Synthetic method of marine cyanobacteria metabolite Dragocins A-C and analogues thereof and application of marine cyanobacteria metabolite Dragocins A-C and analogues thereof in antitumor drugs

Abstract

The invention belongs to the field of carbohydrate chemistry and medicinal chemistry, and particularly relates to a synthetic method of marine cyanobacteria metabolite Dragocins A-C and analogues thereof and application of the marine cyanobacteria metabolite Dragocins A-C and the analogues thereof in antitumor drugs. The preparation method comprises the following steps: taking anise mycin and 2, 3-ester group protected beta-D-ribose thioglycoside as initial raw materials, and carrying out direct stereoselective glycosylation reaction and cross dehydrogenation coupling reaction to obtain an oxa-bridged ring [6.2. 1] undecane skeleton; the obtained oxa-bridged ring intermediate is subjected to an oxidation reaction, a decarboxylation chlorination reaction promoted by silver salt and the like to obtain ribose C-4-site chlorination and methoxyl substitution products Dragocins A-C and analogues of the ribose C-4-site chlorination and methoxyl substitution products Dragocins A-C. In-vitro experiments show that the N-demethylated Dragocin A compound 15 has a good tumor cell inhibition effect and can be used for preparing antitumor drugs. The synthesis method disclosed by the invention is mild in reaction condition, simple and convenient in route, low in price of the initial raw material anise mycin and the reaction reagent, relatively high in final yield, and suitable for large-scale preparation of the Dragocins A-C and analogues thereof.

Description

Technical Field

[0001] The invention belongs to the field of carbohydrate chemistry and medicinal chemistry, and specifically relates to a synthesis method of marine cyanobacteria metabolites Dragocins A-C and analogs thereof and their application in preparing anti-tumor drugs. Background Art

[0002] Cancer, also known as malignant tumors, has seriously threatened human health and life. Natural products are an important source of new drug discovery and play an important role in the development of anti-tumor drugs, such as paclitaxel and camptothecin. Natural products have potential therapeutic effects on cancer, and natural product-derived drugs have the advantages of less residue and low side effects. However, some natural products have low content and limited sources, which seriously restricts their further research on drugability and mechanism of action.

[0003] In 2019, Professor Gerwick's research group at the Scripps Research Institute in the United States isolated the alkaloid Dragocins AC with a unique structure of oxygen-bridged ring [6.2.1] undecane skeleton from the deep red woolly marine cyanobacteria in the Panama Sea. Preliminary activity tests showed that Dragocins A and C have strong cytotoxicity to human H-460 lung cancer cells (Org. Lett., 2019, 21, 266-270.).

[0004] At present, there are few reports on the chemical synthesis of Dragocins AC and its analogs. In 2024, the Baran group reported the first total synthesis of Dragocins AC, which obtained the pyrrolidine module glycosylated receptor with a yield of 14% in 7 steps. The operation was complicated and the yield was low. One of the key technologies is the construction of the oxo-bridged cyclo[6.2.1]undecane skeleton by electrochemical oxidation, and the other is the introduction of the necessary C-4′ substituent by Barton decarboxylation chlorination. This route uses dangerous reagents such as lithium metal and lithium aluminum hydride, and the reaction conditions are harsh, making it difficult to synthesize Dragocins AC on a large scale (Angew. Chem. Int. Ed. 2024, 136, e202401107.). Summary of the invention

[0005] In view of the above problems, one of the objects of the present invention is to provide a method for synthesizing Dragocins AC and its analogues, which have cheap and readily available raw materials, mild reaction conditions, a simple synthesis route and a high yield, and are suitable for the large-scale synthesis of Dragocins AC and its analogues epi-Dragocins AC.

[0006] In addition, the present invention also provides the use of the Dragocins AC and its analogs synthesized by the above method for preparing anti-tumor drugs.

[0007] The structures of Dragocins AC and epi-Dragocins AC are shown below:

[0008]

[0009] The invention uses anisomycin 7 and 2,3-ester protected β-D-ribose glucosides 9 as starting materials, obtains an oxo-bridged ring [6.2.1] undecane skeleton through direct stereoselective glycosylation reaction and cross dehydrogenation coupling reaction (CMC); the obtained oxo-bridged ring intermediate is subjected to oxidation reaction, silver salt-promoted decarboxylation chlorination reaction, etc. to obtain ribose C-4′ chlorination and methoxy substitution products Dragocins AC and its analogs.

[0010] The synthetic route of the present invention is as follows:

[0011]

[0012] Among them, R3 is a sulfonyl protecting group, selected from any one of methylsulfonyl, ethylsulfonyl, p-toluenesulfonyl, o-nitrotoluenesulfonyl, p-nitrotoluenesulfonyl, and 2,4-dinitrobenzenesulfonyl; R4 is a silyl protecting group, selected from any one of TMS (trimethylsilyl), TES (triethylsilyl), TBS (tert-butyldimethylsilyl), TIPS (triisopropylsilyl), and TBDPS (tert-butyldiphenylsilyl); R5 is a silyl protecting group, selected from any one of TMS, TES, TBS, TIPS, and TBDPS; R6 is an acyl protecting group, selected from any one of acetyl, trichloroacetyl, trimethylacetyl, trifluoroacetyl, propionyl, benzoyl, and p-methoxybenzoyl.

[0013] The specific synthesis steps of the present invention are as follows:

[0014] Step 1: Preparation of compound 8:

[0015] 1) In a polar or non-polar solvent, compound 7 reacts with a sulfonylating agent at 1-100 atmospheres and 0-100° C. for 30-3000 minutes to obtain an N-sulfonylated intermediate; the solvent is one or more of pyridine, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dichloromethane, and 2,6-lutidine, and the preferred solvent is a mixed solvent of dichloromethane and 2,6-lutidine, and the volume ratio of the two is dichloromethane:2,6-lutidine=5:1. The sulfonylating agent is any one of methanesulfonyl chloride, ethanesulfonyl chloride, p-toluenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, and 2,4-dinitrobenzenesulfonyl chloride, and the preferred agent is p-nitrotoluenesulfonyl chloride. The molar ratio of the compound 7 to the sulfonylating agent is 1:(1-100), preferably 1:1.5.

[0016] 2) In a polar or non-polar solvent, the N-sulfonylated intermediate is reacted with a silicon etherification agent under the action of an organic base at 1-100 atmospheres and 0-100°C for 30-3000 minutes to obtain a silicon etherification intermediate; the solvent is one or more of pyridine, THF, DMF, DMA, and dichloromethane, and the preferred solvent is dichloromethane. The organic base is 4-dimethylaminopyridine (DMAP), imidazole, etc., and the preferred reagent is imidazole. The silicon etherification agent is any one of TMSCl, TESCl, TBSCl, TIPSCl, and TBDPSCl, and the preferred reagent is TBSCl. The molar ratio of the N-sulfonylated intermediate, the silicon etherification agent, and the organic base is 1:(1-100):(1-100), and the preferred molar ratio is 1:1.5:3.0.

[0017] 3) In a polar or non-polar solvent, the siliconized intermediate is reacted under the action of a base at 0-100°C for 30-3000 minutes to obtain compound 8. The solvent is one or more of methanol, DMF, DMA, THF, and dichloromethane, and the preferred solvent is a mixed solvent of methanol and dichloromethane, and the volume ratio of the two is methanol: dichloromethane = 1:1. The base is NaH, sodium methoxide, sodium ethoxide, sodium hydroxide, etc., and the preferred base is NaH. The molar ratio of the siliconized intermediate and the base is 1:(0.1-10); the preferred molar ratio is 1:0.1.

[0018] Step 2: Preparation of compound 10:

[0019] In a polar or non-polar solvent, compounds 8 and 9 react under the protection of an inert gas at 1-100 atmospheres at -20-100°C for 30-3000 minutes under the action of a donor activator to obtain compound 10; the solvent is one or more of dichloroethane (DCE), chlorobenzene, DMF, DMA, and dichloromethane, and the preferred solvent is dichloromethane. The donor activator is one of N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), trimethylsilyl trifluoromethanesulfonate (TMSOTf), and tert-butyl dimethylsilyl trifluoromethanesulfonate (TBSOTf). The molar ratio of the compounds 8, 9, and the donor activator is 1:(1-10):(1-10):(0.1-10); the preferred molar ratio is 1:1.6:1.7:0.2.

[0020] Step 3: Preparation of compound 11:

[0021] 1) In a polar or non-polar solvent, compound 10 reacts under the action of a protonic acid at 0-100° C. for 30-3000 minutes to obtain a C2-hydroxy desilylated ether intermediate; the solvent is one or more of acetonitrile, ethyl acetate, dichloromethane, chloroform, and diethyl ether, and the preferred solvent is a mixed solvent of THF and water, and the volume ratio of the two is (1-100): 1. The protonic acid is one of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, and the preferred protonic acid is formic acid.

[0022] 2) In a polar or non-polar solvent, the C2-hydroxy desilylated ether intermediate is reacted with an acylating agent under the action of a base at 1-100 atmospheres and 0-100°C for 30-3000 minutes to obtain an acylated intermediate; the solvent is one or more of pyridine, THF, DMF, DMA, TEA, and dichloromethane, and preferably dichloromethane and TEA. The base is one of DMAP, triethylamine (TEA), and diisopropylethylamine (DIEA), and preferably DMAP. The acylating agent is any one of acetyl chloride, acetic anhydride, propionyl chloride, and benzoyl chloride, and preferably benzoyl chloride. The molar ratio of the C2-hydroxy desilylated ether intermediate, the acylating agent, and the base is 1:(1-100):(1-100); the preferred molar ratio is 1:1.5:0.3.

[0023] 3) In a polar or non-polar solvent, the above acylated intermediate is reacted under the action of a fluoride-containing salt at 0-100°C for 30-3000 minutes; the fluoride-containing salt is one of tetrabutylammonium fluoride, pyridine hydrofluoride, potassium fluoride, and cesium fluoride, and preferably the fluoride-containing salt is pyridine hydrofluoride. The solvent is one or more of methanol, DMF, DMA, and THF, and preferably the solvent is THF. The molar ratio of the acylated intermediate to the fluoride-containing salt is 1:(1-100), and preferably the molar ratio is 1:2.0.

[0024] Step 4: Preparation of compound 12 and epi-12:

[0025] In a polar or non-polar solvent at 0-100°C, compound 11 reacts with an oxidant under acidic conditions for 30-3000 minutes to obtain compound 12 and epi-12; the solvent is one or more of DCE, chlorobenzene, DMF, DMA, and dichloromethane, preferably DCE. The oxidant is one of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), cerium ammonium nitrate (CAN), 2-iodoacetylbenzoic acid (IBX), Dess-Martine reagent (DMP), and sodium hypochlorite, preferably DDQ. The acid is one or more of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, preferably glacial acetic acid. The molar ratio of compound 11, oxidant, and acid is 1:(1-100):(1-100); the preferred molar ratio is 1:7.0:7.0.

[0026] Step 5: Preparation of compound 13 and epi-13:

[0027] 1) In a polar or non-polar solvent, compound 12 or epi-12 reacts with an oxidant at 0-100°C for 30-3000 minutes to obtain an oxidized intermediate acid; the solvent is one or more of DCE, chlorobenzene, DMF, DMA, dichloromethane, and water, preferably dichloromethane and water. The oxidant is one or more of 2,2,6,6-tetramethylpiperidinium oxide (TEMPO), iodobenzene acetate (DAIB), 2-iodobenzoic acid (IBX), Dess-Martine reagent (DMP), and sodium hypochlorite, preferably TEMPO or DAIB. The molar ratio of compound 12 or epi-12 to the oxidant is 1:(1-100):(1-100); preferably 1:0.6:5.

[0028] 2) In a polar or non-polar solvent, the above-mentioned oxidation intermediate acid, silver salt and chlorination agent are reacted at 1-100 atmospheres and 0-100°C for 10-3000 minutes to obtain compound 13 or epi-13; the solvent is one or more of DCE, chlorobenzene, DMF, DMA, dichloromethane and water, preferably DCE. The catalyst is a mixture of one or more silver salts such as Ag(Phen)2OTf, silver nitrate, silver carbonate, silver oxide, AgOTf, etc., preferably Ag(Phen)2OTf. The chlorination agent is one of carbon tetrachloride, tert-butyl hypochlorite, sodium hypochlorite and sodium chlorate, preferably tert-butyl hypochlorite. The molar ratio of the oxidation intermediate acid, silver salt catalyst and chlorination agent is 1:(0.01-100):(1-100); preferably the molar ratio is 1:0.3:3.

[0029] Step 6: Preparation of compound 14 and epi-14:

[0030] In a polar or non-polar solvent, compound 13 or epi-13 reacts under the action of a base at -10-100°C for 30-3000 minutes to obtain compound 14 or epi-14; the solvent is one or more of methanol, DMF, DMA, THF, preferably methanol. The base is NaH, sodium methoxide, metallic sodium, etc., preferably NaH. The molar ratio of compound 13 or epi-13 to the base is 1:(1-100); preferably 1:1.0.

[0031] Step 7: Preparation of compounds 15 and epi-15:

[0032] In a polar or non-polar solvent, compound 14 or epi-14 reacts with a sulfur-containing reagent at 0-100°C for 30-3000 minutes to obtain compound 15 or epi-15; the solvent is one or more of acetonitrile, DMF, DMA, THF, and TEA, and preferably acetonitrile and TEA. The sulfur-containing reagent is one of thiophenol, p-toluene thiophenol, ethanethiol, and sodium ethanethiolate, and preferably thiophenol. The molar ratio of compound 14 or epi-14 to the sulfur-containing reagent is 1:(1-100); preferably 1:2.0.

[0033] Step 8: Preparation of compounds Dragocin A trifluoroacetate and epi-Dragocin A trifluoroacetate:

[0034] In a polar or non-polar solvent, compound 15 or epi-15 reacts with a methylating agent under the action of a reducing agent at 0-100°C for 30-3000 minutes to obtain compound Dragocin A trifluoroacetate or epi-Dragocin A trifluoroacetate; the solvent is methanol, one or more of DMF, DMA, and THF, preferably methanol. The reducing agent is one of sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, and lithium borohydride, preferably sodium cyanoborohydride. The methylating agent is one of paraformaldehyde, formaldehyde aqueous solution, iodomethane, and dimethyl sulfate, preferably paraformaldehyde. The molar ratio of compound 15 or epi-15, reducing agent, and methylating agent is 1:(1-100):(1-100); the preferred molar ratio is 1:3.0:10.0. The obtained compound Dragocin A or epi-Dragocin A is dissolved in a mixed solvent of methanol and trifluoroacetic acid, and concentrated to obtain Dragocin A trifluoroacetate or epi-Dragocin A trifluoroacetate.

[0035] Step 9: Preparation of compounds 16 and epi-16:

[0036] In a polar or non-polar solvent, compound 13 or epi-13 reacts with a sulfur-containing reagent at 0-100°C for 30-3000 minutes to obtain compound 16 or epi-16; the solvent is one or more of acetonitrile, DMF, DMA, THF, and TEA, and preferably acetonitrile and TEA. The sulfur-containing reagent is one of thiophenol, p-toluene thiophenol, ethanethiol, and sodium ethanethiolate, and preferably the sulfur-containing reagent is thiophenol. The molar ratio of compound 13 or epi-13 to the sulfur-containing reagent is 1:(1-100); preferably the molar ratio is 1:2.0.

[0037] Step 10: Preparation of compounds Dragocin B trifluoroacetate and epi-Dragocin B trifluoroacetate:

[0038] In a polar or non-polar solvent, compound 16 or epi-16 reacts under the action of a reducing agent at -78-50°C for 30-3000 minutes to obtain Dragocin B trifluoroacetate or epi-Dragocin B trifluoroacetate. The solvent is one or more of dichloromethane, DMF, DMA, and THF, preferably dichloromethane. The reducing agent is one of lithium aluminum tetrahydride, borane, diisobutylaluminum hydride, and sodium borohydride, preferably diisobutylaluminum hydride. The molar ratio of compound 16 or epi-16 to the reducing agent is 1:(1-100); the preferred molar ratio is 1:10.0. The obtained compound Dragocin B or epi-Dragocin B is dissolved in a mixed solvent of methanol and trifluoroacetic acid, and concentrated to obtain Dragocin B trifluoroacetate or epi-Dragocin B trifluoroacetate.

[0039] Step 11: Preparation of compounds Dragocin C trifluoroacetate and epi-Dragocin C trifluoroacetate:

[0040] 1) In a polar or non-polar solvent, under 1-100 atmospheric pressure of hydrogen, compound 16 or epi-16 reacts at 0-100°C for 30-3000 minutes under the action of a metal catalyst to obtain a methylated intermediate; the solvent is one or more of methanol, DMF, DMA, and ethanol, preferably methanol. The metal catalyst is one of palladium carbon, platinum carbon, palladium hydroxide carbon, and platinum dioxide, preferably palladium carbon. The mass ratio of compound 16 or epi-16 to the metal catalyst is 1:(1-100); the preferred mass ratio is 1:1.4.

[0041] 2) In a polar or non-polar solvent, the above methylated intermediate reacts under the action of a reducing agent at -78-50°C for 30-3000 minutes to obtain Dragocin C trifluoroacetate or epi-Dragocin C trifluoroacetate. The solvent is one or more of dichloromethane, DMF, DMA, and THF, preferably dichloromethane. The reducing agent is one of lithium aluminum tetrahydride, borane, diisobutylaluminum hydride, and sodium borohydride, preferably diisobutylaluminum hydride. The molar ratio of the above methylated intermediate and the reducing agent is 1:(1-100); the preferred molar ratio is 1:10.0. The obtained compound Dragocin C or epi-Dragocin C is dissolved in a mixed solvent of methanol and trifluoroacetic acid, and concentrated to obtain Dragocin C trifluoroacetate or epi-Dragocin C trifluoroacetate.

[0042] The synthesized Dragocins AC and its analogs are used for preparing anti-tumor drugs, especially for preparing drugs for treating non-small cell lung cancer, colon cancer or breast cancer.

[0043] The N-demethylated Dragocin A compound 15 synthesized by the present invention is used for preparing medicines for treating non-small cell lung cancer, colon cancer or breast cancer.

[0044] The advantages of the present invention are as follows: (1) the starting materials anisomycin and β-D-ribosyl glucosinolate used are commercially available and inexpensive; (2) the reaction conditions are mild and the route is simple; most reactions in the route are insensitive to oxygen and water, which reduces the difficulty of synthesis, has a high final yield, and is suitable for large-scale preparation; (3) the synthesized Dragocins AC and its analogs can inhibit human non-small cell lung cancer cells A549, colon cancer cells HCT 116 and human breast cancer cells MCF7, especially compound 15, which has excellent inhibitory effect and is expected to be further developed into an anti-tumor drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 This is a graph showing the relationship between the A549 inhibition rate and the dosage of compound 15 prepared in the present invention.

[0046] Figure 2 1 is a graph showing the relationship between the HCT 116 inhibition rate and the dosage of compound 15 prepared in the present invention.

[0047] Figure 3 This is a graph showing the relationship between the MCF7 inhibition rate and the dosage of compound 15 prepared in the present invention. DETAILED DESCRIPTION

[0048] The present invention is described in detail by taking the following synthesis as an example, but the present invention is not limited to the following contents.

[0049] Embodiment 1:

[0050] Step 1: Preparation of compound 8:

[0051] 1) In an ice-water bath, 4-nitrobenzenesulfonyl chloride (NosCl, 6.89 g, 31.06 mmol, 1.5 eq) was added to a cooled solution of compound 7 (5.49 g, 20.70 mmol, 1.0 eq) in dichloromethane / 2,6-lutidine (volume ratio 5:1, 164 mL). The mixture was stirred at room temperature for 5 hours and then quenched with saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound N-Nos protected intermediate (9.04 g, 20.08 mmol, 97%) as an orange foam.

[0052] 2) TBSCl (1.70 g, 11.29 mmol, 1.5 eq) was added to a 0°C solution of the above N-Nos intermediate (3.39 g, 7.53 mmol, 1.0 eq) and imidazole (1.54 g, 22.64 mmol, 3.0 eq) in anhydrous dichloromethane (64 mL). The reaction mixture was stirred at room temperature for 2 hours. After removing the volatiles under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain the silyl ether protected intermediate (3.67 g, 6.47 mmol, 86%) as an orange foam.

[0053] 3) In an ice-water bath, 60% sodium hydride (17.3 mg, 0.43 mmol, 0.1 eq) was added to a stirred solution of the above silyl ether protected intermediate (2.42 g, 4.28 mmol, 1.0 eq) in dichloromethane / methanol (volume ratio 1:1, 30 mL). The mixture was stirred at room temperature for 8 hours and then quenched with an acidic resin to pH = 7. The mixture was filtered through diatomaceous earth. The filtrate was concentrated under vacuum to give a light yellow foam 8 (2.12 g, 4.07 mmol, 95%). 1H NMR (400MHz, CDCl3) δ8.36(d,J=8.8Hz,2H),8.04(d,J=8.8Hz,2H),7.20(d,J=8.5 Hz,2H),6.85(d,J=8.6Hz,2H),3.90–3.81(m,2H),3.80(s,3H),3.74(dd,J=11.3, 4.1Hz,1H),3.65–3.60(m,1H),3.46(dd,J=13.9,4.3Hz,1H),3.27(dd,J=11.2,1. 5Hz,1H),3.00(dd,J=13.9,10.4Hz,1H),0.66(s,9H),-0.13(s,3H),-0.18(s,3H). 13 C NMR (101MHz, CDCl3) δ158.5,150.2,144.0,130.3,129.9,128.8,124.4,114.2,7 6.9,74.1,63.9,55.5,55.4,34.2,25.6,18.0,-4.8,-5.0.HRMS(m / z)calcd.for C 24 H 35 N2O7SSi[M+H + ]523.1929,found 523.1915.

[0054] Step 2: Preparation of compound 10:

[0055] Compound 9 (8.50 g, 8.76 mmol, 1.6 eq), anisomycin receptor 8 (2.86 g, 5.47 mmol, 1.0 eq) and Molecular sieves (2.02 g) were mixed in dichloromethane (20 mL) and stirred at room temperature for 30 minutes. NIS (2.03 g, 9.03 mmol, 1.7 eq) and TMSOTf (100 μL, 1.22 mmol, 0.2 eq) were added at -10 ° C. The mixture was stirred at -10 ° C for 1 hour and then quenched with TEA (0.5 mL). After filtration, the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate=8:1) to give compound 10 (7.18 g, 5.25 mmol, 96%) as an orange foam. 1H NMR (400MHz, CDCl3) δ8.22(d,J=8.8Hz,2H),7.85(d,J=8.8Hz,2H),7.79–7.69(m,6H),7.68–7.56(m,6H),7.56–7.49(m,1 H),7.47–7.22(m,13H),7.21–7.07(m,6H),6.71(d,J=8.6Hz,2H),5.97(d,J=5.1Hz,1H),5.74(m,1H),5.25(d,J=2.8Hz,1H ),4.40(d,J=9.7Hz,1H),4.28(d,J=10.7Hz,1H),3.97(d,J=10.6Hz,1H),3.88–3.84(m,1H),3.74(s,3H),3.68–3.57(m,3H ),3.42(m,1H),2.96–2.90(m,1H),2.83–2.79(m,1H),1.04(s,9H),0.99(s,9H),0.63(s,9H),-0.19(s,3H),-0.25(s,3H). 13 C NMR (101MHz, CDCl3) δ164.9,164.8,158.4,150.1,143.8,135.8,135.7,135.6,133.5,133.4,133. 3,133.0,132.7,132.6,131.5,130.1,130.0,129.8,129.7,129.6,129.3,128.9,128.52,128.49, 128.4,128.10,128.07,127.8,127.7,124.4,113.8,105.6,87.0,83.3,75.9,74.3,72.4,65.6,63 .4,62.5,55.3,52.6,34.5,26.9,26.8,25.6,19.4,19.3,17.9,-5.0,-5.1.HRMS(m / z)calcd.forC 76 H 92 N3O 14 SSi3[M+NH4 + ]1386.5602, found 1386.5602.

[0056] Step 3: Preparation of compound 11:

[0057] 1) Compound 10 (7.01 g, 5.12 mmol, 1.0 eq) was dissolved in THF / formic acid / water (6:6:1, v1 / v2 / v3, 65 mL) and stirred at room temperature. Three days later, saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was then extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain an easily separable C3-desilyl ether intermediate (4.56 g, 3.63 mmol, 71%).

[0058] 2) Benzoyl chloride (660 μL, 4.80 mmol, 1.5 eq) and DMAP (117.5 mg, 0.96 mmol, 0.3 eq) were added to a stirred solution of C3-desilyl ether intermediate (4.02 g, 3.20 mmol, 1.0 eq) in dichloromethane / TEA (6:1, v1 / v2, 35 mL). The mixture was stirred at room temperature for 5 hours and then quenched with saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was used directly in the next step without further purification.

[0059] 3) The crude product obtained above was dissolved in THF (30 mL), and pyridine·(HF)n (6.4 mL) was added thereto at 0°C. After stirring at 50°C for 8 hours, the mixture was quenched with a saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate=2:1) ​​to obtain compound 11 (2.45 g, 2.78 mmol, two-step total yield of 87%) as an orange foam. 1H NMR(400MHz, CDCl3)δ8.14(d,J=8.8Hz,2H),7.95–7.79(m,6H),7.65(dd,J=8.4,1.4Hz,2H),7.60–7.46(m,3H), 7.41–7.29(m,6H),7.26–7.24(m,2H),6.87(d,J=8.6Hz,2H),5.76(d,J=5.5Hz,1H),5.66(dd,J=5.6,1.6Hz,1H) ,5.51(d,J=1.6Hz,1H),5.29(dd,J=4.9,2.4Hz,1H),4.41(dd,J=5.6,3.0Hz,1H),4.26–4.22(m,1H),4.04–3.88 (m,3H),3.80-3.77(m,4H),3.65(d,J=11.7Hz,1H),3.34(dd,J=14.3,4.9Hz,1H),3.21(dd,J=14.3,9.2Hz,1H). 13 C NMR (101MHz, CDCl3) δ165.6,165.4,165.2,158.6,149.7,143.9,134.0,133.83,133.80,130.2,129.8,129.7,129.6,129.5,128.7,128.65 ,128.63,128.48,128.46,128.38,124.34,114.2,103.7,87.1,79.0,74.5,72.9,65.3,63.9,63.3,55.3,51.6,34.1.HRMS(m / z)calcd.for C 45 H 46 N3O 15 S[M+NH4 + ]900.2644,found 900.2644.

[0060] Step 4: Preparation of compound 12:

[0061] The diol compound 11 (2.30 g, 2.61 mmol, 1.0 eq) was dissolved in DCE (15 mL). To the suspension were added DDQ (4.15 g, 18.3 mmol, 7.0 eq), glacial acetic acid (1.1 mL, 18.3 mmol, 7.0 eq) and Molecular sieves. The reaction mixture was stirred at 55 ° C for 5 hours. Afterwards, the mixture was filtered through a celite pad, quenched with a saturated aqueous sodium thiosulfate solution, and then extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (dichloromethane / ethyl acetate=50:1) to obtain a separable product 12 (643.1 mg, 0.73 mmol, 28%) as an orange foam. 1 H NMR (400MHz, CDCl3) δ8.07–8.01(m,4H),8.00–7.94(m,2H),7.88–7.80(m,2H),7.63–7.54(m,2H),7.54–7.38(m,5 H),7.37–7.28(m,4H),7.19(d,J=8.2Hz,2H),6.64(d,J=8.4Hz,2H),5.95(d,J=5.3Hz,1H),5.80(d,J=5.4Hz,1H),5 .60(s,1H),5.48–5.45(m,1H),5.10(dd,J=10.2,6.3Hz,1H),4.76–4.74(m,1H),4.59(d,J=10.1Hz,1H),4.10(d,J= 13.0Hz,1H),3.98(d,J=11.8Hz,1H),3.79–3.75(m,1H),3.74(s,3H),3.62–3.56(m,2H),2.16(s,1H),1.70(s,1H). 13 C NMR(101MHz, CDCl3)δ:166.2,165.5,165.1,159.8,149.3,146.3,133.8,133.7,130.1,129.99,129.96,129.8,129.7,129.0, 128.8,128.7,128.6,127.6,123.7,113.6,104.5,86.1,80.8,77.3,76.6,76.4,74.9,63.1,55.2,51.2.HRMS(m / z)calcd.for C 45 H 44 N3O 15 S[M+NH4 + ]898.2488, found 898.2495.

[0062] Step 5: Preparation of compound 13:

[0063] 1) To a stirred solution of compound 12 (778.6 mg, 0.88 mmol, 1.0 eq) in dichloromethane / water (2:1, v1 / v2, 12 mL), TEMPO (83.2 mg, 0.53 mmol, 0.6 eq) and DAIB (1.42 g, 4.42 mmol, 5.0 eq) were added. The mixture was stirred at room temperature for 12 hours and then quenched with a saturated aqueous sodium thiosulfate solution. The resulting mixture was extracted three times with ethyl acetate, and the organic layer was washed with brine. The organic layer was collected, dried over sodium sulfate, the solid was filtered off and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane / methanol=50:1) to give an intermediate carboxylic acid (689.6 mg, 0.77 mmol, 87%) as an orange foam.

[0064] 2) Under nitrogen atmosphere, tert-butyl hypochlorite (t-BuOCl) (113 μL, 1.00 mmol, 3.0 eq) was added to anhydrous DCE (10 mL) solution of intermediate acid (300.2 mg, 0.33 mmol, 1.0 eq) and Ag (phen) 2 OTf (62.5 mg, 0.10 mmol, 0.3 eq). The mixture was stirred at 70 ° C for 1 hour, then quenched with 1N aqueous hydrochloric acid solution and extracted three times with dichloromethane. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 4: 1) to obtain two separable products 13 (178.6 mg, 0.20 mmol, 60%). 1 H NMR (400MHz, CDCl3) δ8.18–8.16(m,2H),8.05–8.01(m,4H),7.86–7.83(m,2H),7.66–7.59(m,2H),7 .52–7.45(m,6H),7.39–7.33(m,4H),7.29(d,J=7.7Hz,2H),6.76(d,J=8.4Hz,2H),6.20(d,J=4.6Hz ,1H),5.82(d,J=4.6Hz,1H),5.63(s,1H),5.60–5.54(m,1H),5.31(dd,J=11.3,6.1Hz,1H),4.87(d, J=11.3Hz,1H),4.55(t,J=6.2Hz,1H),4.02(d,J=13.0Hz,1H),3.92–3.82(m,2H),3.82–3.74(m,4H). 13C NMR (101MHz, CDCl3) δ166.4,165.4,165.1,160.3,149.6,145.9,133.9,133.7,130.8,130.2,130.1,130.0,129.0,128.9,128.8,128.7,128.6 3,128.56,128.3,128.0,127.9,123.9,114.0,104.0,103.8,81.9,78.3,76.8,76.3,73.9,72.7,68.7,60.6,55.3,49.9.HRMS(m / z)calcd.forC 44 H 41 N3O 14 ClS[M+NH4 + ]902.1992,found902.1992.

[0065] Step 6: Preparation of compound 14:

[0066] In an ice-water bath, 60% sodium hydride (4.9 mg, 0.11 mmol, 1.0 eq) was added to a stirred solution of compound 13 (100.4 mg, 0.11 mmol, 1.0 eq) in methanol (5 mL). The mixture was stirred at 45 ° C for 8 hours, then quenched with an acidic resin until pH = 5, and stirred for another 30 minutes. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane / methanol = 100: 1) to give a colorless oil compound 14 (45.4 mg, 79.1 μmol, 70%). 1 H NMR (400MHz, CDCl3) δ8.07(d,J=8.8Hz,2H),7.32(d,J=8.7Hz,2H),7.16(d,J=8.3Hz,2H), 6.71(d,J=8.2Hz,2H),5.21(s,1H),5.00–4.96(m,1H),4.43(d,J=6.2Hz,1H),4.36(d,J=1 0.1Hz,1H),4.21–4.09(m,3H),3.93(d,J=13.4Hz,1H),3.76(s,3H),3.58-3.50(m,4H),3. 35(dd,J=12.3,6.0Hz,1H),3.25(d,J=13.5Hz,1H),3.17(s,1H),3.02(s,1H),2.87(s,1H). 13C NMR(101MHz, CDCl3)δ130.0,128.1,123.9,113.6,83.5,81.6,74.4,74.1,73.1,63.6,55.3,52.0,51.4.HRMS(m / z)calcd.for C 18 H 25 ClNO7[M+NH4 + ]586.1701,found586.1701.

[0067] Step 7: Preparation of compound 15:

[0068] To a mixture of compound 14 (40.5 mg, 71.3 μmol, 1.0 eq) in acetonitrile / TEA (10:1, v1 / v2, 5.5 mL) was added thiophenol (14 μL, 0.14 mmol, 2.0 eq). The reaction was stirred at room temperature for 4 hours. After the solvent was removed under reduced pressure, the residue was purified by flash column chromatography (dichloromethane / methanol=8:1) to give a white foam compound 15 (24.3 mg, 62.7 μmol, 88%). 1 H NMR(400MHz,CD3OD)δ7.41(d,J=8.7Hz,2H),6.98(d,J=8.7Hz,2H),5.27(s,1H) ,4.63–4.60(m,1H),4.54(d,J=4.8Hz,1H),4.50(d,J=10.1Hz,1H),4.34(m,1H) ,4.09(d,J=4.7Hz,1H),3.95(dd,J=10.1,4.0Hz,1H),3.80(s,3H),3.65(q,J=1 3.7Hz,1H),3.45(dd,J=12.2,4.5Hz,1H),3.38(s,3H),3.02(d,J=12.2Hz,1H). 13 C NMR(101MHz,CD3OD)δ160.5,130.0,128.8,114.0,104.1,104.0,78.7,77.61,77.58,73.4,72.9,68.9,65.0,54.4,52.1,49.0.HRMS(m / z)calcd.for C 18 H 26 NO8[M+H + ]384.1654,found384.1653.

[0069] Step 8: Preparation of compound Dragocin A trifluoroacetate:

[0070] To a solution of compound 15 (8.3 mg, 21.7 μmol, 1.0 eq) and paraformaldehyde (7.2 mg, 0.21 mmol, 10.0 eq) in anhydrous methanol (5 mL), sodium cyanoborohydride (4.2 mg, 6.1 μmol, 3.0 eq) was added. The reaction was stirred at 45 °C for 4 hours. After the solvent was removed under reduced pressure, the residue was purified by flash column chromatography (dichloromethane / methanol=8:1) to obtain a colorless oil Dragocin A (1) (6.6 mg, 16.7 μmol, 77%). Dragocin A (1) (6.6 mg, 16 μmol, 1.0 eq) was dissolved in methanol (5 mL), and trifluoroacetic acid (100 μL, 1.30 mmol, 54.4 eq) was added thereto at room temperature. After stirring at 25°C for 1 hour, the solvent was removed under reduced pressure to obtain Dragocin A trifluoroacetate (8.5 mg, 16 μmol, 99%) as a white powder. 1 H NMR(400MHz,CD3OD)δ7.51(d,J=8.3Hz,2H),7.03(d,J=8.3Hz,2H),5.28(s,1H), 4.85–4.80(m,1H),4.61(d,J=10.0Hz,1H),4.54(d,J=4.8Hz,1H),4.37(d,J=3.6 Hz,1H),4.11(d,J=4.7Hz,1H),4.07–3.96(m,2H),3.83(s,3H),3.71(d,J=13.7H z,1H),3.65(d,J=13.8Hz,1H),3.39(s,3H),3.16(d,J=12.5Hz,1H),2.36(s,3H). 13 CNMR(101MHz,CD3OD)δ162.4,130.8,115.6,105.6,105.1,80.4,79.2,77.8,76.6,74.8,73.1,70.6,65.4,55.8,50.5,45.4. 19 F NMR(376MHz,CD3OD)δ–77.0.HRMS(m / z)calcd.for C 19 H 28 NO8[M+H + ]398.1809found 398.1805.

[0071] Step 9: Preparation of compound 16:

[0072] To a mixture of compound 13 (78.3 mg, 88.6 μmol, 1.0 eq) in acetonitrile / TEA (10: 1, v1 / v2, 5.5 mL) was added thiophenol (18 μL, 0.18 mmol, 2.0 eq). The reaction was stirred at room temperature for 4 hours. The reaction solution was poured into brine and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (dichloromethane / methanol=30: 1) to give compound 16 (52.3 mg, 77.4 μmol, 84%) as a white foam. 1 H NMR (400MHz, CDCl3) δ8.20 (dd, J=8.3, 1.4Hz, 2H), 8.02 (dd, J=8.4, 1.4Hz, 2H), 7.89 (dd, J=8.4, 1.4Hz, 2H ),7.65–7.56(m,2H),7.54–7.37(m,7H),7.32–7.27(m,2H),6.96(d,J=8.7Hz,2H),6.34(d,J=4.5Hz,1H),5 .88(d,J=4.5Hz,1H),5.84(s,1H),5.40–5.44(m,1H),4.73–4.68(m,2H),4.32(d,J=13.5Hz,1H),4.00(d,J =13.5Hz,1H),3.83(s,3H),3.80–3.75(m,1H),3.61(dd,J=12.1,6.6Hz,1H),3.01(dd,J=12.1,3.9Hz,1H). 13 C NMR (101MHz, CDCl3) δ166.2,165.4,165.3,159.8,133.7,133.6,133.4,131.3,130.2,130.0,129.7,129 .6,129.2,128.9,128.6,128.5,114.2,104.9,103.5,79.6,78.8,73.9,55.4,50.0.HRMS(m / z)calcd.for C 38 H 35 NO 10 Cl[M+H + ]700.1944, found 700.1944.

[0073] Step 10: Preparation of compound Dragocin B trifluoroacetate:

[0074] Under argon atmosphere, a solution of diisobutylaluminum hydride (DIBAL-H) ​​(1.0 M, 465 μL, 0.46 mmol, 10.0 eq) was added dropwise to a stirred solution of compound 16 (32.3 mg, 46.2 μmol, 1.0 eq) in anhydrous dichloromethane (5 mL) at -78°C. After stirring for 2 hours, the solution was treated with trifluoroacetic acid (100 μL, 1.30 mmol, 54.4 eq) and stirred at -78°C for 30 minutes. After removing the solvent under reduced pressure, the residue was purified by flash column chromatography (dichloromethane / methanol=8:1) to give Dragocin B (2) trifluoroacetate (12.2 mg, 31.9 μmol, 69%) as a white powder. 1 H NMR(400MHz,CD3OD)δ7.44(d,J=8.6Hz,2H),7.01(d,J=8.6Hz,2H),5.39(s,1H),4 .80(d,J=4.3Hz,1H),4.69(d,J=3.6Hz,1H),4.64(d,J=10.0Hz,1H),4.40(d,J=3.9 Hz,1H),4.13(d,J=4.2Hz,1H),4.11–4.08(m,1H),4.03(d,J=13.6Hz,1H),3.90(d, J=13.6Hz,1H),3.81(s,3H),3.53(dd,J=12.5,4.0Hz,1H),3.15(d,J=12.5Hz,1H). 13 C NMR (101MHz, CD3OD) δ162.3,130.4,130.0,115.6,107.9,106.2,79.6,79.1,77.5,75.6,74.6,73.5,66.7,55.8,53.5. 19 F NMR(376MHz,CD3OD)δ:–76.9.HRMS(m / z)calcd.for C 17 H 23 ClNO7[M+H + ]381.1158, found 388.1161.

[0075] Step 11: Preparation of compound Dragocin C trifluoroacetate:

[0076] 1) Pd / C (46.7 mg, 5%) was added to a solution of compound 16 (32.3 mg, 46.2 μmol, 1.0 eq) in methanol (10 mL). The mixture was evacuated and backfilled with hydrogen three times at normal pressure. After the mixture was stirred at 25° C. for 10 hours, the solid was filtered off and the filtrate was concentrated under vacuum. The residue was used directly in the next step without further purification.

[0077] 2) To a solution of the above-obtained crude product in anhydrous dichloromethane (5 mL), a solution of diisobutylaluminum hydride (DIBAL-H) ​​(1.0 M, 465 μL, 0.46 mmol, 10.0 eq) was added dropwise at -78°C under an argon atmosphere. After stirring for 2 hours, the solution was treated with D(-)-tartaric acid (69.1 mg, 0.46 mmol, 10.0 eq) and stirred at -78°C for 30 minutes. After removing the solvent under reduced pressure, the residue was purified by flash column chromatography (dichloromethane / methanol = 8:1) to obtain a colorless oil Dragocin C (3) (11.2 mg, 27.2 μmol, total yield of two steps is 59%). Dragocin C (3) (11.2 mg, 27.2 μmol, 1.0 eq) was dissolved in methanol (5 mL), and trifluoroacetic acid (100 μL, 1.30 mmol, 54.4 eq) was added thereto. After stirring at 25°C for 1 hour, the solvent was removed under reduced pressure to give Dragocin C·trifluoroacetate (14.4 mg, 27.2 μmol, 99%). 1 H NMR (400MHz, CD3OD) δ7.48(d,J=8.7Hz,2H),7.03(d,J=8.8Hz,2H),5.37(s,1H),4.81(m,1H),4.77(d,J=3.7Hz,1H),4.69(d,J=9.6Hz,1H), 4.36(d,J=2.4Hz,1H),4.12(d,J=4.2Hz,1H),4.08–3.92(m,3H),3.88(d,J=13.5Hz,1H),3.83(s,3H),3.15(d,J=13.9Hz,1H),2.39(s,3H). 13 C{ 1 H}NMR(101MHz,CD3OD)δ162.5,131.0,115.7,107.7,106.0,80.8,79.0,77.3,76.4,74.6,73.0,65.2,55.9. 19 F NMR(376MHz,CD3OD)δ–77.0.HRMS(m / z)calcd.forC 18 H 25 ClNO7[M+H + ]402.1314, found 402.1314.

[0078] Example 2: Compound cytotoxicity test

[0079] The prepared compounds were tested for anti-tumor in vitro cell activity, and the results showed that they could effectively inhibit human non-small cell lung cancer cells A549, colon cancer cells HCT116 and human breast cancer cells MCF7, and are expected to be further developed into anti-tumor drugs.

[0080] 1. The activity test is as follows:

[0081] (1) Cell inoculation: Tumor cells were prepared into a single cell suspension using a culture medium containing 10% fetal bovine serum, and 90 μL of cell culture medium was inoculated into each well of a 96-well plate (adherent cells were plated at 5×10 4 / mL, the suspension cells were 9×10 4 / mL), and then cultured under 5% CO2, 37°C for 24 hours.

[0082] (2) Add the sample solution to be tested: add 10 μL of sample solution to each well. For the initial screening, set one concentration for each sample and set three replicate wells for each concentration. Determine IC 50 Each sample was set up with eight concentration gradients, and each concentration was set up with three replicate wells. The 96-well plate was incubated at 5% CO2 and 37°C for 48 hours. The experiment was divided into a blank group, a control group, and a drug group.

[0083] (3) Color development: Aspirate the old culture medium and drug solution of the adherent cells, add 100 μL CCK-8 solution (diluted ten times with the basal culture medium), and directly add 10 μL CCK-8 stock solution to the suspended cells. Incubate at 37°C and 5% CO2 for 1-4 hours (keep away from light and observe in real time).

[0084] (4) Result detection: Use an enzyme-labeled instrument to measure the absorbance at 450 nm and record the original data and results.

[0085] (5) Toxicity was expressed as cell inhibition rate, and the calculation formula was as follows: cell inhibition rate (%) = (OD control - OD drug) / (OD control - OD blank) × 100%. IC was calculated using GraphPad Prism 8 (version 8.0.2, from GraphPad Software Inc.) 50 , experimental results are expressed as mean ± SD.

[0086] (6) Positive control: cisplatin.

[0087] Table 1 Inhibitory effects of compounds on A549, HCT116 and MCF7

[0088]

[0089] 2. Activity test results:

[0090] The data in Table 1 show that the synthesized Dragocins AC and its analogs can inhibit human non-small cell lung cancer cells A549, colon cancer cells HCT116 and human breast cancer cells MCF7. In particular, N-demethylated Dragocin A compound 15 exhibits excellent inhibitory effects on A549, HCT116 and MCF7. Even at a concentration 50 times lower than that of cisplatin, its inhibitory effect on MCF7 is still better than the positive control cisplatin. Figure 1 It can be seen that compound 15 has a good dose-inhibition rate linear relationship for A549, HCT116 and MCF7, and its IC50 values ​​are 838.9±12.5, 761.9±2.3, and 193.7±5.0 nM, respectively. In summary, compound 15 is expected to be further developed into an anti-tumor drug.

[0091] Although the content of the present invention has been described in detail through the above specific embodiments, it should be appreciated that the above description should not be considered as a limitation of the present invention. After reading the above content, it will be obvious to those skilled in the art for various modifications and substitutions of the present invention. Therefore, the protection scope of the present invention should be limited by the appended claims.

Claims

1. A method for synthesizing marine cyanobacteria metabolites Dragocins AC and their analogs, characterized in that: The following steps are involved: (1) Anisomycin 7 and 2, 3-ester protected β -D-ribose glucosinolate 9 is used as the raw material, and the oxo-bridged ring [6.2.1] undecane skeleton is obtained through direct stereoselective glycosylation reaction and cross-dehydrogenation coupling reaction; (2) the obtained oxo-bridged ring intermediate is subjected to oxidation reaction and silver salt-promoted decarboxylation chlorination reaction to obtain the ribose C-4´ chlorinated and methoxy substituted products Dragocins AC and its analogs.

2. The method for synthesizing Dragocins AC and its analogs according to claim 1, characterized in that: The cross-dehydrogenation coupling reaction is an oxidant-mediated reaction.

3. The synthesis method according to claim 2, characterized in that The oxidant is one of 2,3-dichloro-5,6-dicyanobenzoquinone, cerium ammonium nitrate, 2-iodoxybenzoic acid, Dess-Martine reagent, and sodium hypochlorite.

4. The method for synthesizing Dragocins AC and its analogs according to claim 1, characterized in that: The oxidant of the oxidation reaction is one or more of 2, 2, 6, 6-tetramethylpiperidine nitrogen oxide, iodobenzene acetate, 2-iodoacylbenzoic acid, Dess-Martine reagent, and sodium hypochlorite.

5. The synthesis method according to claim 1, characterized in that The silver salt is a mixture of one or more of Ag(Phen)2OTf, silver nitrate, silver carbonate, silver oxide and AgOTf.

6. The synthesis method according to claim 1, characterized in that The reagent for the chlorination reaction is one of carbon tetrachloride, tert-butyl hypochlorite, sodium hypochlorite and sodium chlorate.

7. Use of the marine cyanobacterial metabolite Dragocins AC and its analogs synthesized by the synthesis method according to any one of claims 1 to 8 in the preparation of anti-tumor drugs.

8. Use of the marine cyanobacterial metabolite Dragocins AC and its analogs synthesized by the synthesis method according to any one of claims 1 to 8 in the preparation of drugs for treating non-small cell lung cancer, colon cancer or breast cancer.

9. The method according to any one of claims 1 to 8 N -Demethylated Dragocin A compound 15 is used for preparing drugs for treating non-small cell lung cancer, colon cancer or breast cancer.

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