Lamellarin D and N disaccharide monosubstituted derivative, preparation method and application

Abstract

The invention discloses a disaccharide monosubstituted derivative of Lamellarin D and N. The structure of the disaccharide monosubstituted derivative is as follows: R1 and R2 are respectively and independently selected from one of H, methyl, benzyl, acetyl and disaccharide, R3 is selected from H, benzyl or disaccharide, R4 is selected from H, methylsulfonyl or disaccharide, and at least one of R1-R4 is disaccharide; the disaccharide group is one of cellobiose group, acetylated cellobiose group, lactosyl group, acetylated lactosyl group, maltose group and acetylated maltose group. According to the present invention, at least one disaccharide group is introduced into R1-R4 to obtain the disaccharide mono-substituted derivative of Lamellarin D and N, the proliferation inhibition activity of tumor cells is improved with the compound and the monosaccharide substituted derivative, and the inhibition effect on non-solid tumor cell line Jurkat is significantly improved by about 5 times;

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular to a disaccharide monosubstituted derivative of Lamellarin D and N, a preparation method and application. BACKGROUND

[0002] Lamellarin D and Lamellarin N are both polycyclic pyrrole alkaloids isolated from marine soft-bodied animals Lamellaria sp. and Plakobranchus ocellatus, respectively (Andersen R J, et al. Metabolites of the marine prosobranch mollusk Lamellaria sp [J]. J. Am. Chem. Soc., 1985, 107(19): 5492-5495.), and their structures are as follows: Lamellaria Didemnum They exhibit different degrees of biological activities such as tumor cell proliferation inhibition, Topo I inhibition, kinase inhibition, interference with normal mitochondrial function and induction of cell aging. However, the unique five-ring coplanar skeleton structure of Lamellarin D / N leads to poor water solubility, which affects its drugability, so various modification strategies such as amino acid derivatization, polyethylene glycol derivatization, Mannich base derivatization and monosaccharide derivatives have emerged.

[0003] Reference 1 (Zheng Liuliu, et al. Design, Synthesis and Structure-Activity Relationship Studies of Glycosylated Derivatives of Marine Natural Product Lamellarin D. Eur. J. Med. Chem. 2021, 214: 113226.) discloses a series of glycosylated derivatives of Lamellarin D, including monosaccharide derivatives with a monosaccharide group introduced at position 8, 14 or 20, and disaccharide derivatives with monosaccharide groups introduced at positions 14 and 20. The monosaccharide derivatives show excellent in vitro anti-tumor activity, while the disaccharide derivatives show lower anti-tumor activity than Lamellarin D.

[0004] ​​​The monosubstituted disaccharide has more complex spatial structure than the disubstituted monosaccharide, and the novel structural difference significantly affects the biological activity, solubility and recognition characteristics of the molecule. By modifying the disaccharide by monosubstitution, the selective regulation of specific hydroxyl groups can be achieved, thereby more finely studying the structure-activity relationship. SUMMARY

[0005] To solve the above technical problems, the present application provides a disaccharide monosubstituted derivative of Lamellarin D and N, which improves the proliferation inhibition activity of the compound on tumor cells by introducing at least one disaccharide group in R1~R4, and the inhibition effect on non-solid tumor cell line Jurkat is significantly improved by about 5 times.

[0006] A disaccharide monosubstituted derivative of Lamellarin D and N has the following structure:

[0007] wherein R1 and R2 are independently selected from one of H, methyl, benzyl, acetyl and disaccharide group, R3 is selected from H, benzyl or disaccharide group, R4 is selected from H, methylsulfonyl or disaccharide group, and at least one of R1~R4 is a disaccharide group; The disaccharide group is one of cellobiose group, acetylated cellobiose group, lactose group, acetylated lactose group, maltose group and acetylated maltose group.

[0008] In the present application, by introducing at least one disaccharide group in R1~R4, a disaccharide monosubstituted derivative of Lamellarin D and N is obtained, which improves the proliferation inhibition activity of the compound on tumor cells, and the inhibition effect on non-solid tumor cell line Jurkat is significantly improved by about 5 times. In addition, the activity of the unacetylated disaccharide monosubstituted derivative is significantly better than that of the acetylated disaccharide monosubstituted derivative.

[0009] Preferably, R1 is a disaccharide group, R2 is methyl, R3 is benzyl, and R4 is methylsulfonyl; or R1 is a disaccharide group, R2, R3 and R4 are H or methyl; or R1 is methyl, R2 is a disaccharide group, R3 is benzyl, and R4 is methylsulfonyl; or R1, R3 and R4 are H or methyl, and R2 is a disaccharide group; or R1 is acetyl, R2 is methyl, R3 is a disaccharide group, and R4 is methylsulfonyl; or R1, R2 and R4 are H or methyl, and R3 is a disaccharide group; or R1 is benzyl, R2 is methyl, R3 is benzyl, and R4 is a disaccharide group; or R1, R2, R3 are H or methyl, and R4 is a disaccharide group; said disaccharide group is one of cellobiose group, acetylated cellobiose group, lactose group, acetylated lactose group, maltose group, acetylated maltose group.

[0010] Further preferably, said disaccharide monosubstituted derivatives of Lamellarin D and N are selected from any one of the following structures: , , , , , , , , , , , , , , , , , , , .

[0011] The present application also provides a preparation method of the above-mentioned disaccharide monosubstituted derivatives of Lamellarin D and N, comprising the following steps: a bromine-substituted pyrano[4',3':4,5]pyrrolo[2,1- a ]isoquinoline-6-ketone compound (i.e. compound A) is subjected to Suzuki reaction with a meta-substituted phenylboronic acid ester compound to obtain a compound with hydroxyl protecting groups at positions 8, 13, 14 and 20 (i.e. compound B), followed by addition reaction on the tetrahydroisoquinoline ring to obtain the skeleton of Lamellarin D and N (i.e. compound C), removal of the hydroxyl protecting group at any one of positions 8, 13, 14 or 20 (i.e. compound D) and reaction with a glycosyl donor to obtain an acetylated disaccharide monosubstituted derivative substituted at any one of positions 8, 13, 14 or 20 (i.e. compound E), followed by removal of the acetyl group on the glycosyl group and removal of the hydroxyl protecting group at the remaining position to obtain the disaccharide monosubstituted derivative (i.e. compound F).

[0012] The specific reaction route is as follows:

[0013] In the preparation method of the present application, the method for removing the protecting group (-OBn, -OAc, -OMs) of the hydroxyl group at position 8, 13, 14 or 20 in compounds A~F, i.e. the method for converting into a hydroxyl group, is the prior art, which can be found in the existing literature Shen L, Xie N, Yang B, Hu Y, Zhang Y: Design and total synthesis of Mannich derivatives of marine natural product lamellarin D as cytotoxic agents. Eur. J. Med. Chem. 2014, 85:807-817.

[0014] Preferably, the glycosyl donor is one of 2,2',3,3',4',6,6'-Hepta-O-acetyl-β-D-cellobiosyl trichloroimidate, 2,2',3,3',4',6,6'-Hepta-O-acetyl-β-D-lactosyl trichloroimidate, 2,2',3,3',4',6,6'-Hepta-O-acetyl-β-D-maltosyl trichloroimidate.

[0015] Preferably, the preparation method of the bromo-substituted pyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one compound (i.e. compound A) comprises the following steps: After the ring formation of 6-(benzyloxy)-7-methoxy-1-methyl-3,4-dihydroisoquinoline (i.e. compound G) and 2-(2-bromoacetyl)-4-methoxy-5-((methylsulfonyl)oxy)benzeneacetic acid (i.e. compound H), the hydroxyl group on compound I is acetylated to obtain compound J, and then compound J is subjected to Vilsmeier-Haack reaction, oxidation, deacetylation and intramolecular cyclization to obtain the bromo-substituted pyrano[4',3':4,5]pyrrolo[2,1- a ]isoquinolin-6-one compound; The specific route is as follows: .

[0016] The present application also provides the use of the above-mentioned disaccharide monosubstituted derivative of Lamellarin D and N in the preparation of a medicament for treating liver cancer and leukemia, wherein R1 is methyl, R2 and R4 are both H, and R3 is a maltosyl group.

[0017] The application further provides the use of the above-mentioned disaccharide monosubstituted derivative of Lamellarin D and N in the preparation of a medicament for treating liver cancer and leukemia, wherein R1 is methyl, R2 and R3 are both H, and R4 is a maltobiose group.

[0018] The application further provides the use of the above-mentioned disaccharide monosubstituted derivative of Lamellarin D and N in the preparation of a medicament for treating leukemia, wherein R1 and R4 are both H, R2 is methyl, and R3 is a maltobiose group.

[0019] The application further provides the use of the above-mentioned disaccharide monosubstituted derivative of Lamellarin D and N in the preparation of a medicament for treating breast cancer and leukemia, wherein R1 and R3 are both H, R2 is methyl, and R4 is a maltobiose group.

[0020] Compared with the prior art, the application has the following beneficial effects: In the application, at least one disaccharide group is introduced into R1-R4 to obtain a disaccharide monosubstituted derivative of Lamellarin D and N, which has improved proliferation inhibition activity on tumor cells, and in particular, the inhibition effect on non-solid tumor cell line Jurkat is significantly improved by about 5 times. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figures 1-3 The H-NMR spectrum, 1 H-NMR spectrum, 13 C-NMR spectrum and HR-MS spectrum of the compound MZ13 in Example 13.

[0022] Figure 4 The columnar graph and IC curve of the proliferation inhibition activity of the compounds MZ13, ZL-9, Lamellarin D and N on MDA-MB-231 cell line in Example 13. 50 The columnar graph and IC curve of the proliferation inhibition activity of the compounds MZ13, ZL-9, Lamellarin D and N on MDA-MB-231 cell line in Example 13. DETAILED DESCRIPTION

[0023] The application will be further described in detail below in combination with examples, but the implementation manner of the application is not limited to the following examples.

[0024] The raw materials used in the application are all commercially available.

[0025] 6-(benzyloxy)-7-methoxy-1-methyl-3,4-dihydroisoquinoline (i.e. Compound F) was synthesized according to the procedure described in the reference (Dohle W, Leese M P, Jourdan F L, et al. Synthesis, Antitubulin, and Antiproliferative SAR of C3 / C1-Substituted Tetrahydroisoquinolines [J]. Chemmedchem, 2014, 9(2): 350-370.).

[0026] 2-(2-bromoacetyl)-4-methoxy-5-((methylsulfonyl)oxy)benzeneacetic acid (i.e. Compound G) was synthesized according to the procedure described in the reference (Shen L, Xie N, Yang B, et al. Design and total synthesis of Mannich derivatives of marine natural product lamellarin D as cytotoxic agents [J]. European Journal of Medicinal Chemistry, 2014, 85: 807-817.).

[0027] Example 1: Synthesis of Compound MZ1 (1) Synthesis of Compound I

[0028] Compound G (147 mg, 0.46 mmol, 1.0 equiv.) and Compound H (130 mg, 0.39 mmol, 1.2 equiv.) were dissolved in 7 mL of ethanol, and stirred at 50 °C under nitrogen protection for 2 h. After the reaction was monitored to be completed by TLC, it was cooled to room temperature, concentrated, and the residue was purified by column chromatography (eluent DCM / EA = 50 / 1, v / v) to obtain 91 mg of yellow foamy solid with a yield of 45%. 1 H NMR (500 MHz, DMSO- d 6) δ 9.57 (s, 1H), 7.49 – 7.45 (m, 2H), 7.43(d, J = 1.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.30 (s,1 H), 7.21 (s, 1 H ), 7.00 (s, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 5.08 (s, 2H), 4.06 (t, J = 6.5 Hz, 2H), 3.86 (s, 3), 3.84 (s, 3H), 3.31 (s, 3H), 2.94 (t, J =6.5 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 149.29, 147.19, 146.68, 145.40, 137.18,136.95, 131.57, 128.73, 128.05, 127.45, 123.17, 122.45, 122.27, 119.43,118.92, 114.34, 113.62, 112.11, 106.68, 101.84, 71.42, 56.87, 56.39, 44.51,38.29, 28.86.HR-MS(ESI / QTOF) m / z: [M+H] + Calcd for C 28 H 28 NO7S + 522.1581; Found522.1579.

[0029] (2) Synthesis of compound J Compound J (490 mg, 0.94 mmol, 1.0 equiv.) was dissolved in 20 mL of DCM, TEA (0.15 mL, 1.41 mmol, 1.5 equiv.) and AcCl in DCM (1.41 mL, 1.41 mmol, c = 1.0 mol / L, 1.5 equiv.) were added slowly under ice-bath condition. TLC indicated the starting material was consumed completely, the reaction was quenched with ice-water, the organic layer was separated, washed with water (2 x 20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The residue was concentrated under reduced pressure and directly dissolved in 2 mL of DMF. Meanwhile, POCl3(0.13 mL, 1.41 mmol, 1.5 equiv.) was added slowly into anhydrous DMF under ice-water bath condition. After the dropping was completed, the reaction was stirred for half an hour, then the DMF solution of the crude product from the previous step was added. Subsequently, the reaction was slowly warmed to room temperature and stirred for 3 hours. TLC indicated the starting material was consumed completely, 20 mL of ice-water was added and stirred for half an hour. The aqueous phase was extracted with EA for three times (3 x 30 mL), the organic phases were combined, washed with water (2 x 30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by column chromatography (eluent DCM / EA = 50 / 1, v / v) to give 338 mg of a light yellow foamy solid, 61% yield for two steps.

[0030] 1 H NMR (500 MHz, CDCl3) δ 9.43 (s, 1), 7.45 (d, J = 7.5 Hz, 2H), 7.39(t, J = 7.5 Hz, 2), 7.35 – 7.31 (m, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 7.02 (s,1H), 6.79 (s, 1), 6.50 (s, 1H), 5.19 (s, 2H), 4.67 (t, J = 7.0 Hz, 2H), 3.92(s, 3H), 3.91 (s, 3H), 3.24 (s, 3H), 3.00 (t, J = 7.0 Hz, 2H), 2.10 (s, 3H). 13CNMR (125 MHz, CDCl3) δ 179.93, 169.19, 149.41, 149.20, 149.13, 141.48,137.73, 137.50, 136.76, 133.78, 128.81, 128.21, 127.38, 127.35, 126.93,125.82, 120.09, 119.64, 115.78, 113.67, 108.13, 106.15, 71.19, 56.65, 56.48,42.59, 38.59, 28.26, 20.92.HR-MS(ESI / QTOF) m / z: [M+H] + Calcd for C 31 H 30 NO9S + 592.1636; Found 592.1629.

[0031] (3) Synthesis of compound A Compound J was dissolved in 56 mL of THF / tBuOH (v / v = 1 : 1) and 1.58 mL of 2-methyl-but-2-ene was added. Subsequently, the solution was cooled to -10 °C in an ice-ethanol bath and 4 mL of an aqueous solution of 80% sodium chlorite (321 mg, 2.85 mmol, 3.0 equiv.) and sodium phosphate monobasic (340 mg, 2.85 mmol, 3.0 equiv.) was added. The mixture was stirred at 5-10 °C for 12 h, the solution turned yellow and a white precipitate appeared. TLC indicated complete conversion of the starting material. The reaction was quenched with ice-saturated ammonium chloride solution and diluted with 60 mL of EA. The organic layer was separated and washed with water (2 x 50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed by rotary evaporation under reduced pressure. The residue was dissolved in a mixture of 1,4-dioxane / MeOH (v / v = 1 : 1) without purification. The reaction was equilibrated in an ice-water bath and 1 M LiOH solution was added dropwise until complete conversion of the substrate. The reaction was quenched with ice 0.1 M hydrochloric acid and the aqueous phase was extracted with EA (3 x 50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in anhydrous DCM and DCC in DCM (0.95 mL, 0.95 mmol, c = 1.0 mol / L, 1.0 equiv.) was added under ice-water bath. The reaction was allowed to warm to room temperature and stirred for 1 h. TLC indicated complete conversion of the starting material. The reaction was filtered and the filter cake was washed with DCM three times. The filtrate was collected and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by column chromatography (eluent PE / EA = 1 / 1, v / v) to give 179 mg of white solid with a total yield of 34% over three steps. To a solution of the above white solid (200 mg, 0.37 mmol, 1.0 equiv.) in DCM (2 mL) was added Ph2CH2N + (C2H5)3Br3 - in DCM (0.48 mL, 0.48 mmol, c = 1.00 mol / L, 1.3 equiv.) dropwise under ice-bath condition. Subsequently, the reaction was allowed to warm to room temperature and stirred for half an hour. The reaction was quenched with saturated sodium thiosulfate solution. The aqueous phase was extracted with DCM three times (3 x 20 mL), and the combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was recrystallized with MeOH to give 210 mg of white powder with a yield of 92%.

[0032] 1 H NMR (500 MHz, DMSO- d6) δ 8.39 (s, 1), 8.08 (s, 1H), 7.55 (s, 1H),7.49 (d, J = 7.0 Hz, 2), 7.42 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.21(s, 1H), 5.18 (s, 2H), 4.67 (t, J = 6.5 Hz, 2H), 3.97 (s, 3H), 3.87 (s, 3H),3.45 (s, 3H), 3.07 (t, J =6.5 Hz, 2H).HR-MS (ESI / QTOF) m / z: [M+H] + Calcd forC 29 H 25 BrNO8S + 626.0479; Found 626.0478。

[0033] (4) Synthesis of compound B-1

[0034] Compound A (62.6 mg, 0.010 mmol, 1.0 equiv.), 2-methoxy-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (58.4 mg, 0.020 mmol, 2.0 equiv.) and Pd(dppf)Cl2(7.3 mg, 0.001 mmol, 0.1 equiv.) were dissolved in 5 mL of tetrahydrofuran, and an aqueous solution of K2CO3(0.200 mL, 0.002 mmol, c = 1.0 mol / L, 2.0 equiv.) was added. After the reaction was replaced with nitrogen three times, it was heated to reflux and stirred for 24 hours. After TLC detection showed that the starting material was completely converted, the reaction solution was diluted with 20 mL of EA, and the reaction was quenched by adding a saturated solution of ammonium chloride (10 mL). The organic layer was separated, washed with water (2 x 10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent PE / EA = 3 / 2, v / v) to obtain 66.6 mg of a white solid, with a yield of 94%.

[0035] 1 H NMR (500 MHz, CDCl3) δ 7.42 (d, J= 7.0 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.32 (d, J = 7.5 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H,), 7.14 (dd, J = 8.0, 2.0Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.78 (s, 1H), 6.73 (s, 1H), 6.72 (s, 1H), 5.17 (s, 2H), 4.76 – 4.80 (m, 2H), 3.82 (s, 3H), 3.49 (s, 3H), 3.41 (s, 3H),3.18 (s, 3H), 3.07 (q, J = 6.5 Hz, 2H), 2.36 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ168.89, 154.94, 152.40, 148.56, 148.49, 148.09, 144.88, 140.17, 136.99,136.76, 136.11, 134.27, 128.80, 128.19, 127.34, 126.81, 126.42, 124.06,123.40, 120.14, 117.61, 115.15, 114.89, 114.79, 113.66, 113.59, 109.06,106.05, 71.09, 56.38, 56.03, 55.58, 42.69, 38.70, 28.59, 24.99, 20.74.HR-MS(ESI / QTOF) m / z: [M+H] + Calcd for C 38 H 34 NO 11 S + 712.1847; Found 712.1834.

[0036] (5) Synthesis of compound C-1 To a solution of compound B-1 (281 mg, 0.395 mmol, 1.0 equiv.) in DCM (30 mL) was added DDQ (100 mg, 0.434 mmol, 1.1 equiv.) at room temperature, and the reaction mixture was heated to reflux and stirred for 30 h. After cooling to room temperature, the reaction mixture was diluted with 30 mL of DCM, and the organic layer was washed with saturated sodium bicarbonate (3 x 30 mL), water (2 x 30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. After concentration under reduced pressure, the residue was purified by column chromatography (eluent PE / EA = 1 / 1, v / v) to give 66.6 mg of a white solid as a product in 94% yield.

[0037] 1 H NMR (500 MHz, DMSO- d 6) δ 9.06 (d, J = 7.5 Hz, 1H, C-8- H ), 7.54 (s,1H, C-4- H ), 7.53 (s, 1H, C-1- H ), 7.47 (d, J = 8.0 Hz, 3H), 7.44 – 7.38 (m, 3H),7.30 – 7.40 (m, 2H), 7.25 (dd, J = 8.0, 2.0 Hz, 1H), 7.08 (s, 1H), 6.85 (s,1H), 5.19 (s, 2H), 3.80 (s, 3H), 3.43 (s, 3H), 3.41 (s, 3H), 3.37 (s, 3H),2.34 (s, 3H). 13 C NMR (125 MHz, DMSO- d6) δ 169.33, 154.23, 152.66, 150.02,149.74, 148.45, 145.16, 140.32, 137.93, 136.88, 134.13, 133.95, 129.03,128.58, 127.48, 124.78, 124.72, 123.91, 122.63, 118.87, 117.02, 115.95,114.24, 113.61, 111.89, 110.15, 108.10, 106.85, 105.29, 70.45, 56.84, 55.99,55.31, 39.09, 20.95.HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 38 H 32 NO 11 S + 710.1691;Found 710.1684.

[0038] (6) Synthesis of compound D-1 Compound C-1 (100 mg) was completely dissolved in 40 mL of EA, and 10 mg of 10% Pd-C powder was added. After purging with hydrogen three times, the mixture was heated to 40 °C and reacted for 6 hours. The mixture was filtered through diatomaceous earth, and the filter cake was washed three times with EA. The filtrate was collected. After concentration, the residue was purified by column chromatography (eluent DCM / EA = 25 / 1, v / v) to give 82.9 mg of a pale yellow solid, with a yield of 95%.

[0039] 1 H NMR (500 MHz, DMSO- d 6) δ 10.04 (s, 1H), 9.05 (d, J = 7.5 Hz, 1H),7.56 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.5Hz, 1H), 7.26 (dd, J = 8.0, 2.0 Hz, 1H), 7.24 (s, 1H), 7.07 (s, 1H), 6.87 (s,1H), 3.80 (s, 3H), 3.44 (s, 3H), 3.41 (s, 3H), 3.39 (s, 3H), 2.34 (s, 3H).13 CNMR (125 MHz, CDCl3) δ 169.23, 155.09, 152.84, 148.39, 147.73, 147.49,145.72, 140.67, 138.00, 134.92, 134.83, 128.03, 125.67, 124.49, 124.12,123.46, 119.00, 117.58, 115.59, 114.10, 113.66, 111.41, 111.30, 108.89,107.06, 105.12, 56.70, 56.29, 56.11, 39.04, 21.02.HR-MS(ESI / QTOF) m / z: [M+H] + Calcd for C 31 H 26 NO 11 S + 620.1221; Found 620.1208。

[0040] (7) Synthesis of compound E-1 In the glove box, compound D-1 (20.0 mg, 0.0323 mmol, 1.0 equiv.), 2,2',3,3',4',6,6'-Hepta-O-acetyl-β-D-cellobiosyl trichloroimidate (67.6 mg, 0.0867 mol, 2.6 equiv.) and 20 mg 4 Å molecular sieves were dispersed in 10 mL DCM. The reaction was cooled to -15 ℃, and after stirring for 30 min, 46% BF3·Et2O (24.0 μL, 0.0867 mol, 2.6 equiv.) was added, and the temperature was slowly raised to 0 ℃, and stirred for 3 h. After TLC detection of the reaction was complete, 10% wt TEA / DCM (140 μL, 0.0969 mol, 3.0 equiv.) was added at 0 ℃ to quench, concentrated, and the residue was purified by column chromatography (eluent DCM / EA = 3 / 1, v / v) to give 33.1 mg of white solid, 83% yield.

[0041] 1 H NMR (500 MHz, CDCl3) δ 9.24 (d, J = 7.5 Hz, 1H), 7.40 (s, 1H), 7.39(s, 1H), 7.31 (dd, J= 8.0, 4.5 Hz, 1H), 7.25 – 7.22 (m, 1H), 7.20 (s, 1H),7.14 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.85 (d, J = 6.0 Hz, 1H), 5.30 – 5.26 (m,1H), 5.22 (dd, J = 9.5, 7.5 Hz, 1H), 5.16 (t, J = 9.5 Hz, 1H), 5.08 (t, J = 9.5 Hz,1H), 5.03 (dd, J = 7.5, 5.0 Hz, 1H), 4.94 (dd, J = 9.0, 7.5 Hz, 1H), 4.58 (dt, J =12.0, 2.5 Hz, 1H), 4.55 (d, J = 8.0 Hz, 1H), 4.38 (dd, J = 12.5, 4.5 Hz, 1H),4.16 (ddd, J = 12.0, 5.5, 3.0 Hz, 1H), 4.06 (dd, J = 12.5, 2.5 Hz, 1H), 3.86 (td, J = 9.5, 9.0, 2.5 Hz, 1H), 3.83 (s, 3H), 3.79-3.73 (m, 1H), 3.71 – 3.66 (m,1H), 3.51(s, 3H),3.43(s, 3H), 3.21 (s, 3H), 2.37 (s, 3H)2.12 (d, J = 2.0 Hz,3H), 2.09 (s, 3H), 2.05 (s, 3H), 2.04 (d, J = 1.5 Hz, 6H), 2.02 (s, 3H), 1.99(s, 3H). 13C NMR (125 MHz, CDCl3) δ 170.66, 170.38, 169.92, 169.71, 169.47,169.20, 168.92, 154.93, 150.88, 148.25, 145.48, 140.53, 137.87, 134.37,133.93, 124.30, 124.19, 123.78, 123.30, 121.73, 117.22, 116.45, 115.17,113.97, 113.28, 112.10, 109.13, 106.79, 106.20, 101.01, 100.24, 73.29, 73.02,72.28, 72.19, 71.77, 71.39, 67.92, 61.96, 61.71, 56.43, 56.06, 55.64, 38.84,29.86, 21.01, 20.81, 20.77, 20.70.HR-MS (ESI / QTOF) m / z: [M+H] + Calcd forC 57 H 59 NNaO 28 S + 1260.2837; Found 1260.2837。

[0042] (8) Synthesis of compound MZ1 Compound E-1 (30.0 mg, 0.0242 mmol, 1.0 equiv.) was dissolved in 5 mL MeOH / 1,4-dioxane (v / v = 1:1) mixed solvent. 30% wt NaOMe / MeOH (98.0 μL, 0.484 mmol, 20.0 equiv.) was added under ice bath condition, and slowly warmed to room temperature with stirring for 3 hours. After TLC detection showed the reaction was completely converted, an appropriate amount of cation exchange resin IR120 was added until the solution pH was less than 7. The mixture was filtered, and the filtrate was diluted twice with deionized water, then added to a dialysis bag, dialyzed for 24 hours, and concentrated under reduced pressure to obtain 18.8 mg of light brown solid, with a yield of 94%.

[0043] 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.83 (s, 1H), 9.34 (s, 1H), 9.07 (d, J = 7.5Hz, 1H), 7.57 (d, J= 2.5 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 2.5 Hz,1H), 7.16 (dd, J = 4.0, 2.0 Hz, 1H), 7.11 (dd, J = 8.0, 2.0 Hz, 1H), 7.03 (ddd, J =8.0, 4.0, 2.0 Hz, 1H), 6.88 (s, 1H), 6.74 (d, J = 2.0, 1H), 5.49 – 5.47 (m,1H), 5.24 (d, J = 5.0 Hz, 1H), 5.20 (t, J = 7.5 Hz, 1H), 5.00 (dd, J = 15.5, 5.0Hz, 2H), 4.83 – 4.81 (m, 1H), 4.62 (dt, J = 9.0, 5.5 Hz, 2H), 4.31 (d, J = 8.0Hz, 1H), 3.77 (d, J = 1.0 Hz, 4H), 3.75 – 3.72 (m, 1H), 3.72 – 3.67 (m, 1H),3.67 – 3.61 (m, 2H), 3.49 – 3.41 (m, 4H), 3.39 (s, 3H), 3.37 (s, 3H), 3.35(s, 1H), 3.24-3.20 (m, 1H), 3.17 (dt, J = 9.0, 4.5 Hz, 1H), 3.10 – 3.00 (m,2H). 13 C NMR (125 MHz, DMSO- d6) δ 154.40, 149.07, 148.73, 147.91, 146.88, 146.32, 144.63, 133.60, 128.96, 125.23, 124.08, 122.30, 119.29, 116.46, 114.94, 111.50, 108.26, 106.73, 105.75, 105.45, 103.75, 103.16, 99.25, 79.77, 76.81, 76.48, 75.23, 75.03, 73.29, 72.81, 70.05, 66.34, 61.04, 55.98, 55.07, 54.54. HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 40 H 42 NO 18 + 824.2396; Found 824.2401.

[0044] Example 2: Synthesis of compound MZ2

[0045] The synthesis method was the same as Example 1, except that the glycosyl donor in step (7) was 2,2',3,3',4',6,6'-hepta-O-acetyl-β-D-galactosyl trichloroimidate, to obtain the product MZ2 as a light brown solid in a yield of 81%).

[0046] 1 H NMR (500 MHz, DMSO- d 6) δ 9.83 (s, 1H), 9.34 (s, 1H), 9.07 (d, J = 7.3Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 2.1 Hz,1H), 7.16 (dd, J = 3.7, 2.0 Hz, 1H), 7.11 (dd, J = 7.9, 1.7 Hz, 1H), 7.03 (ddd, J =8.0, 3.6, 1.9 Hz, 1H), 6.88 (s, 1H), 6.74 (d, J= 2.1 Hz, 1H), 5.48 (dd, J = 5.6,1.1 Hz, 1H), 5.21 (t, J = 7.5 Hz, 1H), 5.10 (s, 1H), 4.82 (s, 1H), 4.79 (d, J =5.9 Hz, 1H), 4.67 (t, J = 5.2 Hz, 1H), 4.59 (ddd, J = 9.8, 6.5, 5.3 Hz, 1H), 4.53(d, J = 4.6 Hz, 1H), 4.25 (d, J = 7.4 Hz, 1H), 3.77 (d, J = 0.9 Hz, 4H), 3.68 –3.61 (m, 4H), 3.55 (d, J = 5.3 Hz, 1H), 3.54 – 3.52 (m, 1H), 3.49 (dd, J = 8.5,6.7 Hz, 3H), 3.46 – 3.43 (m, 1H), 3.41 (s, 1H), 3.39 (s, 4H), 3.37 (s, 3H),3.37 – 3.34 (m, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 154.39, 149.07, 148.73,147.91, 147.43, 146.88, 146.32, 144.63, 133.60, 128.97, 125.24, 124.08,123.74, 122.30, 119.29, 116.47, 114.95, 112.75, 111.50, 108.26, 106.73,105.75, 105.45, 103.85, 103.75, 80.09, 75.56, 75.16, 75.01, 73.26, 72.84,70.57, 68.17, 66.34, 60.45, 60.05, 55.98, 55.07, 54.55.HR-MS(ESI / QTOF) m / z:[M+H] + Calcd for C 40 H 42 NO 18+ 824.2396; Found 824.2393.

[0047] Example 3: Synthesis of compound MZ3

[0048] The synthesis method was the same as Example 1, except that the glycosyl donor in step (7) was 2,2',3,3',4',6,6'-hepta-O-acetyl- -D-maltosyl trichloroimidate, to obtain the product MZ3 as a light brown solid with a yield of 84%.

[0049] 1 H NMR (500 MHz, DMSO- d6) δ 9.34 (s, 1H), 9.08 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.16 (dd, J = 3.3, 2.0 Hz, 1H), 7.11 (dd, J = 7.9, 2.2 Hz, 1H), 7.03 (ddd, J = 8.0, 3.6, 1.9 Hz, 1H), 6.88 (s, 1H), 6.74 (d, J = 2.2 Hz, 1H), 5.62 (d, J = 3.3 Hz, 1H), 5.44 (td, J = 6.5, 5.9, 1.6 Hz, 2H), 5.18 (t, J = 7.9 Hz, 1H), 5.06 (d, J = 3.8 Hz, 1H), 4.93 (d, J = 5.5 Hz, 1H), 4.90 (d, J = 4.9 Hz, 1H), 4.54 (dt, J = 17.6, 5.5 Hz, 2H), 3.77 (d, J = 0.9 Hz, 4H), 3.75 – 3.69 (m, 1H), 3.66 – 3.58 (m, 5H), 3.52 (td, J = 4.8, 4.3, 1.7 Hz, 1H), 3.51 – 3.49 (m, 1H), 3.48 – 3.45 (m, 2H), 3.44 – 3.40 (m, 2H), 3.39 (s, 3H), 3.38 (s, 3H), 3.35 (d, J = 1.0 Hz, 2H), 3.26 (ddd, J = 9.8, 6.2, 3.7 Hz, 1H), 3.08 (td, J = 9.2, 5.4 Hz, 1H). 13 C NMR (125 MHz, DMSO- d6) δ 154.40, 149.07, 148.73,147.92, 147.44, 146.89, 146.33, 144.64, 133.60, 128.97, 125.24, 124.11, 123.75, 122.32, 119.28, 116.47, 114.95, 112.75, 111.82, 111.50, 108.26, 106.74, 105.75, 105.45, 103.75, 100.69, 99.44, 78.95, 76.46, 75.35, 73.57, 73.32, 72.66, 72.47, 69.90, 60.81, 55.98, 55.07, 54.56. HR-MS (ESI / QTOF) m / z: [M-H] - Calcd for C 40 H 40 NO 18 - 822.2251 Found 822.2268.

[0050] Example 4: Synthesis of compound MZ4

[0051] The synthesis method was the same as Example 1 to obtain the product MZ4 as a light brown solid with a yield of 68%.

[0052] 1 H NMR (500 MHz, DMSO- d 6) δ 9.02 (dd, J = 7.4, 1.4 Hz, 1H), 7.43 (d, J =8.4 Hz, 1H), 7.26 – 7.22 (m, 2H), 7.20 (d, J = 4.5 Hz, 1H), 7.14 (dd, J = 8.2,2.0 Hz, 1H), 7.07 (d, J = 27.7 Hz, 1H), 6.87 (d, J = 4.9 Hz, 1H), 6.68 (d, J = 26.9Hz, 1H), 5.62 (d, J = 3.2 Hz, 1H), 5.49 (d, J = 6.1 Hz, 1H), 5.45 (dd,J = 7.0, 5.5Hz, 1H), 5.14 – 5.07 (m, 2H), 4.93 (d, J = 5.5 Hz, 1H), 4.91 (d, J = 4.8 Hz, 1H),4.58 – 4.54 (m, 1H), 4.49 (q, J = 5.0 Hz, 1H), 3.77 (s, 3H), 3.72 (dd, J = 12.0,4.8 Hz, 2H), 3.68 – 3.59 (m, 4H), 3.57 (s, 1H), 3.55 –3.50 (m, 5H), 3.50 – 3.45 (m, 2H), 3.44 (d, J = 2.5 Hz, 1H), 3.41 (td, J = 4.7, 4.1, 2.2 Hz, 4H), 3.38(d, J = 1.0 Hz, 3H), 3.38 (d, J = 1.1 Hz, 3H), 3.08 (td, J = 9.2, 5.5 Hz, 1H).HR-MS (ESI / QTOF) m / z: [M+H] + C 40 H 42 NO 18 + 824.2396; Found 824.2391.

[0053] Example 5: Synthesis of compound MZ5

[0054] The synthesis method was the same as Example 1, except that step (8) was omitted, to obtain the product MZ5 as a colorless solid with a yield of 89%.

[0055] 1 H NMR (500 MHz, DMSO- d 6) δ 9.98 (s, 1H), 9.36 (s, 1H), 9.01 (d, J = 7.3Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.23 (d, J= 2.2 Hz, 1H), 7.21 (s, 1H), 7.17 – 7.13 (m, 2H), 7.10 (dd, J = 8.0, 4.1 Hz, 1H), 7.01 (td, J = 7.6, 2.0 Hz, 1H),6.78 (s, 1H), 5.44 (t, J = 7.8 Hz, 1H), 5.27 (t, J = 9.5 Hz, 2H), 5.02 – 4.97 (m,1H), 4.92 – 4.85 (m, 2H), 4.67 (dd, J = 9.7, 8.0 Hz, 1H), 4.42 (d, J = 8.6 Hz,1H), 4.26 (dd, J = 12.4, 4.1 Hz, 1H), 4.16 (p, J = 7.7, 7.2 Hz, 2H), 4.03 (d, J =9.5 Hz, 1H), 3.97 (d, J = 14.6 Hz, 1H), 3.90 – 3.84 (m, 1H), 3.76 (s, 3H), 3.38(s, 3H), 3.35 (s, 3H), 2.15 (d, J = 3.5 Hz, 3H), 2.03 (s, 3H), 2.02 (s, 4H),1.97 (s, 9H), 1.93 (s, 3H). 13 C NMR (125 MHz, DMSO- d6) δ 170.25, 170.06, 169.63, 169.45, 169.23, 169.09, 154.06, 148.76, 148.61, 148.44, 146.91, 146.09, 145.72, 145.55, 134.17, 128.05, 125.12, 124.66, 123.71, 121.94, 117.58, 116.49, 114.86, 112.93, 112.07, 111.57, 111.44, 106.78, 106.39, 105.78, 105.33, 99.54, 97.80, 76.47, 72.17, 72.09, 71.93, 71.16, 70.66, 70.48, 67.67, 62.03, 61.49, 55.96, 55.43, 54.53, 20.58, 20.45, 20.36, 20.27, 20.22. HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 54 H 56 NO 25 + 1118.3136; Found1118.3117.

[0056] Example 6: Synthesis of compound MZ6

[0057] The synthesis method was the same as Example 1, except that step (8) was omitted, to obtain the product MZ6 as a light brown solid with a yield of 89%.

[0058] 1 H NMR (500 MHz, DMSO- d 6) δ 9.94 (s, 1H), 9.33 (s, 1H), 8.97 (d, J = 7.4Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.17 (s, 1H), 7.13 –7.10 (m, 2H), 7.06 (dd, J = 7.9, 4.0 Hz, 1H), 6.98 (ddd, J= 7.9, 6.9, 1.9 Hz,1H), 6.74 (s, 1H), 5.43 (t, J = 7.7 Hz, 1H), 5.23 (t, J = 9.4 Hz, 1H), 5.21 (d, J =3.6 Hz, 1H), 5.15 (dd, J = 10.3, 3.6 Hz, 1H), 4.99 – 4.93 (m, 1H), 4.83 (dd, J =10.2, 8.0 Hz, 1H), 4.76 (d, J = 8.0 Hz, 1H), 4.39 – 4.32 (m, 1H), 4.20 (t, J =6.2 Hz, 1H), 4.13 (t, J = 7.7 Hz, 2H), 3.99 (dt, J = 7.0, 3.1 Hz, 2H), 3.87 (t, J =9.1 Hz, 1H), 3.73 (d, J = 1.1 Hz, 3H), 3.34 (s, 3H), 3.32 (s, 3H), 2.10 (d, J =3.4 Hz, 3H), 2.08 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H), 1.96 (s, 3H), 1.94 (d, J = 0.7 Hz, 3H). 13 C NMR (125 MHz, DMSO- d6) δ 170.75, 170.45, 170.06, 169.90,169.65, 154.59, 149.28, 149.14, 148.97, 147.44, 146.60, 146.56, 146.25,146.09, 134.70, 128.58, 125.65, 125.19, 124.24, 122.46, 118.11, 116.99,115.39, 113.44, 112.58, 112.10, 111.96, 107.31, 106.92, 106.33, 105.86,100.47, 98.33, 76.80, 72.74, 72.60, 71.28, 70.81, 70.25, 69.41, 67.60, 62.61,61.41, 56.49, 55.96, 55.06, 21.08, 21.02, 20.96, 20.92, 20.88, 20.85.HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 54 H 56 NO 25 + 1118.3136; Found 1118.3090.

[0059] Example 7: Synthesis of compound MZ7

[0060] The synthesis method was the same as Example 1, except that step (8) was omitted, to obtain the product MZ7 as a light brown solid in a yield of 89%.

[0061] 1 H NMR (500 MHz, DMSO- d 6) δ 9.98 (s, 1H), 9.36 (d, J = 2.9 Hz, 1H), 9.02(d, J = 7.3 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H), 7.21 (s,1H), 7.17 – 7.14 (m, 2H), 7.10 (dd, J = 7.9, 3.3 Hz, 1H), 7.02 (ddd, J= 7.9,5.9, 1.9 Hz, 1H), 6.78 (d, J = 0.8 Hz, 1H), 5.53 – 5.48 (m, 1H), 5.43 (t, J = 9.2Hz, 1H), 5.31 (d, J = 3.9 Hz, 1H), 5.24 (dd, J = 10.5, 9.5 Hz, 1H), 5.04 – 4.95(m, 2H), 4.90 (dd, J = 10.5, 3.8 Hz, 1H), 4.47 (d, J = 10.8 Hz, 1H), 4.30 – 4.22(m, 2H), 4.18 (dd, J = 12.5, 5.0 Hz, 1H), 4.08 – 3.98 (m, 4H), 3.76 (s, 3H),3.38 (s, 3H), 3.35 (s, 4H), 2.12 (d, J = 3.2 Hz, 3H), 2.03 (s, 3H), 2.00 (s,6H), 1.97 (s, 3H), 1.96 (s, 6H). 13 C NMR (125 MHz, DMSO- d 6) δ 170.12, 170.06,169.89, 169.67, 169.53, 169.24, 169.20, 154.07, 148.76, 148.61, 148.44,146.91, 145.84, 145.52, 134.18, 128.04, 125.12, 124.67, 123.71, 121.96,117.59, 116.50, 114.86, 112.94, 111.57, 111.46, 106.80, 105.97, 105.33,95.58, 74.02, 73.79, 71.66, 71.18, 69.44, 68.87, 68.14, 67.76, 61.51, 55.96,55.41, 54.53, 20.56, 20.54, 20.45, 20.38, 20.36, 20.32, 20.29.HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 54 H56 NO 25 + 1118.3136; Found 1118.3131.

[0062] Example 8: Synthesis of compound MZ8

[0063] The synthesis was the same as example 1 to give the product MZ8 as a light brown solid in 87% yield.

[0064] 1 H NMR (500 MHz, DMSO- d 6) δ 9.93 (s, 1H), 9.32 (s, 1H), 8.99 (d, J = 7.3Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.17 (s, 1H), 7.13(s, 2H), 7.07 (dd, J = 7.9, 2.3 Hz, 1H), 6.99 (dt, J = 8.0, 2.4 Hz, 1H), 6.73 (d, J = 3.0 Hz, 1H), 5.46 (dd, J = 5.6, 2.2 Hz, 1H), 5.24 (d, J = 4.9 Hz, 1H), 5.10(t, J = 7.9 Hz, 1H), 5.01 (d, J = 4.9 Hz, 1H), 4.98 (d, J = 5.4 Hz, 1H), 4.78 (s,1H), 4.61 (dt, J = 19.5, 5.7 Hz, 2H), 4.26 (d, J = 7.8 Hz, 1H), 4.12 – 4.03 (m,1H), 3.73 (s, 3H), 3.69 (dd, J = 11.2, 6.2 Hz, 1H), 3.61 (d, J= 8.2 Hz, 2H),3.53 (s, 1H), 3.46 – 3.37 (m, 3H), 3.35 (s, 6H), 3.21 – 3.15 (m, 1H), 3.13(d, J = 5.1 Hz, 3H), 3.06 – 2.96 (m, 2H). 13 C NMR (125 MHz, DMSO- d 6) δ 154.31,148.73, 148.58, 148.41, 146.88, 145.88, 145.43, 134.14, 128.44, 125.27,124.69, 123.78, 122.02, 117.60, 116.47, 114.96, 112.74, 111.56, 111.24,110.62, 106.72, 105.80, 105.36, 104.18, 103.20, 99.34, 79.95, 76.83, 76.50,75.07, 74.98, 73.30, 72.85, 70.06, 66.37, 61.07, 60.03, 55.98, 55.06, 54.55,48.62.HR-MS (ESI / QTOF) m / z: [M+Na] + Calcd for C 40 H 41 NNaO 18 + 846.2216; Found846.2220。

[0065] Example 9: Synthesis of compound MZ9

[0066] The synthesis method was the same as Example 1 to obtain the product MZ9 as a light brown solid with a yield of 99%.

[0067] 1 H NMR (500 MHz, DMSO- d 6) δ 9.93 (s, 1H), 9.32 (s, 1H), 8.99 (d, J = 7.0Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.17 (s, 1H), 7.13(d, J= 8.0, 2.1 Hz, 1H), 6.99 (dt, J = 7.9, 2.3 Hz,1H), 6.73 (d, J = 7.9, 2.3 Hz,1H), 6.73 (d, J = 3.0 Hz, 1H), 5.46 (dd, J = 5.6, 2.3 Hz, 1H), 5.11 (dd, J = 9.8,6.3 Hz, 2H), 4.78 (dd, J = 3.5, 1.8 Hz, 2H), 4.65 (t, J = 5.1 Hz, 1H), 4.59 (dt, J = 10.0, 5.8 Hz, 1H), 4.51 (d, J = 4.7 Hz, 1H), 4.20 (d, J = 7.3 Hz, 1H), 4.07 (q, J = 5.2 Hz, 1H), 3.73 (s, 4H), 3.64 – 3.57 (m, 3H), 3.53 – 3.47 (m, 2H), 3.47– 3.42 (m, 2H), 3.37 (d, J = 9.6 Hz, 1H), 3.36 – 3.34 (m, 6H), 3.28 (dd, J = 7.2,2.1 Hz, 2H), 3.13 (d, J = 5.2 Hz, 2H). 13 C NMR (125 MHz, DMSO- d6) δ 154.32, 148.74, 148.58, 148.40, 146.88, 145.88, 145.43, 134.14, 128.44, 125.28, 124.69, 123.78, 122.03, 117.60, 116.47, 114.96, 112.74, 111.57, 111.24, 110.62, 106.73, 105.80, 105.36, 104.19, 103.91, 99.38, 80.24, 75.58, 75.02, 74.95, 73.28, 72.88, 70.56, 68.19, 60.46, 60.12, 55.99, 55.06, 54.55, 48.62. HR-MS (ESI / QTOF) m / z: [M+Na] + Calcd for C 40 H 41 NNaO 18 + 846.2216; Found846.2219.

[0068] Example 10: Compound MZ10

[0069] The synthesis method was the same as Example 1 to obtain the product MZ10 as a light brown solid with a yield of 96%.

[0070] 1 H NMR (500 MHz, DMSO- d 6) δ 9.94 (s, 1H), 9.33 (s, 1H), 8.99 (d, J = 7.3Hz, 1H), 7.24 – 7.20 (m, 2H), 7.17 (s, 1H), 7.13 (s, 2H), 7.07 (dd, J = 7.9,1.9 Hz, 1H), 7.00 (dt, J = 7.9, 1.9 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 5.59 (d, J =3.4 Hz, 1H), 5.45 (d, J = 4.5 Hz, 1H), 5.41 (dd, J = 5.7, 2.3 Hz, 1H), 5.08 (t, J= 8.2 Hz, 1H), 5.02 (d, J = 3.9 Hz, 1H), 4.90 (dd, J = 7.5, 5.3 Hz, 2H), 3.73 (s,3H), 3.72 – 3.66 (m, 1H), 3.57 (td, J = 18.1, 17.4, 7.6 Hz, 5H), 3.50 – 3.36(m, 5H), 3.35 (s, 6H), 3.22 (ddt, J = 9.7, 6.1, 3.4 Hz, 1H), 3.08 – 3.01 (m,1H). 13 C NMR (125 MHz, DMSO- d 6) δ 154.31, 148.73, 148.58, 148.40, 146.88,145.90, 145.44, 134.14, 128.43, 125.27, 124.68, 123.78, 122.02, 117.60,116.47, 114.96, 112.74, 111.56, 111.24, 110.63, 106.73, 105.84, 105.36,104.22, 100.74, 99.59, 79.06, 76.36, 75.29, 73.55, 73.31, 72.70, 72.46,69.90, 60.79, 60.25, 55.98, 55.09, 54.55.HR-MS (ESI / QTOF) m / z: [M-H] - Calcdfor C 40 H 40 NO 18 - 822.2251; Found 822.2266。

[0071] Example 11: Synthesis of compound MZ11

[0072] The synthesis method was the same as Example 1 to obtain the product MZ11 as a light brown solid with a yield of 90%.

[0073] 1 H NMR (500 MHz, DMSO- d 6) δ 9.85 (s, 1H), 9.39 (d, J= 1.3 Hz, 1H), 9.07(d, J = 7.3 Hz, 1H), 7.57 (s, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 2.9 Hz,1H), 7.22 (s, 1H), 7.05 – 7.01 (m, 2H), 6.88 (s, 1H), 6.78 (d, J = 1.7 Hz, 1H),5.48 (d, J = 5.6 Hz, 1H), 5.24 (d, J = 4.9 Hz, 1H), 5.20 (d, J = 7.7 Hz, 1H), 5.02(d, J = 4.9 Hz, 1H), 4.99 (d, J = 5.5 Hz, 1H), 4.82 (d, J = 2.0 Hz, 1H), 4.61 (q, J =5.9 Hz, 2H), 4.30 (d, J = 7.9 Hz, 1H), 3.87 (s, 3H), 3.75 (dd, J = 17.6, 6.7 Hz,2H), 3.69 (dd, J = 18.5, 5.4 Hz, 2H), 3.64 (t, J = 7.1 Hz, 2H), 3.49 – 3.45 (m,3H), 3.43 (q, J = 3.9, 3.0 Hz, 1H), 3.41 (s, 1H), 3.40 (s, 3H), 3.39 (s, 3H),3.38 – 3.33 (m, 2H), 3.22 (t, J = 8.8 Hz, 1H), 3.17 (td, J = 5.9, 5.4, 3.7 Hz,1H), 3.10 – 3.00 (m, 2H).HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 40 H 40 NO 18 - 824.2251; Found 824.2313.

[0074] Example 12: Synthesis of compound MZ12

[0075] The synthesis method was the same as Example 1 to obtain the product MZ12 as a light brown solid with a yield of 96%.

[0076] 1 H NMR (500 MHz, DMSO- d 6) δ 9.85 (s, 1H), 9.39 (s, 1H), 9.07 (d, J = 7.3Hz, 1H), 7.57 (s, 1H), 7.27 (d, J = 3.1 Hz, 1H), 7.25 (d, J = 3.8 Hz, 1H), 7.22(s, 1H), 7.03 (dq, J = 9.1, 2.3 Hz, 2H), 6.88 (s, 1H), 6.77 (d, J = 1.7 Hz, 1H),5.48 (d, J = 5.6 Hz, 1H), 5.21 (d, J = 7.8 Hz, 1H), 5.10 (d, J = 4.6 Hz, 1H), 4.82(d, J = 1.8 Hz, 1H), 4.79 (d, J = 5.3 Hz, 1H), 4.67 (t, J = 5.1 Hz, 1H), 4.60 (t, J =5.8 Hz, 1H), 4.52 (d, J = 4.7 Hz, 1H), 4.25 (d, J = 7.3 Hz, 1H), 3.87 (s, 3H),3.79 – 3.74 (m, 1H), 3.64 (dt, J = 12.3, 4.8 Hz, 3H), 3.56 – 3.50 (m, 3H), 3.50– 3.47 (m, 2H), 3.47 – 3.43 (m, 2H), 3.40 (s, 3H), 3.39 (s, 3H), 3.36 (d, J =6.6 Hz, 2H). 13C NMR (125 MHz, DMSO- d 6) δ 148.03, 147.90, 147.75, 147.45,146.31, 144.63, 128.77, 124.09, 122.33, 118.16, 111.16, 108.16, 106.84,105.69, 103.86, 80.09, 75.57, 75.16, 75.01, 73.26, 70.57, 68.17, 60.45,56.12, 55.07, 54.57.HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 40 H 42 NO 18 + 824.2396;Found 824.2395。

[0077] Example 13: Synthesis of compound MZ13

[0078] The synthesis method was the same as Example 1 to obtain the product MZ13 as a light brown solid with a yield of 80%.

[0079] 1 H NMR (500 MHz, DMSO- d 6) δ 9.85 (s, 1H), 9.39 (d, J = 3.1 Hz, 1H), 9.07(d, J = 7.3 Hz, 1H), 7.56 (s, 1H), 7.25 (dd, J = 7.8, 2.7 Hz, 2H), 7.22 (s, 1H),7.05 – 7.00 (m, 2H), 6.88 (s, 1H), 6.77 (d, J = 1.3 Hz, 1H), 5.62 (d, J = 3.3 Hz,1H), 5.46 – 5.42 (m, 2H), 5.18 (d, J = 7.8 Hz, 1H), 5.06 (d, J = 3.8 Hz, 1H),4.91 (dd, J= 16.2, 5.2 Hz, 2H), 4.57 – 4.49 (m, 2H), 3.87 (s, 3H), 3.73 (dd, J =10.6, 5.0 Hz, 1H), 3.67 – 3.59 (m, 4H), 3.57 (s, 2H), 3.54 – 3.44 (m, 4H),3.40 (s, 3H), 3.39 (s, 3H), 3.38 – 3.34 (m, 2H), 3.30 – 3.24 (m, 2H), 3.08(td, J = 9.2, 5.5 Hz, 1H). 13 C NMR (125 MHz, DMSO- d 6) δ 154.39, 149.10, 148.03,147.90, 147.76, 147.44, 146.31, 144.63, 133.37, 128.77, 127.16, 124.11,122.05, 119.18, 118.17, 113.69, 111.15, 108.16, 106.84, 105.68, 105.38,103.78, 100.69, 78.94, 76.46, 75.35, 73.57, 73.32, 72.65, 72.47, 69.90,66.34, 60.81, 60.10, 56.11, 55.07, 54.58.HR-MS (ESI / QTOF) m / z: [M+H] + Calcdfor C 40 H 42 NO 18 + 824.2396; Found 824.2386。

[0080] Example 14: Synthesis of compound MZ14

[0081] The synthesis method was the same as Example 1 to obtain the product MZ14 as a light brown solid with a yield of 30%.

[0082] 1 H NMR (500 MHz, DMSO- d 6) δ 9.90 (s, 1H), 9.83 (s, 1H), 9.01 (dd, J= 7.4, 2.7 Hz, 1H), 7.39 (dd, J = 3.6, 2.0 Hz, 1H), 7.32 (dd, J = 8.4, 1.9 Hz, 1H),7.22 (d, J = 7.4 Hz, 1H), 7.21 – 7.16 (m, 2H), 7.10 (d, J = 47.6 Hz, 1H), 6.87(d, J = 2.3 Hz, 1H), 6.68 (d, J = 41.8 Hz, 1H), 5.57 – 5.48 (m, 1H), 5.36 (ddd, J =12.7, 6.0, 3.2 Hz, 2H), 5.12 (dd, J = 11.2, 7.7 Hz, 1H), 4.97 (d, J = 3.8 Hz,1H), 4.83 (d, J = 5.0 Hz, 2H), 4.47 (s, 1H), 4.11 (dt, J = 11.2, 5.7 Hz, 1H),3.90 – 3.85 (m, 4H), 3.61 – 3.52 (m, 2H), 3.54 – 3.42 (m, 5H), 3.39 (s, 4H),3.38 (d, J = 2.8 Hz, 5H), 3.22 – 3.15 (m, 1H), 2.99 (q, J = 7.9 Hz, 1H).HR-MS (ESI / QTOF) m / z: [M-H] - Calcd for C 40 H 40 NO 18 - 822.2251; Found 822.2316。

[0083] Example 15: Synthesis of compound MZ15

[0084] The synthesis method was the same as Example 1, except that step (8) was omitted to give the product MZ15 as a light brown solid in 80% yield.

[0085] 1H NMR (500 MHz, DMSO- d 6) δ 9.93 (s, 1H), 9.35 (d, J = 11.5 Hz, 1H),8.97 (d, J = 7.3 Hz, 1H), 7.24 – 7.20 (m, 2H), 7.17 (s, 1H), 7.14 (d, J = 1.9 Hz,1H), 7.00 – 6.97 (m, 1H), 6.96 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 3.3 Hz, 1H),5.41 (dd, J = 8.0, 2.9 Hz, 1H), 5.24 (t, J = 9.5 Hz, 2H), 4.96 (dd, J = 9.7, 8.0Hz, 1H), 4.89 – 4.81 (m, 2H), 4.64 (dd, J = 9.7, 8.0 Hz, 1H), 4.38 (d, J = 9.3Hz, 1H), 4.28 – 4.24 (m, 1H), 4.24 – 4.20 (m, 1H), 4.12 (p, J = 7.7, 7.3 Hz,2H), 3.99 (dt, J = 10.1, 3.6 Hz, 1H), 3.93 (dd, J = 12.4, 2.3 Hz, 1H), 3.87 –3.81 (m, 4H), 3.36 (s, 3H), 3.33 (s, 4H), 2.11 (d, J = 2.1 Hz, 3H), 1.99 (s,3H), 1.99 (s, 3H), 1.94 (s, 3H), 1.94 (s, 6H), 1.89 (s, 3H). 13 C NMR (125 MHz,DMSO- d6) δ 170.22, 170.02, 169.59, 169.41, 169.19, 169.06, 154.02, 148.62, 148.42, 148.05, 147.77, 146.08, 145.70, 145.54, 133.95, 127.79, 127.03, 124.65, 122.02, 121.94, 118.13, 117.46, 113.67, 112.92, 111.96, 111.60, 111.07, 106.89, 106.36, 105.80, 105.27, 99.52, 76.43, 72.16, 72.09, 71.92, 71.14, 70.69, 70.47, 70.28, 67.68, 62.00, 61.48, 56.10, 55.46, 54.54, 20.55, 20.42, 20.33, 20.30, 20.24, 20.19, 19.21, 18.16. HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 54 H 56 NO 25 + 1118.3136; Found 1118.3197.

[0086] Example 16: Synthesis of compound MZ16

[0087] The synthesis method was the same as Example 1, except that step (8) was omitted, to give the product MZ16 as a light brown solid in a yield of 88%.

[0088] 1 H NMR (500 MHz, DMSO- d 6) δ 9.97 (s, 1H), 9.38 (d, J = 11.6 Hz, 1H),9.01 (d, J = 7.3 Hz, 1H), 7.25 (dd, J = 7.9, 5.7 Hz, 2H), 7.23 (s, 1H), 7.21 (s,1H), 7.18 (d, J = 1.9 Hz, 1H), 7.04 – 6.99 (m, 2H), 6.83 (d, J= 3.1 Hz, 1H),5.46 (dd, J = 8.0, 2.7 Hz, 1H), 5.29 – 5.23 (m, 2H), 5.18 (dd, J = 10.3, 3.6 Hz,1H), 5.00 (dd, J = 9.7, 8.0 Hz, 1H), 4.87 (dd, J = 10.2, 8.0 Hz, 1H), 4.79 (d, J =8.0 Hz, 1H), 4.39 (d, J = 9.6 Hz, 1H), 4.23 (t, J = 6.6 Hz, 1H), 4.16 (d, J = 9.3Hz, 2H), 4.03 (dt, J = 6.9, 4.0 Hz, 2H), 3.90 (t, J = 9.1 Hz, 1H), 3.87 (d, J = 1.3Hz, 3H), 3.40 (s, 3H), 3.37 (s, 3H), 2.14 (d, J = 2.1 Hz, 3H), 2.11 (s, 3H),2.05 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.98 (s, 3H), 1.91 (s, 3H). 13 C NMR(125 MHz, DMSO- D6) δ 170.18, 169.89, 169.50, 169.33, 169.09, 154.03, 148.63, 148.42, 148.06, 147.77, 146.07, 145.71, 145.55, 133.95, 127.80, 127.04, 124.65, 122.02, 118.14, 117.46, 113.68, 112.91, 111.95, 111.60, 111.07, 106.89, 105.81, 105.27, 99.92, 97.75, 76.23, 72.20, 72.06, 70.76, 70.27, 69.72, 68.88, 67.07, 62.06, 60.87, 56.10, 55.46, 54.54, 30.93, 22.03, 20.52, 20.45, 20.40, 20.35, 20.30, 13.93. HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 54 H 56 NO 25 + 1118.3136; Found 1118.3120.

[0089] Example 17: Synthesis of compound MZ17

[0090] The synthesis method was the same as Example 1, except that step (8) was omitted, to give the product MZ20 as a light brown solid in a yield of 89%.

[0091] 1 H NMR (500 MHz, DMSO- d 6) δ 9.97 (s, 1H), 9.39 (d, J = 11.5 Hz, 1H),9.02 (d, J = 7.4 Hz, 1H), 7.28 – 7.25 (m, 1H), 7.25 – 7.22 (m, 2H), 7.21 (s,1H), 7.18 (d, J = 1.7 Hz, 1H), 7.02 (td, J = 9.3, 8.8, 2.1 Hz, 2H), 6.87 (s, 4H),6.84 (d, J= 2.7 Hz, 1H), 6.63 (s, 2H), 5.50 (dd, J = 7.9, 2.6 Hz, 1H), 5.42 (t, J = 9.2 Hz, 1H), 5.31 (d, J = 3.8 Hz, 1H), 5.24 (dd, J = 10.5, 9.5 Hz, 1H), 5.03 –4.95 (m, 2H), 4.90 (dd, J = 10.5, 3.8 Hz, 1H), 4.48 (d, J = 10.9 Hz, 1H), 4.30 –4.16 (m, 4H), 4.04 (dt, J = 15.9, 9.9 Hz, 4H), 3.87 (d, J = 1.2 Hz, 3H), 3.40 (s,3H), 3.37 (s, 3H), 2.12 (d, J = 2.1 Hz, 3H), 2.03 (s, 3H), 2.00 (d, J = 0.9 Hz,6H), 1.97 (s, 3H), 1.96 (s, 6H). 13 C NMR (125 MHz, DMSO- D 6) δ 170.08, 170.02,169.85, 169.62, 169.49, 169.20, 154.03, 148.63, 148.42, 148.05, 147.76,145.82, 145.51, 133.95, 128.02, 127.78, 127.04, 122.01, 118.12, 117.46,113.68, 112.92, 112.07, 111.60, 111.08, 106.91, 106.38, 105.98, 105.27,95.56, 74.01, 73.80, 71.66, 71.18, 69.42, 68.86, 68.12, 67.76, 66.34, 66.00,62.70, 61.49, 56.10, 55.43, 54.54, 31.82, 29.00, 20.53, 20.50, 20.41, 20.34,20.33, 20.26.HR-MS (ESI / QTOF) m / z: [M+H]+ Calcd for C 54 H 56 NO 25 + 1118.3136; Found1118.3061.

[0092] Example 18: Synthesis of compound MZ18

[0093] The synthesis method was the same as Example 1 to obtain the product MZ18 as a light brown solid with a yield of 90%.

[0094] 1 H NMR (500 MHz, DMSO- d 6) δ 9.95 (s, 1H), 9.39 (s, 1H), 9.02 (d, J = 7.3Hz, 1H), 7.26 (s, 1H), 7.25 (s, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 7.19 (d, J =2.0 Hz, 1H), 7.02 (dd, J = 6.6, 2.1 Hz, 2H), 6.82 (s, 1H), 5.47 (d, J = 5.5 Hz,1H), 5.25 (d, J = 4.9 Hz, 1H), 5.13 (d, J = 7.8 Hz, 1H), 5.04 – 4.96 (m, 2H),4.81 (d, J = 2.2 Hz, 1H), 4.63 (d, J = 15.1 Hz, 2H), 4.30 (d, J = 7.9 Hz, 1H), 4.09(s, 1H), 3.87 (s, 3H), 3.80 – 3.69 (m, 2H), 3.68 – 3.62 (m, 2H), 3.50 – 3.42(m, 3H), 3.40 (d, J = 1.8 Hz, 6H), 3.22 (ddd, J = 9.2, 6.6, 2.3 Hz, 1H), 3.17 (s,3H), 3.10 – 2.98 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6) δ 154.27, 148.59, 148.38,148.02, 147.74, 146.90, 145.85, 145.41, 133.93, 128.16, 127.18, 124.67,122.02, 118.19, 117.47, 113.67, 112.72, 111.59, 110.87, 110.51, 106.81,105.76, 105.30, 104.19, 103.17, 99.37, 79.92, 76.81, 76.49, 75.05, 74.97,73.29, 72.83, 70.05, 61.05, 60.02, 56.11, 55.08, 54.55, 48.59.HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 40 H 42 NO 18 + 824.2396; Found 1118.2415。

[0095] Example 19: Synthesis of compound MZ19

[0096] The synthesis method was the same as Example 1 to obtain the product MZ19 as a light brown solid with a yield of 91%.

[0097] 1 H NMR (500 MHz, DMSO- d 6) δ 9.96 (s, 1H), 9.39 (s, 1H), 9.02 (d, J = 7.4Hz, 1H), 7.25 (dd, J = 8.2, 3.6 Hz, 3H), 7.22 – 7.18 (m, 2H), 7.03 (d, J = 9.3Hz, 2H), 6.82 (s, 1H), 5.47 (d, J = 5.5 Hz, 1H), 5.14 (d, J = 7.7 Hz, 1H), 5.11(d, J = 4.6 Hz, 1H), 4.82 – 4.77 (m, 2H), 4.69 – 4.65 (m, 1H), 4.62 (t, J= 5.8Hz, 1H), 4.52 (d, J = 4.6 Hz, 1H), 4.24 (d, J = 7.3 Hz, 1H), 3.87 (s, 3H), 3.77(dd, J = 10.1, 5.1 Hz, 1H), 3.67 – 3.61 (m, 3H), 3.58 – 3.56 (m, 1H), 3.53 (q, J = 6.0 Hz, 2H), 3.48 (t, J = 6.1 Hz, 3H), 3.40 (s, 8H). 13 C NMR (125 MHz, DMSO- d 6 )δ 154.27, 148.59, 148.38, 148.02, 147.74, 146.90, 145.85, 145.42, 133.93,128.16, 127.18, 124.67, 122.04, 118.19, 117.47, 113.68, 112.72, 111.75,110.87, 110.51, 106.81, 105.77, 105.30, 104.21, 103.86, 99.36, 80.19, 75.56,74.94, 73.26, 72.85, 70.54, 68.16, 66.34, 60.44, 60.10, 56.11, 55.08,54.55.HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 40 H 42 NO 18 + 824.2396; Found 824.2396。

[0098] Example 20: Synthesis of compound MZ20

[0099] The synthesis method was the same as Example 1 to obtain the product MZ20 as a light brown solid with a yield of 88%.

[0100] 1 H NMR (500 MHz, DMSO- d 6) δ 9.97 (s, 1H), 9.41 (d, J= 2.6 Hz, 1H), 9.02(d, J = 7.4 Hz, 1H), 7.27 – 7.23 (m, 3H), 7.20 (d, J = 7.8 Hz, 2H), 7.05 – 7.00(m, 2H), 6.83 (d, J = 1.3 Hz, 1H), 5.61 (d, J = 3.4 Hz, 1H), 5.46 (d, J = 7.4 Hz,1H), 5.43 (d, J = 5.7 Hz, 1H), 5.11 (d, J = 7.7 Hz, 1H), 5.06 (d, J = 3.9 Hz, 1H),4.91 (dd, J = 10.8, 5.3 Hz, 2H), 4.58 (t, J = 5.5 Hz, 1H), 4.53 (t, J = 5.6 Hz,1H), 4.30 (dd, J = 8.7, 4.4 Hz, 1H), 3.87 (s, 3H), 3.66 – 3.55 (m, 4H), 3.53 –3.47 (m, 2H), 3.46 (s, 2H), 3.45 – 3.42 (m, 2H), 3.40 (d, J = 2.0 Hz, 6H), 3.37(d, J = 0.9 Hz, 4H), 3.29 – 3.22 (m, 4H), 3.08 (td, J = 9.2, 5.6 Hz, 1H).HR-MS (ESI / QTOF) m / z: [M+H] + Calcd for C 40 H 42 NO 18 + 824.2396; Found 824.2391.

[0101] Sample analysis The 20 disaccharide monosubstituted derivatives MZ1-20 of Lamellarin D and N synthesized were tested for in vitro cytotoxic activity. Lamellarin D, Lamellarin N and Lamellarin D monosaccharide monosubstituted derivative ZL-9 (preparation method see reference 1: Zheng Liuliu, et al. Design, Synthesis and Structure-Activity Relationship Studies of Glycosylated Derivatives of Marine Natural Product Lamellarin D. Eur. J. Med. Chem. 2021, 214:113226.) were used as positive controls, and human breast cancer cells MDA-MB-231, human liver cancer cells HepG2, leukemia cells Jurkat were selected to investigate the effect of disaccharide glycosylation on the in vitro cytotoxic activity of Lamellarin compounds.

[0102] Table 1: In vitro cytotoxic activity of compounds MZ1-MZ20

[0103]

[0104] Note: -: IC 50 >5.00 μM; +: 0.25 μM < IC 50 <5.00 μM; ++: 0.05 μM < IC 50 <0.25 μM; +++: 0.01 μM < IC 50 <0.05 μM; ++++: IC 50 <0.01 μM Experimental results: As shown in Table 1, the tumor inhibitory activity of Lamellarin disaccharide monosubstituted derivatives (MZ3, MZ10, MZ13, MZ20) was improved compared with Lamellarin monosaccharide monosubstituted derivative ZL-9, Lamellarin D and N, and the proliferation inhibition activity of tumor cells was improved, especially for non-solid tumor cell line Jurkat, the inhibition effect was significantly improved by about 5 times. For solid tumor cell lines human breast cancer cells MDA-MB-231 (as shown in Figure 4 Table 1) and human liver cancer cells HepG2, Lamellarin disaccharide monosubstituted derivatives (MZ3, MZ10, MZ13, MZ20) also achieved comparable inhibition effect as G20, Lamellarin D and N.

[0105] The above merely describes the preferred embodiments of the present application and is not used to limit the present application, and although the present application is described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions recorded in the foregoing embodiments, or equivalently replace some technical features thereof. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A disaccharide monosubstituted derivative of Lamellarin D and N, characterized in that, The structure is as follows: R1 and R2 are each independently selected from one of H, methyl, benzyl, acetyl, and disaccharide, R3 is selected from H, benzyl, or disaccharide, and R4 is selected from H, methanesulfonyl, or disaccharide, and at least one of R1 to R4 is a disaccharide. The disaccharide is one of cellobiose, acetylated cellobiose, lactose, acetylated lactose, maltose, and acetylated maltose.

2. The disaccharide monosubstituted derivative of Lamellarin D and N according to claim 1, characterized in that, R1 is a disaccharide, R2 is a methyl group, R3 is a benzyl group, and R4 is a methanesulfonyl group; Alternatively, R1 can be a disaccharide, and R2, R3, and R4 can be H or methyl. Alternatively, R1 can be methyl, R2 can be disaccharide, R3 can benzyl, and R4 can be methanesulfonyl. Alternatively, R1, R3, and R4 can be H or methyl groups, and R2 can be a disaccharide group; Alternatively, R1 can be acetyl, R2 methyl, R3 disaccharide, and R4 methanesulfonyl. Alternatively, R1, R2, and R4 can be H or methyl groups, and R3 can be a disaccharide group; Alternatively, R1 can be benzyl, R2 can be methyl, R3 can benzyl, and R4 can be disaccharide. Alternatively, R1, R2, and R3 can be H or methyl groups, and R4 can be a disaccharide group; The disaccharide is one of cellobiose, acetylated cellobiose, lactose, acetylated lactose, maltose, and acetylated maltose.

3. The disaccharide monosubstituted derivative of Lamellarin D and N according to claim 2, characterized in that, The aforementioned disaccharide monosubstituted derivatives of Lamellarin D and N are selected from any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 4. The method for preparing the disaccharide monosubstituted derivatives of Lamellarin D and N according to any one of claims 1 to 3, characterized in that, Includes the following steps: Bromine-substituted pyrano[4',3':4,5]pyrrolo[2,1- a Isoquinoline-6-one compounds undergo a Suzuki reaction with meta- and para-substituted phenylboronic acid esters to yield compounds with hydroxyl protecting groups at positions 8, 13, 14, and 20. Subsequent addition reactions of the tetrahydroisoquinoline ring yield Lamellarin D and N skeletons. Removal of any hydroxyl protecting group at position 8, 13, 14, or 20 followed by reaction with a glycosyl donor yields a monosubstituted acetylated disaccharide derivative substituted at any position 8, 13, 14, or 20. Subsequently, removal of the acetyl group from the glycosyl group and the removal of the remaining hydroxyl protecting groups yields the monosubstituted disaccharide derivative.

5. The method for preparing the disaccharide monosubstituted derivatives of Lamellarin D and N according to claim 4, characterized in that, The glycosyl donor is one of 2,2',3,3',4',6,6'-hepta-O-acetyl-β-D-cellobiose trichloroimide ester, 2,2',3,3',4',6,6'-hepta-O-acetyl-β-D-lactosyl trichloroimide ester, and 2,2',3,3',4',6,6'-hepta-O-acetyl-β-D-maltose trichloroimide ester.

6. The method for preparing the disaccharide monosubstituted derivatives of Lamellarin D and N according to claim 4, characterized in that, The bromine-substituted pyrano[4',3':4,5]pyrrolo[2,1- a The preparation method of isoquinoline-6-one compounds includes the following steps: Compound I was obtained by cyclizing 6-(benzoxy)-7-methoxy-1-methyl-3,4-dihydroisoquinoline and 2-(2-bromoacetyl)-4-methoxy-5-((methanesulfonyl)oxy)phenylacetic acid. The hydroxyl group of compound I was then acetylated for protection, followed by a Vilsmeier-Haack reaction to yield compound J. Compound J was then oxidized, deacetylated, and intramolecularly cyclized to obtain a bromo-substituted pyrano[4',3':4,5]pyrrolo[2,1- a Isoquinoline-6-one compounds; The specific route is as follows: 。 7. The use of the disaccharide monosubstituted derivatives of Lamellarin D and N according to any one of claims 1 to 3 in the preparation of medicaments for treating liver cancer and leukemia, characterized in that, In the disaccharide monosubstituted derivatives of Lamellarin D and N, R1 is methyl, R2 and R4 are both H, and R3 is maltodextrin.

8. The use of the disaccharide monosubstituted derivatives of Lamellarin D and N according to any one of claims 1 to 3 in the preparation of medicaments for treating liver cancer and leukemia, characterized in that, In the disaccharide monosubstituted derivatives of Lamellarin D and N, R1 is methyl, R2 and R3 are both H, and R4 is maltodextrin.

9. The use of the disaccharide monosubstituted derivatives of Lamellarin D and N according to any one of claims 1 to 3 in the preparation of a medicament for treating leukemia, characterized in that, In the disaccharide monosubstituted derivatives of Lamellarin D and N, R1 and R4 are both H, R2 is methyl, and R3 is maltodextrin.

10. The use of the disaccharide monosubstituted derivatives of Lamellarin D and N according to any one of claims 1 to 3 in the preparation of medicaments for treating breast cancer and leukemia, wherein R1 and R3 are both H, R2 is methyl, and R4 is maltose.

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