Synthesis method of marine cyanobacterial metabolites dragocins a-c and analogues and application in antitumor drugs

Abstract

The application belongs to the field of sugar chemistry and medicinal chemistry, and particularly relates to a synthesis method of marine blue bacteria metabolites Dragocins A-C and analogs thereof and application thereof in antitumor drugs. β -D-ribose thioside as a starting material, an oxygen-bridged ring [6.2.1] undecane skeleton is obtained through a direct stereoselective glycosylation reaction and a cross dehydrogenative coupling reaction; the obtained oxygen-bridged ring intermediate is subjected to an oxidation reaction, a silver salt promoted decarboxylation chlorination reaction and the like to obtain a chloro and methoxy substitution product at a ribose C-4' position, Dragocins A-C and analogs thereof. In vitro experiments show that N The demethylated Dragocin A compound 15 has good tumor cell inhibition effect and can be used for preparing antitumor drugs. The synthesis method has mild reaction conditions, a simple route, low prices of anisomycin and reaction reagents as starting materials, and a high final yield, and is suitable for large-scale preparation of Dragocins A-C and analogs thereof.

Description

Technical Field

[0001] The present invention belongs to the fields of carbohydrate chemistry and medicinal chemistry, and particularly relates to a method for synthesizing marine cyanobacteria metabolites Dragocins A-C and analogs thereof and their use in preparing anti-tumor drugs. Background Art

[0002] Cancer, also known as malignant tumors, poses a serious threat to human health and life. Natural products, such as paclitaxel and camptothecin, are a crucial source for new drug discovery and play a crucial role in the development of anti-tumor drugs. Natural products have potential therapeutic effects against cancer, and natural product-derived drugs offer the advantages of low residual content and minimal side effects. However, the low content and limited sources of some natural products severely limit further research into their drugability and mechanisms of action.

[0003] In 2019, Professor Gerwick's research group at the Scripps Research Institute in the United States isolated two alkaloids, Dragocins AC, with a unique oxo-bridged cyclic [6.2.1] undecane skeleton, from a deep red, woolly marine cyanobacteria found in the Panamanian Sea. Preliminary bioactivity testing showed that Dragocins A and C exhibited potent cytotoxicity against 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 analogues. In 2024, the Baran group reported the first total synthesis of Dragocins AC, which obtained a 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 cyclic [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 hazardous reagents such as metallic lithium 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 response to the above problems, one of the objectives of the present invention is to provide a method for synthesizing Dragocins AC and its analogs, which are metabolites of marine cyanobacteria and have inexpensive and readily available raw materials, mild reaction conditions, a simple synthetic route, and high yields, which is suitable for the large-scale synthesis of Dragocins AC and its analogs, epi-Dragocins AC.

[0006] In addition, the present invention also provides the use of Dragocins AC and its analogs synthesized by the above method in 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 glucoside 9 as starting materials, and obtains an oxo-bridged cyclic [6.2.1] undecane skeleton through direct stereoselective glycosidation reaction and cross-dehydrogenation coupling reaction (CMC); the obtained oxo-bridged cyclic intermediate is subjected to oxidation reaction, silver salt-promoted decarboxylation chlorination reaction, etc. to obtain ribose C-4′-position chlorination and methoxy substitution products Dragocins AC and its analogues.

[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, pivaloyl, 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) Compound 7 is reacted with a sulfonylating agent in a polar or non-polar solvent at 1-100 atm and 0-100 °C for 30-3000 min 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, 2,6-dimethylpyridine, preferably the solvent is a mixed solvent of dichloromethane and 2,6-dimethylpyridine, the volume ratio of which is dichloromethane:2,6-dimethylpyridine = 5:1. The sulfonylating agent is any one of methanesulfonyl chloride, ethanesulfonyl chloride, p-toluenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, preferably the agent is p-nitrobenzenesulfonyl chloride. The molar ratio of compound 7 to the sulfonylating agent is 1:(1-100), preferably the molar ratio is 1:1.5.

[0016] 2) The above N-sulfonylated intermediate is reacted with a silylating agent in the presence of an organic base in a polar or non-polar solvent at 1-100 atm and 0-100 °C for 30-3000 min to obtain a silylated intermediate; the solvent is one or more of pyridine, THF, DMF, DMA, dichloromethane, preferably the solvent is dichloromethane. The organic base is 4-dimethylaminopyridine (DMAP), imidazole, etc., preferably the agent is imidazole. The silylating agent is any one of TMSCl, TESCl, TBSCl, TIPSCl, TBDPSCl, preferably the agent is TBSCl. The molar ratio of the N-sulfonylated intermediate, the silylating agent, and the organic base is 1:(1-100):(1-100), preferably the molar ratio is 1:1.5:3.0.

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

[0018] Step 2: Preparation of compound 10:

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

[0020] Step 3: Preparation of compound 11:

[0021] 1) Compound 10 is reacted in a polar or non-polar solvent 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, preferably a mixed solvent of THF and water in a volume ratio of (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, preferably formic acid.

[0022] 2) The C2-hydroxy desilylated ether intermediate is reacted with an acylating agent in a polar or non-polar solvent 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, preferably dichloromethane and TEA. The base is one of DMAP, triethylamine (TEA), and diisopropylethylamine (DIEA), preferably DMAP. The acylating agent is any one of acetyl chloride, acetic anhydride, propionyl chloride, and benzoyl chloride, preferably benzoyl chloride. The molar ratio of the C2-hydroxy desilylated ether intermediate, acylating agent, and base is 1:(1-100):(1-100); preferably, the molar ratio is 1:1.5:0.3.

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

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

[0025] Compound 11 is reacted with an oxidant under acidic conditions in a polar or non-polar solvent at 0-100°C for 30-3000 minutes to produce compounds 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), ceric 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), preferably 1:7.0:7.0.

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

[0027] 1) Compound 12 or epi-12 is reacted with an oxidant in a polar or non-polar solvent 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 N-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, the molar ratio is 1:0.6:5.

[0028] 2) The oxidative intermediate acid is reacted with a silver salt and a chlorination agent in a polar or non-polar solvent 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, and AgOTf, 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 oxidative 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] Compound 13 or epi-13 is reacted in a polar or non-polar solvent with 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, and THF, with methanol being preferred. The base is NaH, sodium methoxide, or metallic sodium, with NaH being preferred. 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 compound 15 and epi-15:

[0032] Compound 14 or epi-14 is reacted with a sulfur-containing reagent in a polar or non-polar solvent 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, with acetonitrile and TEA being preferred. The sulfur-containing reagent is one of thiophenol, p-toluenethiophenol, ethanethiol, and sodium ethanethiolate, with thiophenol being preferred. 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] Compound 15 or epi-15 is reacted with a methylating agent in a polar or non-polar solvent 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 one or more of methanol, 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, aqueous formaldehyde, methyl iodide, 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); preferably, the 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 compound 16 and epi-16:

[0036] Compound 13 or epi-13 is reacted with a sulfur-containing reagent in a polar or non-polar solvent 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, with acetonitrile and TEA being preferred. The sulfur-containing reagent is one of thiophenol, p-toluenethiophenol, ethanethiol, or sodium ethanethiolate, with thiophenol being preferred. The molar ratio of compound 13 or epi-13 to the sulfur-containing reagent is 1:(1-100), preferably 1:2.0.

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

[0038] Compound 16 or epi-16 is reacted in a polar or non-polar solvent 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), preferably 1:10.0. The resulting 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 atmospheres of hydrogen, compound 16 or epi-16 is reacted with a metal catalyst at 0-100°C for 30-3000 minutes 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); preferably, the mass ratio is 1:1.4.

[0041] 2) The methylated intermediate is reacted in a polar or non-polar solvent 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 methylated intermediate to the reducing agent is 1:(1-100), preferably 1:10.0. The resulting 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, in particular 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 a drug 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 used, anisomycin and β-D-ribosyl glucosinolate, 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, and the final yield is high, making it 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 This is a graph showing the relationship between the HCT 116 inhibition rate and the dose 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] Example 1:

[0050] Step 1: Preparation of compound 8:

[0051] 1) To a cooled solution of compound 7 (5.49 g, 20.70 mmol, 1.0 eq) in dichloromethane / 2,6-dimethylpyridine (5:1 by volume, 164 mL) was added 4-nitrobenzenesulfonyl chloride (NosCl, 6.89 g, 31.06 mmol, 1.5 eq) in an ice-water bath. The mixture was stirred at room temperature for 5 h, then quenched with saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate three times. 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 the N-Nos-protected intermediate (9.04 g, 20.08 mmol, 97%) as an orange foam.

[0052] 2) To a 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 dry dichloromethane (64 mL) at 0 °C was added TBSCl (1.70 g, 11.29 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 2 h. After removal of 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 in vacuo. The crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to give the silyl ether-protected intermediate (3.67 g, 6.47 mmol, 86%) as an orange foam.

[0053] 3) To a stirred solution of the above silyl ether-protected intermediate (2.42 g, 4.28 mmol, 1.0 eq) in dichloromethane / methanol (1:1 by volume, 30 mL) at 0 °C was added 60% sodium hydride (17.3 mg, 0.43 mmol, 0.1 eq) in an ice-water bath. The mixture was stirred at room temperature for 8 h, then quenched with acidic resin to pH = 7. The mixture was filtered through celite. The filtrate was concentrated in vacuo to give 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 obtain 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. After three days, saturated aqueous sodium bicarbonate 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 flash column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain an easily isolated C3-desilylated intermediate (4.56 g, 3.63 mmol, 71%).

[0058] 2) To a stirred solution of C3-desilylated intermediate (4.02 g, 3.20 mmol, 1.0 eq) in dichloromethane / TEA (6:1, v1 / v2, 35 mL) was added benzoyl chloride (660 μL, 4.80 mmol, 1.5 eq) and DMAP (117.5 mg, 0.96 mmol, 0.3 eq). The mixture was stirred at room temperature for 5 hours and then quenched with saturated aqueous sodium bicarbonate 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 saturated aqueous sodium bicarbonate 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 purified by flash column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain compound 11 (2.45 g, 2.78 mmol, 87% total yield for two steps) 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 isolatable 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 the intermediate carboxylic acid (689.6 mg, 0.77 mmol, 87%) as an orange foam.

[0064] 2) Under a nitrogen atmosphere, tert-butyl hypochlorite (t-BuOCl) (113 μL, 1.00 mmol, 3.0 eq) was added to a solution of the intermediate acid (300.2 mg, 0.33 mmol, 1.0 eq) and Ag(phen)2OTf (62.5 mg, 0.10 mmol, 0.3 eq) in anhydrous DCE (10 mL). 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 phases were 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 give 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 compound 14 (45.4 mg, 79.1 μmol, 70%) as a colorless oil. 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 removing the solvent under reduced pressure, the residue was purified by flash column chromatography (dichloromethane / methanol = 8:1) to give compound 15 (24.3 mg, 62.7 μmol, 88%) as a white foam. 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 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) was added sodium cyanoborohydride (4.2 mg, 6.1 μmol, 3.0 eq). 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 at room temperature. After stirring at 25°C for 1 hour, the solvent was removed under reduced pressure to give 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 an 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 obtain 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) To a solution of compound 16 (32.3 mg, 46.2 μmol, 1.0 eq) in methanol (10 mL) was added Pd / C (46.7 mg, 5%). The mixture was evacuated and backfilled with hydrogen three times at atmospheric pressure. After stirring the mixture 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 crude product obtained above 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, 59% total yield for two steps). 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 compound was tested for anti-tumor in vitro cell activity, and the results showed that it could effectively inhibit human non-small cell lung cancer cells A549, colon cancer cells HCT116 and human breast cancer cells MCF7, and is expected to be further developed into an anti-tumor drug.

[0080] 1. 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℃ 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 three replicates were set up for each concentration. The 96-well plate was incubated at 5% CO2 and 37°C for 48 hours. The experiment was divided into blank group, control group, and drug group.

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

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

[0085] (5) Toxicity was expressed as cell inhibition rate, which was calculated 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 ± 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 the growth of 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 exhibited excellent inhibitory effects on A549, HCT116 and MCF7. Even at a concentration 50 times lower than that of cisplatin, its inhibitory effect on MCF7 was still better than that of the positive control cisplatin. Figure 1 As can be seen, compound 15 has a good dose-inhibitory linear relationship against A549, HCT116, and MCF7, with IC50 values ​​of 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 present invention has been described in detail through the above specific embodiments, it should be understood that the above description is not intended to limit the present invention. After reading the above description, various modifications and substitutions of the present invention will be apparent to those skilled in the art. Therefore, the scope of protection of the present invention should be defined by the appended claims.

Claims

1. Trifluoroacetate of a marine cyanobacterial metabolite, Dragocins AC and epi-Dragocins AC N - A method for synthesizing demethylated Dragocin A compound 15, characterized in that: The following steps are involved: ； Among them, Dragocins AC and epi-Dragocins AC and N The structure of the demethylated Dragocin A compound 15 is as follows: ； 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 ether protecting group selected from any one of TMS, TES, TBS, TIPS, and TBDPS; R5 is a silyl ether 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, pivaloyl, trifluoroacetyl, propionyl, benzoyl, and p-methoxybenzoyl; Step 4: Preparation of compound 12 and epi-12: In 0-100 o Compound 11 is reacted with an oxidant in a polar or non-polar solvent under acidic conditions for 30-3000 minutes to obtain compounds 12 and epi-12; the oxidant is one of 2, 3-dichloro-5, 6-dicyanobenzoquinone, ceric ammonium nitrate, 2-iodoxybenzoic acid, Dess-Martine reagent, and sodium hypochlorite.

2. The synthesis method according to claim 1, wherein The oxidant is 2,3-dichloro-5,6-dicyanobenzoquinone.

3. The synthesis method according to claim 1, wherein In step 4, the solvent is one or more of DCE, chlorobenzene, DMF, DMA, and dichloromethane.

4. The synthesis method according to claim 1 or 3, characterized in that The solvent is DCE.

5. The synthesis method according to claim 1, characterized in that In step 4, the acid is one or more of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

6. The synthesis method according to claim 1 or 5, characterized in that The acid is acetic acid.

7. The method according to any one of claims 1 to 6 N - Use of the demethylated Dragocin A compound 15 for preparing a drug for treating non-small cell lung cancer, colon cancer or breast cancer.

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