological activities. Bisindole alkaloids have great potential in enhancing biological activity, reducing side effects, overcoming drug resistance and changing pharmacokinetic, pharmacodynamic or physicochemical characteristics.

[0004] A wide variety of active indole compounds have been reported, but only a few have been developed into drugs. Converting indole sugar glycosides into macrocyclic indole sugar glycosides is a new approach, but there are currently no literature or patents reporting the synthesis and application of similar compounds. Summary of the Invention

[0005] In view of the deficiencies of the prior art, the present invention provides an indole sugar carbon glycoside macrocyclic compound and a preparation method and application thereof.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0007] The present invention discloses an indole sugar carbon glycoside macrocyclic compound, the structural formula of which is shown in the following formula (I) and / or formula (II):

[0008] and / or

[0009] Wherein, Pg is any one of a hydrogen atom, a methyl group, an acetyl group, a benzoyl group, a benzyl group, an allyl group, a sulfonyl group, and a silicon group;

[0010] PgO can be substituted by azide, substituted amino, sulfhydryl, alkyl sulfide, and aryl sulfide;

[0011] R 1 is any one of a hydrogen atom, a methyl group, a benzyl group, an allyl group, a propargyl group, an alkyl group, a cycloalkyl group, a sulfonyl group, an acyl group, and an alkoxycarbonyl group;

[0012] R 2 is one or more of a hydrogen atom, a halogen, a methyl group, an alkyl group, a methoxy group, a benzyloxy group, an aromatic ring, an aromatic heterocycle, an allyloxy group, a propargyloxy group, a nitro group, an ester group, a carbonyl group, a cyano group, an alkyl sulfide group, an aryl sulfide group, and a substituted amino group;

[0013] R 3 is any one of a hydrogen atom, a methyl group, a benzyl group, an allyl group, a propargyl group, an alkyl group, a cycloalkyl group, a sulfonyl group, an acyl group, and an alkoxycarbonyl group;

[0014] R 4 are one or more of hydrogen, halogen, methyl, alkyl, methoxy, benzyloxy, aromatic ring, aromatic heterocycle, allyloxy, propargyloxy, nitro, ester group, carbonyl, cyano, alkyl sulfide, aryl sulfide, and substituted amino groups;

[0015] X is any one of C, N, O, S, and Si;

[0016] n=0, 1, 2…1000.

[0017] Preferably, when Pg is any one of methyl, acetyl, benzoyl, benzyl, allyl, sulfonyl, and silicon, it can be replaced by one or more independent R X Substituents substituted;

[0018] When PgO is any one of amino, mercapto, alkyl sulfide, and aryl sulfide, it can be replaced by one or more independent R X Substituents substituted;

[0019] When R 1 、R 3 When each of the following groups is selected from methyl, benzyl, allyl, propargyl, alkyl, cycloalkyl, sulfonyl, acyl, and alkoxycarbonyl, each of the following groups may be replaced by one or more independent R X Substituents substituted;

[0020] When R 2 、R 4 When it is any one of methyl, alkyl, methoxy, benzyloxy, aromatic ring, aromatic heterocycle, allyloxy, propargyloxy, nitro, ester group, carbonyl, cyano, alkyl sulfide group, aryl sulfide group, and substituted amino group, it may be replaced by one or more independently RX Substituents substituted;

[0021] The R X It is any one of a hydrogen atom, a halogen, an alkyl group, a fluoroalkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, an aryl group, an amino group, an alkoxy group, a substituted amino group, an amide group, a hydroxyl group and a sulfonamide group.

[0022] Preferably, when R X When it is any one of alkyl, fluoroalkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, aryl, amino, alkoxy, substituted amino, amide, hydroxyl, and sulfonamide, it may be substituted by one or more hydrogen atoms, alkyl, fluoroalkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, aryl, amino, alkoxy, substituted amino, amide, hydroxyl, and sulfonamide.

[0023] Correspondingly, a method for preparing an indole sugar carbon glycoside macrocyclic compound comprises adding a catalyst to 6-azido-substituted 1-indole carbon glycoside or 6-azido-substituted 1,3-bisindole carbon glycoside, stirring in an organic solvent for 0 to 24 hours, and forming an indole sugar carbon glycoside macrocyclic compound.

[0024] Preferably, the concentration of the organic solvent is 0.001 to 100 mol / L, the reaction temperature is -100 to 200° C., and the amount of the catalyst is 0.001 equivalent to 100.0 equivalents.

[0025] Preferably, the organic solvent is one or a mixture of any proportion of dichloromethane, chloroform, acetonitrile, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, tetrahydrofuran, N,N-dimethylformamide, DMF, DMSO, 1,4-dioxane, 2-methyl-tetrahydrofuran, diethyl ether, tert-butyl methyl ether, polyethylene glycol and derivatives thereof;

[0026] The catalyst is Cu(I) halide, sulfate, perchlorate, acetate, triflate, and complexes thereof, or Cu(II) halide, sulfate, triflate in combination with a reducing agent, which can be used in any one of copper-catalyzed click reactions.

[0027] Correspondingly, a pharmaceutical composition comprises the above compound or the compound prepared by the above preparation method, or its stereoisomers, tautomers or salts, or its prodrug molecules and a medically acceptable carrier.

[0028] Correspondingly, the use of the above compound or the compound prepared by the above preparation method, or its stereoisomer, tautomer or salt, or its prodrug molecule or the above pharmaceutical composition in the preparation of drugs for treating cancer or tumors.

[0029] The present invention has the following beneficial effects:

[0030] 1. The present invention adopts a one-step synthesis strategy, using 6-azido-substituted 1-indole carbonyl glycoside or 6-azido-substituted 1,3-bisindole carbonyl glycoside as raw materials to efficiently synthesize a series of indole carbonyl glycoside macrocyclic compounds. The entire synthesis process has the advantages of mild conditions, good selectivity and simple operation.

[0031] 2. Because the protecting groups in the raw materials can be removed under mild conditions, and the nitro groups in the raw materials can be further converted to amino groups through simple reactions and further undergo other reactions, such as deamination to form 2-deoxysugars, which form amide bonds with carboxylic acids and undergo reductive amination to form amine derivatives; the ortho-position (alpha-position) of the nitro group can also further react with other electrophiles under alkaline conditions to form various sugar derivatives; and the unsaturated nitroolefin moiety in structural formula (I) can also undergo a series of reactions with various nucleophiles. Therefore, the present invention provides an irreplaceable route for the diverse synthesis and modification of sugar derivatives of indole carbonyl glycosides.

[0032] 3. Some of the 1,3-bisindole-substituted macrocyclic sugar derivatives obtained in the present invention exhibit broad anti-tumor activity and extremely low toxicity to normal liver cells, and are characterized by high efficiency and low toxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The cytotoxic activity of each compound against the following tumor cells and cancer cells (A549 human lung cancer cells; MKN-45 human gastric cancer cells; L-02 human normal liver cells; MCF7 human breast cancer cells; HCT 116 human colon cancer cells; 5637 human bladder cancer cells; DU145 human prostate cancer cells; CAL-62 human thyroid cancer cells; PATU8988T human pancreatic cancer cells; A-673 human rhabdomyosarcoma cells);

[0034] Figure 2 is the half-maximal inhibitory concentration IC of compound W5 on the positive drug doxorubicin hydrochloride (Dox) against human gastric cancer cells (MKN-45) 50 value. DETAILED DESCRIPTION

[0035] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0036] Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art.

[0037] 1. The present invention discloses a method for synthesizing an indole carbon glycoside macrocyclic compound, the specific process of which is as follows: adding a catalyst to 6-azido-substituted 1-indole carbon glycoside or 6-azido-substituted 1,3-bisindole carbon glycoside, stirring in an organic solvent at a certain temperature for 12 to 24 hours to form an indole sugar carbon glycoside macrocyclic compound. The 6-azido-substituted 1-indole carbon glycoside or 6-azido-substituted 1,3-bisindole carbon glycoside can be synthesized according to the method described in the patent (patent application number: 202211581675.0).

[0038] The sugar ring portion of the 6-azido-substituted 1-indole carbon glycoside or the 6-azido-substituted 1,3-bisindole carbon glycoside is synthesized using glucose as a substrate, the sugar terminal indole portion is one of 5-propargyloxy, 5-n-butynyloxy, and 5-n-pentynyloxy, the concentration of the organic solvent is 0.001 to 100 mol / L, the reaction temperature is -100 to 200° C., and the amount of the catalyst used is 0.001 equivalents to 100.0 equivalents.

[0039] The organic solvent is one or a mixture of any proportion of dichloromethane, chloroform, acetonitrile, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, tetrahydrofuran, N,N-dimethylformamide, DMF, DMSO, 1,4-dioxane, 2-methyl-tetrahydrofuran, diethyl ether, tert-butyl methyl ether, polyethylene glycol and derivatives thereof;

[0040] The catalyst is a Cu(I) halide, sulfate, perchlorate, acetate, triflate, and a complex thereof (such as copper(I) trifluoromethanesulfonate toluene complex {CuOTf·C6H6}, copper(I) tetraacetic cyanide hexafluorophosphate tetrafluoroborate {[Cu(NCCH3)4][PF6]}, cuprous iodide triethoxyphosphine complex {CuI·P(OEt)3}, cuprous bromide tetratriphenylphosphine complex {CuBr·(PPh3)4}), or a Cu(II) halide, sulfate, triflate combined with a reducing agent can be used in a copper-catalyzed click reaction (X.Chen et al Chem.Rev.2016,116,3086-3240; VKTiwari et al Chem.Rev.2021,121,7638-7956).

[0041] 2. The structural formula of the indole sugar carbon glycoside macrocyclic compound prepared by method 1 is shown in the following formula (I):

[0042]

[0043] Wherein, Pg is any one of a hydrogen atom, a methyl group, an acetyl group, a benzoyl group, a benzyl group, an allyl group, a sulfonyl group, and a silicon group;

[0044] PgO can be substituted by azide, substituted amino, sulfhydryl, alkyl sulfide, and aryl sulfide;

[0045] R 1 is any one of a hydrogen atom, a methyl group, a benzyl group, an allyl group, a propargyl group, an alkyl group, a cycloalkyl group, a sulfonyl group, an acyl group, and an alkoxycarbonyl group;

[0046] R 2 is one or more of a hydrogen atom, a halogen, a methyl group, an alkyl group, a methoxy group, a benzyloxy group, an aromatic ring, an aromatic heterocycle, an allyloxy group, a propargyloxy group, a nitro group, an ester group, a carbonyl group, a cyano group, an alkyl sulfide group, an aryl sulfide group, and a substituted amino group;

[0047] X is any one of C, N, O, S, and Si;

[0048] n=0, 1, 2...1000, which is a natural number.

[0049] Furthermore, the structural formula can be shown as follows:

[0050]

[0051] Among them, R 1 、R 2 , Pg, PgO, X, n are the same as above.

[0052] R 3 is any one of a hydrogen atom, a methyl group, a benzyl group, an allyl group, a propargyl group, an alkyl group, a cycloalkyl group, a sulfonyl group, an acyl group, and an alkoxycarbonyl group;

[0053] R 4 They are one or more of hydrogen atom, halogen, methyl, alkyl, methoxy, benzyloxy, aromatic ring, aromatic heterocycle, allyloxy, propargyloxy, nitro, ester group, carbonyl, cyano, alkyl sulfide group, aryl sulfide group and substituted amino group.

[0054] Further, when Pg is any one of methyl, acetyl, benzoyl, benzyl, allyl, sulfonyl, and silicon, it can be replaced by one or more independent R X Substituents substituted;

[0055] When PgO is any one of amino, mercapto, alkyl sulfide, and aryl sulfide, it can be replaced by one or more independent R X Substituents substituted;

[0056] When R 1 、R 3When each of the following groups is selected from methyl, benzyl, allyl, propargyl, alkyl, cycloalkyl, sulfonyl, acyl, and alkoxycarbonyl, each of the following groups may be replaced by one or more independent R X Substituents substituted;

[0057] When R 2 、R 4 When it is any one of methyl, alkyl, methoxy, benzyloxy, aromatic ring, aromatic heterocycle, allyloxy, propargyloxy, nitro, ester group, carbonyl, cyano, alkyl sulfide group, aryl sulfide group, and substituted amino group, it may be replaced by one or more independently R X Substituents substituted;

[0058] The R X It is any one of a hydrogen atom, a halogen, an alkyl group, a fluoroalkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, an aryl group, an amino group, an alkoxy group, a substituted amino group, an amide group, a hydroxyl group and a sulfonamide group.

[0059] Furthermore, when R X When it is any one of alkyl, fluoroalkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, aryl, amino, alkoxy, substituted amino, amide, hydroxyl, and sulfonamide, it may be substituted by one or more hydrogen atoms, alkyl, fluoroalkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, aryl, amino, alkoxy, substituted amino, amide, hydroxyl, and sulfonamide.

[0060] The general reaction formula is as follows:

[0061]

[0062] 3. The present invention discloses a pharmaceutical composition comprising the above-mentioned compound or the compound prepared by the above-mentioned preparation method, or its stereoisomers, tautomers or salts, or its prodrug molecules and a medically acceptable carrier.

[0063] 4. The present invention also discloses the use of the above-mentioned compound or the compound prepared by the above-mentioned preparation method, or its stereoisomers, tautomers or salts, or its prodrug molecules or the above-mentioned pharmaceutical composition in the preparation of drugs for treating cancer or tumors.

[0064] In order to further illustrate the synthesis of the 1,3-bisindole substituted glycoside macrocyclic compound or 1-indole-2-nitroene sugar macrocyclic compound in the present invention, the present invention selectively synthesized the following substances, and described the synthesis process of each compound in combination with specific examples.

[0065]

[0066] Example 1

[0067] To a reaction tube were added (1R,2R,4S,5R)-2-nitro-1-((1H-5-propargyloxy)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose-2-ene (82.2 mg, 0.2 mmol), CuBr (2.9 mg, 0.1 equivalent), and tetrahydrofuran (1.0 mol / L) at room temperature. The reaction was stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3:1) to obtain compound W1 (23.0 mg, 28% yield).

[0068] The reaction equation is:

[0069]

[0070] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0071] 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.42(d,J=2.3Hz,2H),7.30(d,J=8.6Hz,1H),7.09(t,J=2.2Hz,1H),6.84(dd,J=8.8,2.3Hz,1H),6.15(t,J= 2.6Hz,1H),5.31–5.24(m,2H),5.16(dt,J=8.9,2.6Hz,1H),4.90(d,J=14 .6Hz,1H),4.75(dd,J=14.7,3.2Hz,1H),4.39–4.31(m,2H),2.23(s,3H). 13 C NMR(151MHz,DMSO-d6)δ170.0,150.3,149.3,143.1,133.9,131.6,128.5,127.8,124 .4,117.1,116.5,113.1,109.9,70.6,70.0,67.6,63.3,49.4,21.2.HRMS(ESI)calcd for C 19 H 17 N5NaO6[M+Na] + 434.1071,found434.1071.

[0072] Example 2

[0073] To a reaction tube were added (1R,2R,4S,5R)-2-nitro-1-((1H-5-n-butynyloxy)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose-2-ene (85.0 mg, 0.2 mmol), CuBr (2.9 mg, 0.1 equiv) and tetrahydrofuran (1.0 mol / L) at room temperature. The reaction was stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3:1) to give compound W2 (34.8 mg, 41% yield).

[0074] The reaction equation is:

[0075]

[0076] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0077] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.64(s,1H),7.27–7.12(m,3H),6.76(dd ,J=8.7,2.4Hz,1H),6.07(t,J=2.7Hz,1H),5.90(d,J=2.4Hz,1H),5.34(dt,J=8. 9,2.7Hz,1H),4.78(dd,J=14.5,3.5Hz,1H),4.65(dd,J=14.5,5.1Hz,1H),4.52– 4.40(m,1H),4.28(dq,J=11.0,6.5,5.1Hz,2H),3.08–2.83(m,2H),2.21(s,3H). 13 C NMR(101MHz,DMSO-d6)δ170.26,152.13,150.80,145.39,132.24,130.71,126.18,125.86,124.95, 115.06,112.68,109.56,108.07,72.16,70.45,70.39,64.94,49.74,27.58,21.30.HRMS(ESI)calcd for C 20 H 19 N5NaO6[M+Na] + 448.1228, found 448.1224.

[0078] Example 3

[0079] To a reaction tube were added (1R,2R,4S,5R)-2-nitro-1-((1H-5-n-pentynyloxy)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose-2-ene (87.8 mg, 0.2 mmol), CuBr (2.9 mg, 0.1 equiv) and tetrahydrofuran (1.0 mol / L) at room temperature. The reaction was stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3:1) to give compound W3 (28.1 mg, 32% yield).

[0080] The reaction equation is:

[0081]

[0082] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0083] 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),7.62(s,1H),7.30(d,J=2.6Hz,1H),7.24(d,J=8. 7Hz,1H),7.09(s,1H),6.68(dd,J=8.7,2.4Hz,1H),6.45(d,J=2.5Hz,1H),6.17(t,J=2. 6Hz,1H),4.86(d,J=8.9Hz,1H),4.76(t,J=3.9Hz,2H),4.39(dd,J=8.1,4.1Hz,1H),4.0 6(t,J=10.5Hz,1H),3.93–3.72(m,1H),2.67(d,J=5.6Hz,2H),2.19(s,3H),1.88(s,2H). 13 CNMR(151MHz,DMSO-d6)δ170.0,151.3,151.1,146.9,131.8,130.1,126.3,125.8,124.2,1 14.8,113.3,108.5,101.1,73.0,71.2,64.5,64.3,49.7,27.3,21.2,20.8.HRMS(ESI)calcd for C 21 H 21 N5NaO6[M+Na] + 462.1384, found 462.1379.

[0084] Example 4

[0085] To a reaction tube were added (1R,2R,4S,5R)-2-nitro-1-((1-methyl-5-propargyloxy)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose-2-ene (82.2 mg, 0.2 mmol), CuBr (2.9 mg, 0.1 equivalent) and tetrahydrofuran (1.0 mol / L) at room temperature. The reaction was stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3:1) to give compound W4 (38.6 mg, 47% yield).

[0086] Reaction equation:

[0087]

[0088] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0089] 1 H NMR (400MHz, DMSO-d6) δ7.42(d,J=7.0Hz,2H),7.34(d,J=8.6Hz,1H),7.09(s,1H),6.90(d,J=8.8Hz,1H),6.13(t,J=2.7Hz,1H),5.27(d,J=11. 4Hz,2H),5.15(d,J=8.6Hz,1H),4.89(d,J=14.6Hz,1H),4.72(dd,J=15.0,3.1Hz,1H),4.33(dd,J=11.0,7.0Hz,2H),3.72(s,3H),2.21(s,3H). 13 C NMR(101MHz,DMSO-d6)δ170.1,150.2,149.6,143.1,134.7,134.6,131.8,131.6,128.6,12 4.7,117.2,116.6,111.6,108.9,70.7,69.8,67.7,63.3,49.4,33.1,21.2.HRMS(ESI)calcd for C 20 H 19 N5NaO6[M+Na] + 448.1228,found448.1224.

[0090] Example 5

[0091] To a reaction tube were added (1S,2R,3R,4S,5R)-2-nitro-1-((1-methyl-5-propargyloxy)-3-indolyl)-3-((1-methyl)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose (111.4 mg, 0.2 mmol), CuBr (2.9 mg, 0.1 equiv) and tetrahydrofuran (1.0 mol / L) at room temperature. The reaction was stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3:1) to give compound W5 (65.9 mg, 59% yield).

[0092] The reaction equation is:

[0093]

[0094] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0095] 1 H NMR (400MHz, DMSO-d6) δ7.64(s,1H),7.52(s,1H),7.41(d,J=8.2Hz,1H),7.35(d, J=7.5Hz,2H),7.16(d,J=8.5Hz,2H),7.08(t,J=7.5Hz,1H),6.95(dd,J=8.7,2.3Hz ,1H),5.66(s,1H),5.42–5.27(m,3H),5.10(s,1H),4.84(d,J=13.5Hz,1H),4.42(d ,J=12.7Hz,1H),4.32(s,1H),4.19(s,2H),3.77(s,3H),3.72(s,3H),1.72(s,3H). 13 C NMR(101MHz,DMSO-d6)δ149.5,142.7,134.48,131.3,126.8,126.0,121.8,119.5,119.0,117.8,11 7.8,116.4,111.1,110.7,110.5,88.2,77.6,74.3,67.3,51.12,33.1,33.0,20.9.HRMS(ESI)calcd for C 29 H 28 N6NaO6[M+Na] + 579.1963, found 579.1961.

[0096] Example 6

[0097] To a reaction tube were added (1S,2R,3R,4S,5R)-2-nitro-1-((1-H-5-propargyloxy)-3-indolyl)-3-((1-methyl)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose (108.4 mg, 0.2 mmol), CuBr (2.9 mg, 0.1 equiv) and tetrahydrofuran (1.0 mol / L) at room temperature. The reaction was stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3:1) to give compound W6 (65.9 mg, 58% yield).

[0098] The reaction equation is:

[0099]

[0100] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0101] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),7.66(s,1H),7.54(s,1H),7.42(d,J=8.2Hz,1H),7 .36(s,1H),7.31(d,J=8.7Hz,1H),7.25–7.14(m,2H),7.09(t,J=7.5Hz,1H),6.89(dd,J=8 .6,2.2Hz,1H),5.76–5.65(m,1H),5.32(t,J=16.4Hz,3H),5.11(s,1H),4.85(d,J=13.3H z,1H),4.43(d,J=12.7Hz,1H),4.39–4.29(m,1H),4.22(s,2H),3.78(s,3H),1.72(s,3H). 13 C NMR (151MHz, DMSO-d6) δ169.71,149.22,142.79,133.73,131.35,126.54,121.82,119.48,118.95,117. 65,116.09,112.66,111.61,110.44,88.14,77.69,74.45,67.22,51.14,33.04,20.83.HRMS(ESI)calcd for C 28 H 26 N6NaO6[M+Na] + 565.1806,found565.1807.

[0102] Example 7

[0103] To a reaction tube were added (1S,2R,3R,4S,5R)-2-nitro-1-((1H-5-n-pentynyloxy)-3-indolyl)-3-((1-methyl)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose (114.0 mg, 0.2 mmol), CuBr (2.9 mg, 0.1 equiv) and tetrahydrofuran (1.0 mol / L) at room temperature. The reaction was stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3:1) to give compound W7 (57.0 mg, 50% yield).

[0104] The reaction equation is:

[0105]

[0106] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0107] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.69(s,1H),7.60(d,J=8.0Hz,1H),7.52(s,1H),7.38(d,J=8.2H z,1H),7.29–7.23(m,2H),7.16(t,J=7.6Hz,1H),7.07(t,J=7.6Hz,1H),6.83(d,J=12.1Hz,1H),6.76–6. 69(m,1H),5.63(t,J=10.6Hz,1H),5.40(d,J=9.7Hz,1H),4.99(s,1H),4.65(d,J=13.0Hz,1H),4.52(q,J =12.0,9.3Hz,2H),4.15(t,J=8.1Hz,3H),3.73(s,3H),2.68(d,J=6.9Hz,2H),1.96(s,2H),1.67(s,3H). 13 C NMR (101MHz, DMSO) δ168.67,151.45,146.54,131.97,126.28,124.35,124.16,121.73,119.39,114.84,113. 15,110.37,109.71,101.65,89.02,77.34,75.95,64.61,49.56,32.98,27.35,20.81,20.73.HRMS(ESI)calcd for C 30 H 30 N6NaO6[M+Na] + 593.2119, found 593.2118.

[0108] Example 8

[0109] To a reaction tube were added (1S,2R,3R,4S,5R)-2-nitro-1-((1-methyl-5-n-pentynyloxy)-3-indolyl)-3-((1-methyl)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose (116.8 mg, 0.2 mmol), CuBr (2.9 mg, 0.1 equiv) and tetrahydrofuran (1.0 mol / L) at room temperature. The reaction was stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3:1) to give compound W8 (53.7 mg, 46% yield).

[0110] The reaction equation is:

[0111]

[0112] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0113] 1 H NMR (400MHz, DMSO-d6) δ7.62(d,J=23.3Hz,2H),7.51(s,1H),7.38(d,J=8.2Hz,1H),7.31(d,J= 8.7Hz,1H),7.27(s,1H),7.15(t,J=7.6Hz,1H),7.07(t,J=7.5Hz,1H),6.84(s,1H),6.78(dd,J= 8.8,2.3Hz,1H),5.60(t,J=10.6Hz,1H),5.38(d,J=9.7Hz,1H),4.98(s,1H),4.64(d,J=12.2Hz, 1H),4.60–4.44(m,2H),3.71(d,J=9.3Hz,6H),2.67(d,J=6.2Hz,2H),1.95(s,2H),1.67(s,3H). 13 C NMR(151MHz,DMSO-d6)δ168.6,151.6,146.5,132.7,126.6,124.2,121.7,119.4,114.9,1 11.6,108.7,77.3,64.7,56.5,55.4,33.1,33.0,27.3,20.8,20.7,19.0.HRMS(ESI)calcd for C 31 H 30 N6NaO6[M+Na] + 607.2276,found 607.2276.

[0114] Example 9 Activity Test

[0115] The concentration of doxorubicin hydrochloride (Dox) was 10 μM, and the concentration of the other compounds (W2-W8) was 20 μM. The cytotoxic activity of the following cancer cells or tumor cells (A549 human lung cancer cells; MKN-45 human gastric cancer cells; L-02 human normal liver cells; MCF7 human breast cancer cells; HCT 116 human colon cancer cells; 5637 human bladder cancer cells; DU145 human prostate cancer cells; CAL-62 human thyroid cancer cells; PATU8988T human pancreatic cancer cells; A-673 human rhabdomyosarcoma cells) was tested using the CCK-8 method. The results are shown in Figure 2. Figure 1 As shown, compounds W2-W7 have good activity against different tumor cells or cancer cells.

[0116] Figure 2 IC of W5 and positive control doxorubicin hydrochloride (Dox) against MKN-45 human gastric cancer cells 50 Value, IC of compound W5 50 =2.4161±0.2435μM, IC of positive control doxorubicin hydrochloride (Dox) 50 =0.0428±0.0024μM.

[0117] The embodiments described above are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by persons skilled in the art should fall within the scope of protection defined by the claims of the present invention.

Claims

1. An indole sugar carbon glycoside macrocyclic compound, characterized in that: The structural formula is any one of the following structural formulas: 。 2. A method for preparing the indole sugar carbon glycoside macrocyclic compound according to claim 1, characterized in that: A catalyst is added to 6-azido-substituted 1-indole carbonyl glycoside or 6-azido-substituted 1,3-bisindole carbonyl glycoside, and the mixture is stirred overnight in an organic solvent to form an indole sugar carbonyl glycoside macrocyclic compound; The 6-position azide-substituted 1-indole carbon glycoside is (1 R ,2 R ,4 S ,5 R )-2-nitro-1-((1H-5-n-butynyloxy)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose-2-ene, (1 R ,2 R ,4 S ,5 R )-2-nitro-1-((1H-5-n-pentynyloxy)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose-2-ene, (1 R ,2 R ,4 S ,5 R )-2-nitro-1-((1-methyl-5-propargyloxy)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose-2-ene; The 6-position azide-substituted 1,3-bisindole carbon glycoside is (1 S ,2 R ,3 R ,4 S ,5 R )-2-nitro-1-((1-methyl-5-propargyloxy)-3-indolyl)-3-((1-methyl)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose, (1 S ,2 R ,3 R ,4 S ,5 R )-2-nitro-1-((1-H-5-propargyloxy)-3-indolyl)-3-((1-methyl)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose, (1 S ,2 R ,3 R ,4 S ,5 R )-2-nitro-1-((1H-5-n-pentynyloxy)-3-indolyl)-3-((1-methyl)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose, (1 S ,2 R ,3 R ,4 S ,5 R )-2-nitro-1-((1-methyl-5-n-pentynyloxy)-3-indolyl)-3-((1-methyl)-3-indolyl)-4-acetoxy-5-azidomethylenepyranose.

3. The method for preparing an indole sugar carbon glycoside macrocyclic compound according to claim 2, characterized in that: The concentration of the organic solvent is 1.0 mol / L, the reaction temperature is room temperature, and the amount of catalyst used is 0.1 equivalent.

4. The method for preparing an indole sugar carbon glycoside macrocyclic compound according to claim 2, wherein: The organic solvent is one or a mixture of any proportion of dichloromethane, chloroform, acetonitrile, methanol, ethanol, tert-butanol, isopropanol, benzene, toluene, tetrahydrofuran, N,N-dimethylformamide, DMF, DMSO, 1,4-dioxane, 2-methyl-tetrahydrofuran, diethyl ether, tert-butyl methyl ether, polyethylene glycol and derivatives thereof; The catalyst is Cu(I) halide, sulfate, perchlorate, acetate, triflate, and complexes thereof, or Cu(II) halide, sulfate, triflate in combination with a reducing agent, which can be used in any one of copper-catalyzed click reactions.

5. A pharmaceutical composition, characterized in that: The invention comprises the compound according to claim 1 or the compound prepared by the preparation method according to any one of claims 2 to 4, or a salt thereof and a medically acceptable carrier.

6. Use of the compound according to claim 1 or the compound prepared by the method according to any one of claims 2 to 4, or a salt thereof, or the pharmaceutical composition according to claim 5 in the preparation of a drug for treating cancer or tumors, characterized in that: The use of compound W2 in the preparation of drugs for treating MKN-45 human gastric cancer, HCT 116 human colon cancer, 5637 human bladder cancer, and CAL-62 human thyroid cancer; The use of compound W3 in the preparation of drugs for treating MKN-45 human gastric cancer, HCT 116 human colon cancer, 5637 human bladder cancer, DU145 human prostate cancer, CAL-62 thyroid cancer, and A-673 human rhabdomyosarcoma; The use of compound W4 in the preparation of drugs for treating MKN-45 human gastric cancer, HCT 116 human colon cancer, 5637 human bladder cancer, DU145 human prostate cancer, and A-673 human rhabdomyosarcoma; Use of compound W5 in the preparation of a medicament for treating A549 human lung cancer, MKN-45 human gastric cancer, MCF7 human breast cancer, HCT 116 human colon cancer, 5637 human bladder cancer, DU145 human prostate cancer, CAL-62 thyroid cancer, PATU8988T human pancreatic cancer, and A-673 human rhabdomyosarcoma; The invention relates to the use of compound W6 in the preparation of drugs for treating A549 human lung cancer, MKN-45 human gastric cancer, 5637 human bladder cancer, CAL-62 thyroid cancer, PATU8988T human pancreatic cancer and A-673 human rhabdomyosarcoma.

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