Dimerization guaiane sesquiterpene lactone and preparation method and application thereof

Abstract

The invention provides dimerized guaiane sesquiterpene lactone 1-25 shown in a structural formula as well as a pharmaceutical composition, a preparation method and application thereof, and belongs to the technical field of medicines. The preparation method disclosed by the invention comprises the following steps: carrying out Diels-Alder reaction / deprotection on guaiane diene and divinyl ketone, so as to obtain the dimerization guaiane sesquiterpene lactone 1 to 25. The dimerized guaiane sesquiterpene lactone has inhibitory activity on human hepatoma cell lines HepG2, Huh7 and SK-Hep-1, and the compound 17 can significantly inhibit growth of transplanted tumors in nude mice, can form a pharmaceutical composition with a pharmaceutically acceptable carrier, and can be used for preparing anti-hepatoma drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, in particular, the present application relates to a new dimerization guaiane sesquiterpene lactone, its preparation method and the compound as an active ingredient of a pharmaceutical composition for treating liver cancer, and the application of the compound and its pharmaceutical composition in preparing an anti-liver cancer drug. BACKGROUND

[0002] Liver cancer is one of the common malignant tumors, including primary liver cancer and secondary liver cancer, among which hepatocellular carcinoma (HCC) accounts for more than 90%, which can be caused by liver fibrosis, cirrhosis, hepatitis infection, alcoholism, aflatoxin infection and other factors. Globally, the incidence of HCC ranks the 6th among malignant tumors, and currently there are more than 800,000 new cases of liver cancer worldwide each year. Liver cancer has the characteristics of occult onset, long incubation period, strong invasiveness, easy metastasis, and high malignancy. For patients with unresectable or advanced disease, the 5-year survival rate is only 13%. Currently, the main drugs for treating liver cancer in clinical practice are four small molecule synthetic drugs that act on tyrosine kinase inhibitors: sorafenib, regorafenib, and lenvatinib; and three antibody drugs: nivolumab, pembrolizumab and ramucirumab. These drugs have played a significant role in the treatment of liver cancer in clinical practice, and to some extent, they have prolonged the survival of patients. However, there are still some shortcomings, such as low objective response rate (<20%), easy drug resistance, intolerance of some liver cancer patients, obvious side effects, high price, and unsatisfactory effects.

[0003] Sesquiterpene lactones are active ingredients of various medicinal plants used in traditional medicine for the treatment of inflammatory diseases. In recent years, sesquiterpenes have attracted great interest from researchers due to their anticancer activity, and a large amount of work has been done to understand the molecular mechanisms and potential antitumor mechanisms of sesquiterpenes. A large number of proteins responsible for cell function in living organisms exist in dimeric form or need to be activated by dimerization before mediating certain signaling pathways, and targeting the two monomers of dimeric proteins is an important strategy for drug research. Since dimeric sesquiterpenes have the potential to act on both monomers of dimeric proteins, it is of great significance to synthesize dimers and derivatives based on anti-liver cancer active sesquiterpenes.

[0004] There is no related dimerization guaiane sesquiterpene lactone and its synthesis reported in the prior art, nor is there a report of a pharmaceutical composition containing it as an effective ingredient, nor is there a report of the application of dimerization guaiane sesquiterpene lactone or a pharmaceutical composition containing it in the preparation or treatment of liver cancer drugs. SUMMARY

[0005] The present application aims to provide novel dimerization guaiane sesquiterpene lactone 1-25 and its pharmaceutical composition and its preparation method and application, the preparation method of the present application uses aglaiabin derived diene and divinyl ketone as raw materials to prepare novel guaiane-eudesmane sesquiterpene dimers, the method is easy to operate and suitable for industrial production. The method has good substrate universality and can be used for preparing various functional group substituted dimerization guaiane sesquiterpene lactones.

[0006] In order to achieve the above-mentioned purpose of the present application, the present application provides the following technical solutions:

[0007] The present application provides novel dimerization guaiane sesquiterpene lactone 1-25 as shown in the following structural formula,

[0008]

[0009] The present application also provides a preparation method of dimerization guaiane sesquiterpene lactone 1-25, which comprises preparing dimerization guaiane sesquiterpene lactone 1-25 by Diels-Alder reaction / dimethylamine removal from guaiane diene and divinyl ketone with different structures,

[0010]

[0011] The present application also provides the application of novel dimerization guaiane sesquiterpene lactone 1-25 in preparing anti-liver cancer drugs.

[0012] The present application also provides a pharmaceutical composition, which comprises at least one of the above-mentioned dimerization guaiane sesquiterpene lactone 1-25 and a pharmaceutically acceptable carrier. In addition, the application of the pharmaceutical composition in preparing anti-liver cancer drugs is also provided.

[0013] The present application also provides a preparation method of the pharmaceutical composition, which comprises obtaining dimerization guaiane sesquiterpene lactone 1-25 according to the above-mentioned steps of preparing dimerization guaiane sesquiterpene lactone 1-25, and then adding a pharmaceutically acceptable carrier to at least one or any combination of the dimerization guaiane sesquiterpene lactone 1-25.

[0014] The pharmaceutical composition provided by the present application comprises at least one of the above-mentioned compounds 1-25 and a pharmaceutically acceptable carrier. In the present application, the pharmaceutically acceptable carrier is preferably a solid, semi-solid or liquid diluent, a filler and a pharmaceutical product adjuvant. The present application does not have special limitations on the pharmaceutically acceptable carrier, and any pharmaceutically acceptable carrier which is well known in the art and non-toxic and inert to humans and animals can be selected.

[0015] The preparation method of the pharmaceutical composition is not particularly limited in the present application, and at least one of the compounds 1-25 is directly mixed with a pharmaceutically acceptable carrier, and the mixing process is not particularly limited in the present application, and a process well known in the art can be selected to obtain the pharmaceutical composition.

[0016] The present application provides the use of the pharmaceutical composition in the above technical solution in the preparation of an anti-liver cancer drug. The method of the use is not particularly limited in the present application, and a method well known in the art can be selected.

[0017] In the present application, when the pharmaceutical composition is used for preparing an anti-liver cancer drug, the content of the composition in the drug is preferably 0.1-99%, and in the pharmaceutical composition, the content of at least one of the compounds 1-25 in the pharmaceutical composition is preferably 0.5-90%. The pharmaceutical composition of the present application is preferably used in the form of unit body weight dosage. In the present application, the prepared drug is preferably administered in two forms of injection (intravenous injection, intramuscular injection) and oral administration.

[0018] Compared with the prior art, the present application has the following advantages:

[0019] 1. The present application provides a series of new dimerized guaiane sesquiterpene lactones 1-25 (compounds 1-25).

[0020] 2. The present application provides a new method for preparing new compounds 1-25, which has easy raw materials, simple process and easy operation.

[0021] 3. The present application provides a pharmaceutical composition of new compounds 1-25 as an effective ingredient, which provides a new drug with good medicinal effect for a new anti-liver cancer drug.

[0022] 4. The compounds 1-25 of the present application have strong inhibitory activity on three liver cancer cells (HepG2, SK-Hep-1 and Huh7), and the IC 50 values are between 1.1-18.7 μM. In particular, compound 17 shows obvious inhibitory activity, and the IC 50 values are 1.5 (HepG2), 1.1 (Huh7) and 1.1 μM (SK-Hep-1), respectively, which are stronger than the positive drug sorafenib. Compound 17 inhibits the growth of tumors in a nude mouse xenograft tumor model, and the inhibition rate of tumors is as high as 84%.

[0023] 5. The synthesized compounds sesquiterpene dimers 1-25 can be used as drugs for treating diseases related to liver cancer. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1Structure of dimeric guaiane sesquiterpene lactone 1-25 (compound 1-25) of the present application.

[0025] Figure 2 Dimeric guaiane sesquiterpene lactone 17 (compound 17) of the present application inhibits tumor growth in vivo. DETAILED DESCRIPTION

[0026] In order to better understand the present application, the essential content of the present application is further illustrated by the examples of the present application in conjunction with the accompanying drawings, but the present application is not limited by the examples.

[0027] Example 1:

[0028] Preparation of dimeric guaiane sesquiterpene lactone 1-25.

[0029]

[0030] To a solution of divinyl ketone (0.1 mmol, 1.0 equiv) in dichloromethane (2 mL) was added arglabin-derived guaiane diene (58 mg, 0.2 mmol, 2.0 equiv) at room temperature. After mixing well, the solvent was removed by reduced pressure concentration, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, the residue was dissolved in methanol (5 mL), and excess methyl iodide (250 mL, 4 mmol, 40 equiv) was added, and stirred at room temperature for 12 hours. After removing the methanol by reduced pressure, the remaining solid was transferred to a mixed solution containing ethyl acetate (10 mL) and 10% aqueous sodium bicarbonate solution (10 mL), and shaken until the solid was completely dissolved. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by reduced pressure to obtain a crude product. Finally, purification was performed by silica gel column chromatography (ethyl acetate-petroleum ether = 25:75) to obtain compound 1-25.

[0031] Compound 1

[0032] Yield: 62%

[0033] Molecular formula: C 38 H 46 O8

[0034] HRMS (ESI, m / z): [M + Na] + [C 38 H 46 O8Na] + Calcd 653.3085, Found 653.3110.

[0035] 1H NMR (400 MHz, CDCl3) δ 6.15 (d, 2H, J = 3.6 Hz, H-13a), 5.43 (d,2H, J = 3.6 Hz, H-13b), 4.79 (d, 2H, J = 10.0 Hz, H-6), 3.19 (brs, 2H, OH),3.01-2.97 (m, 6H, H-4', H-2), 2.74-2.71 (m, 2H, H-7), 2.57-2.53 (m, 2H, H-2'), 2.18-2.04 (m, 4H, H-1'a, H-8a), 1.89-1.85 (m, 4H, H-9a, H-8b), 1.97-1.74(m, 4H, H-9b, H-1b'), 1.60 (s, 6H, H-15), 1.39 (s, 6H, H-15), 1.32-1.30 (m,2H, H-3a), 1.20-1.18 (m, 2H, H-3b). 13 C NMR (100 MHz, CDCl3) δ 149.8 (C-1),43.8 (C-2), 56.5 (C-3), 60.1 (C-4), 140.9 (C-5), 82.6 (C-6), 47.2 (C-7), 23.9(C-8), 38.4 (C-9), 71.9 (C-10), 139.7 (C-11),170.2 (C-12), 118.9 (C-13), 28.7(C-14), 20.3 (C-15), 34.2 (C-1'), 58.0 (C-2'), 213.3 (C-3'), 38.5 (C-4').

[0036] Compound 2

[0037] Yield: 60%

[0038] Molecular formula: C 39 H 48 O8

[0039] HRMS (ESI, m / z): [M + Na] + [C 39 H 48 O8Na] + Calcd 667.3241, Found 667.3235.

[0040] 1H NMR (400 MHz, CDCl3) δ 6.13 (d, 2H, J = 3.6 Hz, H-13a), 5.43 (d,2H, J = 3.2 Hz, H-13b), 4.80 (d, 2H, J = 10.0 Hz, H-6), 3.17 (brs, 2H, OH),3.03 (brs, 2H, H-2), 2.99-2.96 (m, 2H, H-2'), 2.73-2.68 (m, 2H, H-7), 2.59(t, 4H, J = 7.6 Hz, H-4'), 2.06-1.89 (m, 8H, H-1'a, H-8a, H-9a, H-8b), 1.82-1.71 (m, 4H, H-1b', H-9b), 1.63 (s, 6H, H-15), 1.55-1.52 (m, 2H, H-5'), 1.41(s, 6H, H-15), 1.30-1.28 (m, 2H, H-3a), 1.19-1.17 (m, 2H, H-3b). 13 C NMR (100MHz, CDCl3) δ 149.9 (C-1), 43.9 (C-2), 56.4 (C-3), 61.2 (C-4), 140.2 (C-5),82.8 (C-6), 47.3 (C-7), 24.1 (C-8), 38.7 (C-9),71.7 (C-10), 139.6 (C-11),170.0 (C-12), 118.9 (C-13), 29.2 (C-14), 20.4 (C-15), 33.6 (C-1'), 57.2 (C-2'), 214.0 (C-3'), 44.1 (C-4'), 17.6 (C-5').

[0041] Compound 3

[0042] Yield: 68%

[0043] Molecular formula: C 40 H 50 O8

[0044] HRMS (ESI, m / z): [M + Na] + [C 40 H 50 O8Na] + Calcd 681.3398, Found 681.3402.

[0045] 1 H NMR (400 MHz, CDCl3) δ 6.11 (d, 2H, J = 3.2 Hz, H-13a), 5.42 (d,2H, J = 3.2 Hz, H-13b), 4.74 (d, 2H, J = 10.0 Hz, H-6), 3.08 (s, 2H, OH),3.03-3.02 (m, 2H, H-2), 2.98-2.95 (m, 2H, H-2'), 2.72-2.66 (m, 2H, H-7),2.62-2.49 (m, 4H, H-4'), 2.06-1.87 (m, 8H, H-1'a, H-8a, H-9a, H-8b), 1.75-1.69 (m, 2H, H-9b), 1.63 (s, 6H, H-15), 1.55-1.50 (m, 6H, H-5', H-1'b), 1.39(s, 6H, H-14), 1.28-1.26 (m, 2H, H-3a), 1.17-1.15 (m, 2H, H-3b). 13 C NMR (100MHz, CDCl3) δ 150.0 (C-1), 44.0 (C-2), 56.3 (C-3), 61.3 (C-4), 139.9 (C-5),82.8 (C-6), 47.3 (C-7), 23.9 (C-8), 38.7 (C-9), 71.7 (C-10), 139.5 (C-11),170.1 (C-12), 119.0 (C-13), 29.1 (C-14), 20.5 (C-15), 33.5 (C-1'), 57.3 (C-2'), 214.5 (C-3'), 44.4 (C-4'), 22.9 (C-5').

[0046] Compound 4

[0047] Yield: 62%

[0048] Molecular formula: C 41 H 52 O8

[0049] HRMS (ESI, m / z): [M + Na] + [C 41 H 52 O8Na] + Calcd 695.3554, Found 695.3568.

[0050] 1 H NMR (400 MHz, CDCl3) δ 6.13 (d, 2H, J = 3.2 Hz, H-13a), 5.43 (d,2H, J = 3.2 Hz, H-13b), 4.89 (d, 2H, J = 10.0 Hz, H-6), 3.33 (s, 2H, OH),3.05 (brs, 2H, H-2), 2.98-2.95 (m, 2H, H-2'), 2.74-2.71 (m, 2H, H-7), 2.61-2.49 (m, 4H, H-4'), 2.08-2.02 (m, 4H, H-1'a, H-8a), 1.93-1.88 (m, 4H, H-9a,H-8b), 1.78-1.76 (m, 2H, H-9b), 1.64 (s, 6H, H-15), 1.59-1.56 (m, 4H, H-5'),1.49-1.43 (m, 2H, H-1'b), 1.40 (s, 6H, H-14), 1.31-1.29 (m, 2H, H-3a), 1.23-1.17 (m, 4H, H-6', H-3a). 13 C NMR (100 MHz, CDCl3) δ 150.2 (C-1), 43.9 (C-2),56.4 (C-3), 61.1 (C-4), 139.9 (C-5), 82.6 (C-6), 47.2 (C-7), 23.8 (C-8), 38.7(C-9), 71.8 (C-10), 139.6 (C-11), 170.1 (C-12), 118.9 (C-13), 28.7 (C-14),20.5 (C-15), 33.6 (C-1'), 57.5 (C-2'), 214.7 (C-3'), 44.4 (C-4'), 23.1 (C-5'), 28.3 (C-6').

[0051] Compound 5

[0052] Yield: 64%

[0053] Molecular formula: C 42 H 54 O8

[0054] HRMS (ESI, m / z): [M + Na] + [C42 H 54 O8Na] + Calcd 709.3711, Found 709.3729.

[0055] 1 H NMR (400 MHz, CDCl3) δ 6.11 (d, 2H, J = 3.2 Hz, H-13a), 5.42 (d,2H, J = 3.2 Hz, H-13b), 4.74 (d, 2H, J = 10.0 Hz, H-6), 3.08 (s, 2H, OH),3.03 (brs, 2H, H-2), 2.99-2.96 (m, 2H, H-2'), 2.73-2.70 (m, 2H, H-7), 2.68-2.49 (m, 4H, H-4'), 2.06-1.90 (m, 8H, H-1'a, H-8a, H-9a, H-8b), 1.74-1.72 (m,2H, H-9b), 1.64 (s, 6H, H-15), 1.56-1.48 (m, 2H, H-1'b), 1.40 (s, 6H, H-14),1.29-1.24 (m, 6H, H-6', H-3a), 1.17-1.15 (m, 2H, H-3b). 13 C NMR (100 MHz,CDCl3) δ 149.9 (C-1), 44.0 (C-2), 56.3 (C-3), 61.4 (C-4), 140.0 (C-5), 82.8(C-6), 47.3 (C-7), 23.9 (C-8), 38.7 (C-9), 71.7 (C-10), 139.5 (C-11), 170.0(C-12), 118.9 (C-13), 29.2 (C-14), 20.5 (C-15), 33.5 (C-1'), 57.2 (C-2'),214.9 (C-3'), 44.9 (C-4'), 23.4 (C-5'), 28.7 (C-6').

[0056] Compound 6

[0057] Yield: 69%

[0058] Molecular formula: C 43 H 56 O8

[0059] HRMS (ESI, m / z): [M + Na] + [C 43 H 56 O8Na] + Calcd 727.3867, Found 723.3884.

[0060] 1 H NMR (400 MHz, CDCl3) δ 6.12 (d, 2H, J = 3.2 Hz, H-13a), 5.43(d, 2H,J = 3.2 Hz, H-13b), 4.75 (d, 2H, J = 10.0 Hz, H-6), 3.05 (s, 4H, OH, H-2),3.00-2.97 (m, 2H, H-2'), 2.74-2.68 (m, 2H, H-7), 2.61-2.47 (m, 4H, H-4'),2.06-1.91 (m, 8H, H-1'a, H-8a, H-9a, H-8b), 1.75-1.71 (m, 2H, H-9b), 1.65 (s,6H, H-15), 1.57-1.49 (m, 6H, H-1'b, H-5'), 1.41 (s, 6H, H-14), 1.30-1.16 (m,10H, H-3a, H-3b, H-6', H-7'). 13 C NMR (100 MHz, CDCl3) δ 149.8 (C-1), 44.0 (C-2), 56.3 (C-3), 61.5 (C-4), 140.0 (C-5), 82.8 (C-6), 47.3 (C-7), 23.9 (C-8),38.8 (C-9), 71.7 (C-10), 139.5 (C-11), 170.0 (C-12), 118.8 (C-13), 29.2 (C-14), 20.5 (C-15), 33.5 (C-1'), 57.2 (C-2'), 215.0 (C-3'), 45.1 (C-4'), 23.6(C-5'), 28.8 (C-6'), 29.0 (C-7').

[0061] Compound 7

[0062] Yield: 65%

[0063] Molecular formula: C 44 H 58 O8

[0064] HRMS (ESI, m / z): [M + Na] + [C 44 H 58 O8Na] + Calcd 737.4024, Found 737.4029.

[0065] 1 H NMR (400 MHz, CDCl3) δ 6.12 (d, 2H, J = 3.2 Hz, H-13a), 5.42 (d,2H, J = 3.2 Hz, H-13b), 4.74 (d, 2H, J = 10.0 Hz, H-6), 3.05 (brs, 4H, H-2,OH), 3.00-2.96 (m, 2H, H-2'), 2.73-2.67 (m, 2H, H-7), 2.61-2.47 (m, 4H, H-4'), 2.06-1.91 (m, 8H, H-1'a, H-8a, H-9a, H-8b), 1.74-1.72 (m, 2H, H-9b),1.64 (s, 6H, H-15), 1.57-1.49 (m, 6H, H-1'b, H-5'), 1.41 (s, 6H, H-14), 1.29-1.15 (m, 12H, H-3a, H-3b, H-6', H-7'). 13 C NMR (100 MHz, CDCl3) δ 149.8 (C-1),44.1 (C-2), 56.3 (C-3), 61.5 (C-4), 140.0 (C-5), 82.8 (C-6), 47.3 (C-7), 23.9(C-8), 38.8 (C-9), 71.7 (C-10), 139.5 (C-11), 170.0 (C-12), 118.8 (C-13),29.2 (C-14), 20.5 (C-15), 33.5 (C-1'), 57.2 (C-2'), 215.1 (C-3'), 45.2 (C-4'), 23.7 (C-5'), 29.0 (C-6'), 29.1 (C-7').

[0066] Compound 8

[0067] Yield: 55%

[0068] Molecular formula: C 41 H52 O8

[0069] HRMS (ESI, m / z): [M + Na] + [C 41 H 52 O8Na] + Calcd 695.3554, Found 695.3577.

[0070] 1 H NMR (400 MHz, CDCl3) δ 6.14 (d, 2H, J = 3.2 Hz, H-13a), 5.44 (d,2H, J = 3.2 Hz, H-13b), 4.79 (d, 2H, J = 10.0 Hz, H-6), 3.27 (s, 2H, OH),3.01 (brs, 2H, H-2), 2.95 (d, 2H, J = 16.8 Hz, H-4'a), 2.73-2.68 (m, 2H, H-7), 2.47 (d, 2H, J = 16.8 Hz, H-4'b), 2.08-1.89 (m, 8H, H-1'a, H-8a, H-9a, H-8b), 1.77-1.73 (m, 2H, H-9b), 1.63 (s, 6H, H-15), 1.50-1.47 (m, 2H, H-1'b),1.41 (s, 6H, H-14), 1.28-1.26 (m, 2H, H-3a), 1.16-1.14 (m, 2H, H-3b). 13 C NMR(100 MHz, CDCl3) δ 149.7 (C-1), 43.9 (C-2), 56.3 (C-3), 61.2 (C-4), 140.5 (C-5), 82.9 (C-6), 47.4 (C-7), 24.1 (C-8), 38.8 (C-9), 71.8 (C-10), 139.6 (C-11), 169.9 (C-12), 118.8 (C-13), 29.2 (C-14), 20.4 (C-15), 33.6 (C-1'), 58.4(C-2'), 214.4 (C-3'), 54.4 (C-4'), 32.5 (C-5'), 28.5 (C-6').

[0071] Compound 9

[0072] Yield: 53%

[0073] Molecular Formula: C 42 H 52 O8

[0074] HRMS (ESI, m / z): [M + Na] + [C 42 H 52 O8Na] + Calcd 707.3554, Found 707.3550.

[0075] 1 H NMR (400 MHz, CDCl3) δ 6.13 (d, 2H, J = 3.2 Hz, H-13a), 5.44 (d,2H, J = 3.2 Hz, H-13b), 4.76 (d, 2H, J = 10.0 Hz, H-6), 3.16-3.13 (m, 2H, H-2'), 3.05(brs, 4H, H-2, OH), 2.70-2.67 (m, 2H, H-7), 2.05-1.91 (m, 8H, H-1'a,H-8a, H-9a, H-8b), 1.82-1.69 (m, 8H, H-9b, H-4', H-3'a), 1.62 (s, 6H, H-15),1.55-1.53 (m, 2H, H-1'b), 1.41 (s, 6H, H-14), 1.28-1.15 (m, 8H, H-3a, H-3b,H-4'b). 13 C NMR (100 MHz, CDCl3) δ 149.6 (C-1), 44.2 (C-2), 56.3 (C-3), 62.1(C-4),140.2 (C-5), 83.0 (C-6), 47.4 (C-7), 24.1 (C-8), 38.7 (C-9), 71.6 (C-10), 139.5 (C-11), 170.2 (C-12), 118.9 (C-13), 29.4 (C-14), 20.5 (C-15), 33.9(C-1'), 54.6 (C-2'), 217.4 (C-3'), 49.4 (C-4'), 26.1 (C-5').

[0076] Compound 10

[0077] Yield: 70%

[0078] Molecular Formula: C42 H 46 O8

[0079] HRMS (ESI, m / z): [M + Na] + [C 42 H 46 O8Na] + Calcd 701.3085, Found 701.3083.

[0080] 1 H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H, H-2'), 8.12 (dd, 2H, J = 8.0,0.9 Hz, H-4', H-6'), 7.59 (dd, 1H, J = 8.0, 8.0 Hz, H-5'), 6.12 (d, 2H, J =3.2 Hz, H-13a), 5.44 (d, 2H, J = 3.2 Hz, H-13b), 4.99 (d, 2H, J = 10.0 Hz, H-6), 3.88-3.84 (m, 2H, H-8'), 3.17 (brs, 2H, H-2), 2.79-2.73 (m, 2H, H-7),2.35-2.29 (m, 2H, H-9'a), 2.17-2.07 (m, 2H, H-8a), 2.00-1.92 (m, 4H, H-8b, H-9a), 1.84-1.79 (m, 2H, H-9b), 1.74-1.72 (m, 2H, H-9'b), 1.52 (s, 6H, H-15),1.47 (s, 6H, H-14), 1.42-1.40 (m, 2H, H-3a), 1.37-1.35 (m, 2H, H-3b). 13C NMR (100 MHz, CDC13) δ 150.4 (C-l), 44.2 (C-2), 56.3 (C-3), 61.7 (C-4), 140.5 (C-5), 82.8 (C-6), 47.2 (C-7), 23.8 (C-8), 38.8 (C-9), 72.0 (C-10), 139.7 (C-l l), 170.1 (C-12), 118.9 (C-13), 28.9 (C-14), 20.7 (C-15), 138.5 (C-l', C-3'), 128.4 (C-2'), 132.8 (C-4', C-6'), 129.1 (C-5'), 203.4 (C-7'), 53.0 (C-8'), 35.3 (C-9').

[0081] Compound 11

[0082] Yield: 62%

[0083] Molecular formula: C 42 H 45 O8F

[0084] HRMS (ESI, m / z): [M + Na] + [C 42 H 45 O8FNa] + Calcd 719.2991, Found 719.2965.

[0085] 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H, H-2'), 7.80 (d, 2H, J = 9.2 Hz,H-4', H-6'), 6.12 (d, 2H, J = 3.6 Hz, H-13a), 5.43 (d, 2H, J = 3.2 Hz, H-13b), 4.96 (d, 2H, J = 9.6 Hz, H-6), 3.79-3.76 (m, 2H, H-8'), 3.16 (br s, 2H,H-2), 2.76-2.73 (m, 2H, H-7), 2.36-2.30 (m, 2H, H-9'a), 2.12-2.07 (m, 2H, H-8a), 2.00-1.89 (m, 4H, H-8b, H-9a), 1.83-1.79 (m, 2H, H-9b), 1.72-1.69 (m,2H, H-9'b), 1.54 (s, 6H, H-15), 1.46 (s, 6H, H-14), 1.43-1.41 (m, 2H, H-3a),1.37-1.35 (m, 2H, H-3b). 13 C NMR (100 MHz, CDCl3) δ 150.7 (C-1), 44.2 (C-2),56.4 (C-3), 61.7 (C-4), 140.4 (C-5), 82.6 (C-6), 47.1 (C-7), 23.8 (C-8), 38.8(C-9), 72.1 (C-10), 139.6 (C-11), 170.0 (C-12), 119.0 (C-13), 28.8 (C-14),20.8 (C-15), 140.3 (d, J = 6 Hz, C-1', C-3'), 124.2 (C-2'), 162.8 (d, J = 250Hz, C-5'), 119.7 (d, J = 12 Hz, C-4', C-6'), 202.0 (C-7'), 53.3 (C-8'), 35.5(C-9').

[0086] Compound 12

[0087] Yield: 69%

[0088] Molecular formula: C 42 H 45 O8Cl

[0089] HRMS (ESI, m / z): [M + Na] + [C 42 H 45 O8ClNa] + Calcd 735.2695, Found 735.2692.

[0090] 1 H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H, H-2'), 8.07 (s, 2H, H-4', H-6'), 6.12 (d, 2H, J = 3.5 Hz, H-13a), 5.43 (d, 2H, J = 3.5 Hz, H-13b), 4.97(d, 2H, J = 10.0 Hz, H-6), 3.79-3.77 (m, 2H, H-8'), 3.17-3.16 (m, 2H, H-2),2.77-2.73 (m, 4H, OH, H-7), 2.36-2.31 (m, 2H, H-9'a), 2.12-2.10 (m, 2H, H-8a), 1.99-1.91 (m, 4H, H-9a, H-8b), 1.83-1.81 (m, 2H, H-9b), 1.77-1.69 (m,2H, H-9'b), 1.54 (s, 6H, H-14), 1.46 (s, 6H, H-15), 1.43-1.41 (m, 2H, H-3a),1.38-1.36 (m, 2H, H-3b). 13 C NMR (125 MHz, CDCl3) δ 150.6 (C-1), 44.2 (C-2),56.4 (C-3), 61.7 (C-4), 140.5 (C-5), 82.6 (C-6), 47.1 (C-7), 23.8 (C-8), 38.8(C-9), 72.0 (C-10), 139.8 (C-11), 170.0 (C-12), 119.0 (C-13), 28.8 (C-14),20.7 (C-15), 139.6 (C-1', C-3'), 126.5 (C-2'), 132.6 (C-4', C-6'), 135.7 (C-5'), 202.1 (C-7'), 53.3 (C-8'), 35.5 (C-9').

[0091] Compound 13

[0092] Yield: 66%

[0093] Molecular formula: C 42 H 45 O8Br

[0094] HRMS (ESI, m / z): [M + Na] + [C 42 H 45 O8BrNa] + Calcd 779.2190, Found 779.2205.

[0095] 1 H NMR (500 MHz, CDCl3) δ 8.37 (s, 1H, H-2'), 8.22 (s, 2H, H-4', H-6'), 6.12 (d, 2H, J = 3.5 Hz, H-13a), 5.44 (d, 2H, J = 3.5 Hz, H-13b), 4.98(d, 2H, J = 10.0 Hz, H-6), 3.79-3.76 (m, 2H, H-2'), 3.17-3.16 (m, 2H, H-2),2.77-2.74 (m, 4H, H-7, OH), 2.36-2.31 (m, 2H, H-1'a), 2.12-2.08 (m, 2H, H-8a), 1.97-1.91 (m, 4H, H-8a, H-9a), 1.83-1.79 (m, 2H, H-9b), 1.72-1.69 (m,2H, H-1'b), 1.54 (s, 6H, H-15), 1.46 (s, 6H, H-14), 1.44-1.36 (m, 4H, H-3a,H-3b). 13C NMR (100 MHz, CDCl3) δ 150.7 (C-1), 44.2 (C-2), 56.4 (C-3), 61.7(C-4), 140.5 (C-5), 82.6 (C-6), 47.1 (C-7), 23.8 (C-8), 38.8 (C-9), 72.0 (C-10), 139.6 (C-11), 170.0 (C-12), 119.0 (C-13), 28.8 (C-14), 20.7 (C-15),140.0 (C-1', C-3'), 126.9 (C-2'), 135.5 (C-4', C-6'), 123.5 (C-5'), 202.0 (C-7'), 53.3 (C-8'), 35.5 (C-9').

[0096] Compound 14

[0097] Yield: 63%

[0098] Molecular formula: C 43 H 48 O8

[0099] HRMS (ESI, m / z): [M + Na] + [C 43 H 48 O8Na] + Calcd 715.3241, Found 715.3266.

[0100] 1H NMR (500 MHz, CDCl3) δ 8.27 (s, 1H, H-2'), 7.92 (s, 2H, H-4', H-6'), 6.12 (d, 2H, J = 3.5 Hz, H-13a), 5.44 (d, 2H, J = 3.5 Hz, H-13b), 4.97(d, 2H, J = 10.0 Hz, H-6), 3.86-3.84 (m, 2H, H-8'), 3.17-3.16 (m, 2H, H-2),2.98 (s, 2H, OH), 2.77-2.73 (m, 2H, H-7), 2.48 (s, 3H, H-10'), 2.33-2.28 (m,2H, H-9'a), 2.14-2.08 (m, 2H, H-8a), 2.01-1.96 (m, 4H, H-9a, H-8b), 1.83-1.79(m, 2H, H-9b), 1.74-1.70 (m, 2H, H-9'b), 1.53 (s, 6H, H-14), 1.48 (s, 6H, H-15), 1.42-1.40 (m, 2H, H-3a), 1.37-1.35 (m, 2H, H-3b). 13 C NMR (125 MHz,CDCl3) δ 150.2 (C-1), 44.3 (C-2), 56.3 (C-3), 61.9 (C-4), 140.8 (C-5), 82.9(C-6), 47.3 (C-7), 23.9 (C-8), 38.8 (C-9), 72.0 (C-10), 139.6 (C-11), 170.1(C-12), 118.9 (C-13), 29.0 (C-14), 20.8 (C-15), 138.6 (C-1', C-3'), 125.9 (C-2'), 133.4 (C-4', C-6'), 139.2 (C-5'), 203.8 (C-7'), 53.0 (C-8'), 35.4 (C-9'), 21.4 (Me).

[0101] Compound 15

[0102] Yield: 64%

[0103] Molecular formula: C 43 H 48 O9

[0104] HRMS (ESI, m / z): [M + Na] + [C 43 H 48 O9Na] + Calcd 731.3191, Found 731.3205.

[0105] 1 H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H, H-2'), 7.61 (s, 2H, H-4', H-6'), 6.13 (d, 2H, J = 3.5 Hz, H-13a), 5.44 (d, 2H, J = 3.5 Hz, H-13b), 4.99(d, 2H, J = 10.0 Hz, H-6), 3.89 (s, 3H, OMe), 3.84-3.81 (m, 2H, H-8'), 3.17-3.16 (m, 2H, H-2), 2.90 (s, 2H, OH), 2.77-2.73 (m, 2H, H-7), 2.34-2.30 (m,2H, H-9'a), 2.12-2.09 (m, 2H, H-8a), 2.01-1.96 (m, 4H, H-9a, H-8b), 1.83-1.79(m, 2H, H-9a), 1.72-1.70 (m, 2H, H-9'b), 1.54 (s, 6H, H-15), 1.48 (s, 6H, H-14), 1.42-1.40 (m, 2H, H-3a), 1.37-1.35 (m, 2H, H-3b). 13 C NMR (125 MHz,CDCl3) δ 150.2 (C-1), 44.3 (C-2), 56.3 (C-3), 62.0 (C-4), 140.8 (C-5), 82.9(C-6), 47.3 (C-7), 24.0 (C-8), 38.8 (C-9), 72.0 (C-10), 139.6 (C-11), 170.1(C-12), 118.9 (C-13), 29.1 (C-14), 20.8 (C-15), 139.8 (C-1', C-4'), 121.0 (C-2'), 118.2 (C-4', C-6'), 160.2 (C-5'), 203.5 (C-7'), 55.9 (C-8'), 35.5 (C-9'), 53.2 (OMe).

[0106] Compound 16

[0107] Yield: 59%

[0108] Molecular formula: C 46 H 54 O8

[0109] HRMS (ESI, m / z): [M + Na] + [C 46 H 54 O8Na] + Calcd 757.3711, Found 757.3708.

[0110] 1 H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H, H-2'), 8.17 (s, 2H, H-4', H-6'), 6.12 (d, 2H, J = 3.5 Hz, H-13a), 5.44 (d, 2H, J = 3.5 Hz, H-13b), 4.98(d, 2H, J = 10.0 Hz, H-6), 3.88-3.85 (m, 2H, H-8'), 3.18-3.17 (m, 2H, H-2),2.96 (s, 2H, OH), 2.77-2.73 (m, 2H, H-7), 2.35-2.30 (m, 2H, H-9'a), 2.12-2.10(m, 2H, H-8a), 2.02-1.96 (m, 4H, H-9a, H-8b), 1.84-1.80 (m, 2H, H-9a), 1.75-1.71 (m, 2H, H-9'b), 1.54 (s, 6H, H-14), 1.48 (s, 6H, H-15), 1.41-1.36 (m,13H, H-3a, H-3b, t-Bu). 13C NMR (125 MHz, CDCl3) δ 150.2 (C-1), 44.3 (C-2),56.3 (C-3), 61.8 (C-4), 140.8 (C-5), 82.9 (C-6), 47.3 (C-7), 23.9 (C-8), 38.9(C-9), 72.0 (C-10), 139.6 (C-11), 170.1 (C-12), 118.9 (C-13), 29.0 (C-14),20.9 (C-15), 138.2 (C-1', C-3'), 126.0 (C-2'), 130.1 (C-4', C-6'), 152.5 (C-5'), 203.7 (C-7'), 53.0 (C-8'), 35.5 (C-9'), 35.2 (C-10'), 31.2 (C-11').

[0111] Compound 17

[0112] Yield: 72%

[0113] Molecular formula: C 42 H 46 O8

[0114] HRMS (ESI, m / z): [M + Na] + [C 42 H 46 O8Na] + Calcd 701.3085, Found 701.3089.

[0115] 1H NMR (500 MHz, CDCl3) δ 8.00 (s, 4H, H-2', H-3', H-5', H-6'), 6.11(d, 2H, J = 3.5 Hz, H-13a), 5.43 (d, 2H, J = 3.5 Hz, H-13b), 4.92 (d, 2H, J =10.0 Hz, H-6), 3.87-3.85 (m, 2H, H-8'), 3.17-3.16 (m, 2H, H-2), 2.77-2.73 (m,2H, H-7), 2.33-2.28 (m, 2H, H-9'a), 2.12-2.08 (m, 2H, H-8a), 2.02-1.94 (m,4H, H-8b, H-9a), 1.83-1.79 (m, 2H, H-9b), 1.75-1.72 (m, 2H, H-9'b), 1.52 (s,6H, H-15), 1.47 (s, 6H, H-14), 1.42-1.40 (m, 2H, H-3a), 1.35-1.33 (m, 2H, H-3b). 13 C NMR (125 MHz, CDCl3) δ 150.4 (C-1), 44.3 (C-2), 56.4 (C-3), 62.0 (C-4), 140.5 (C-5), 82.8 (C-6), 47.3 (C-7), 23.8 (C-8), 38.8 (C-9), 72.0 (C-10),139.6 (C-11), 170.1 (C-12), 118.9 (C-13), 28.9 (C-14), 20.8 (C-15), 141.2 (C-1', C-4'), 128.8 (C-2', C-3', C-5', C-6'), 203.7 (C-7'), 53.0 (C-8'), 35.4(C-9').

[0116] Compound 18

[0117] Yield: 67%

[0118] Molecular Formula: C 42 H 44 O8Cl2

[0119] HRMS (ESI, m / z): [M + Na] + [C 42 H 44 O8Cl2Na]+ Calculated 769.2305, found 769.2319.

[0120] 1 H NMR (400 MHz, CDCl3) δ 7.45 (s, 4H, H-2', H-5'), 6.19 (d, 2H, J =3.2 Hz, H-13a), 5.48 (d, 2H, J = 3.2 Hz, H-13b), 5.04 (d, 2H, J = 9.6 Hz, H-6), 3.79-3.76 (m, 2H, H-8'), 3.14 (br s, 2H, H-2), 2.79-2.76 (m, 2H, H-7),2.32-2.26 (m, 2H, H-9'a), 2.15-2.11 (m, 2H, H-8a), 2.04-1.97 (m, 4H, H-8b, H-9a), 1.85-1.81 (m, 2H, H-9b), 1.76-1.73 (m, 2H, H-9'b), 1.48 (s, 6H, H-15),1.47 (s, 6H, H-15), 1.39-1.37 (m, 2H, H-3a), 1.31-1.28 (m, 2H, H-3b). 13 C NMR(100 MHz, CDCl3) δ 151.1 (C-1), 44.2 (C-2), 56.7 (C-3), 63.0 (C-4), 139.4 (C-5), 82.4 (C-6), 47.2 (C-7), 24.0 (C-8), 38.7 (C-9), 72.1 (C-10), 140.0 (C-11), 169.9 (C-12), 119.3 (C-13), 29.0 (C-14), 20.4 (C-15), 143.3 (C-1', C-4'), 130.5 (C-2', C-5'), 129.9 (C-3', C-6'), 206.3 (C-7'), 57.3 (C-8'), 35.2(C-9').

[0121] Compound 19

[0122] Yield: 58%

[0123] Molecular formula: C 44 H 50 O 10

[0124] HRMS (ESI, m / z): [M + Na] + [C 44 H 50 O 10 Na] + Calcd 761.3296, Found 761.3291.

[0125] 1 H NMR (400 MHz, CDCl3) δ 6.99 (s, 2H, H-2', H-5'), 6.17 (d, 2H, J =3.2 Hz, H-13a), 5.49 (d, 2H, J = 3.2 Hz, H-13b), 5.08 (d, 2H, J = 10.0 Hz, H-6), 3.99-3.95 (m, 2H, H-8'), 3.87 (s, 6H, OMe), 3.11 (brs, 2H, H-2), 2.78-2.71 (m, 2H, H-7), 2.24-2.18 (m, 2H, H-9'a), 2.12-2.11 (m, 4H, H-8a, H-9a),2.03-1.97 (m, 2H, H-8b), 1.82-1.72 (m, 2H, H-9b, H-9'b), 1.50 (s, 6H, H-15),1.40 (s, 6H, H-14), 1.31-1.26 (m, 4H, H-3a, H-3b). 13 C NMR (100 MHz, CDCl3) δ149.8 (C-1), 44.3 (C-2), 56.5 (C-3), 63.3 (C-4), 140.9 (C-5), 83.2 (C-6),47.4 (C-7), 24.7 (C-8), 38.6 (C-9), 71.8 (C-10), 139.4 (C-11), 170.1 (C-12),119.2 (C-13), 29.9 (C-14), 19.8 (C-15), 133.8 (C-1', C-4'), 112.2 (C-2', C-5'), 151.8 (C-3', C-6'), 208.9 (C-7'), 56.8 (C-8'), 34.0 (C-9'), 56.2 (OMe).

[0126] Compound 20

[0127] Yield: 70%

[0128] Molecular Formula: C 46 H 48 O8

[0129] HRMS (ESI, m / z): [M + Na] + [C 46 H 48 O8Na] + Calcd 751.3241, Found 751.3236.

[0130] 1 H NMR (400 MHz, CDCl3) δ 8.48 (s, 2H, H-1', H-5'), 8.01 (s, 4H, H-3',H-4', H-7', H-8'), 6.09 (d, 2H, J = 3.2 Hz, H-13a), 5.42 (d, 2H, J = 3.2 Hz,H-13b), 4.94 (d, 2H, J = 9.6 Hz, H-6), 4.04-4.00 (m, 2H, H-10'), 3.19 (br s,2H, H-2), 2.77-2.71 (m, 2H, H-7), 2.35-2.29 (m, 2H, H-11'a), 2.11-1.95 (m,4H, H-8b, H-9a), 1.83-1.78 (m, 4H, H-9b, H-11'b), 1.53 (s, 6H, H-15), 1.48(s, 6H, H-14), 1.43-1.36(m, 4H, H-3a, H-3b). 13C NMR (100 MHz, CDCl3) δ 150.3(C-1), 44.4 (C-2), 56.4 (C-3), 62.2 (C-4), 140.6 (C-5), 82.9 (C-6), 47.3 (C-7), 23.9 (C-8), 38.8 (C-9), 72.0 (C-10), 139.6 (C-11), 170.1 (C-12), 118.9(C-13), 29.1 (C-14), 20.9 (C-15), 129.8 (C-1', C-5'), 134.8 (C-2', C-6'),125.1 (C-3', C-7'), 130.3 (C-4', C-8'), 137.4 (C-4'a, C-8'a), 204.0 (C-9'),52.6 (C-10'), 35.2 (C-11').

[0131] Compound 21

[0132] Yield: 66%

[0133] Molecular formula: C 46 H 48 O8

[0134] HRMS (ESI, m / z): [M + Na] + [C 46 H 48 O8Na] + Calcd 751.3241, Found 751.3241.

[0135] 1H NMR (400 MHz, CDCl3) δ 8.16-8.14 (m, 2H, H-5', H-8'), 7.80 (s, 2H,H-2', H-3'), 7.57-7.55 (m, 2H, H-6', H-7'), 6.18 (d, 2H, J = 3.2 Hz, H-13a),5.48 (d, 2H, J = 3.2 Hz, H-13b), 5.23 (d, 2H, J = 9.6 Hz, H-6), 3.83-3.80 (m,2H, H-10'), 3.17 (br s, 2H, H-2), 2.84-2.78 (m, 2H, H-7), 2.40-2.34 (m, 2H,H-11'a), 2.17-2.13 (m, 2H, H-8a), 2.09-2.04 (m, 4H, H-8b, H-9a), 1.87-1.83(m, 4H, H-9b, H-11'b), 1.50 (s, 6H, H-15), 1.46 (s, 6H, H-14), 1.40-1.38 (m,2H, H-3a), 1.30-1.28 (m, 2H, H-3b). 13 C NMR (100 MHz, CDCl3) δ 150.6 (C-1),44.4 (C-2), 56.6 (C-3), 62.8 (C-4), 140.7 (C-5), 83.0 (C-6), 47.4 (C-7), 24.1(C-8), 38.8 (C-9), 72.1 (C-10), 139.6 (C-11), 170.0 (C-12), 119.1 (C-13),29.2 (C-14), 20.5 (C-15), 141.8 (C-1', C-4'), 125.6 (C-2', C-3'),130.1 (C-4a', C-8a'), 125.2 (C-5', C-8'), 128.0 (C-6', C-7'), 209.8 (C-9'), 57.4 (C-10'), 35.8 (C-11').

[0136] Compound 22

[0137] Yield: 61%

[0138] Molecular formula: C 48 H 50 O8

[0139] HRMS (ESI, m / z): [M + Na] + [C 48 H 50 O8Na] + Calcd 777.3398, Found 777.3380.

[0140] 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, 4H, J = 8.4 Hz, H-2', H-6'), 7.70(d, 4H, J = 8.4 Hz, H-3', H-5'), 6.10 (d, 2H, J = 3.2 Hz, H-13a), 5.42 (d,2H, J = 3.2 Hz, H-13b), 4.89 (d, 2H, J = 10.0 Hz, H-6), 3.93-3.90 (m, 2H, H-8'), 3.17 (brs, 2H, H-2), 2.76-2.70 (m, 2H, H-7), 2.28-2.22 (m, 2H, H-9'a),2.10-1.93 (m, 6H, H-8a, H-9a, H-8b), 1.83-1.75 (m, 4H, H-9b, H-9'b), 1.54 (s,6H, H-15), 1.47 (s, 6H, H-14), 1.41-1.34 (m, 4H, H-3a, H-3b). 13 C NMR (100MHz, CDCl3) δ 150.1 (C-1), 44.4 (C-2), 56.4 (C-3), 62.3 (C-4), 140.6 (C-5),83.0 (C-6), 47.5 (C-7), 23.9 (C-8), 38.8 (C-9), 71.9 (C-10), 139.6 (C-11),170.2 (C-12), 118.8 (C-13), 29.2 (C-14), 20.9 (C-15), 137.3 (C-1'), 127.7 (C-2', C-6'), 129.3 (C-3', C-5'), 144.7 (C-4'), 203.7 (C-8'), 52.2 (C-9'), 35.0(C-10').

[0141] Compound 23

[0142] Yield: 45%

[0143] Molecular Formula: C 41 H 45 NO8

[0144] HRMS (ESI, m / z): [M + Na] + [C 41 H 45 NO8Na] + Calcd 702.3037, Found 702.3030.

[0145] 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, 2H, J = 7.6 Hz, H-2', H-4'), 7.98(dd, 1H, J = 7.6, 7.6 Hz, H-3'), 6.11 (d, 2H, J = 3.6 Hz, H-13a), 5.45 (d,2H, J = 3.6 Hz, H-13b), 4.87 (d, 2H, J = 10.0 Hz, H-6), 4.76-4.73 (m, 2H, H-7'), 3.22 (brs, 2H, H-2), 2.80-2.74 (m, 2H, H-7), 2.30-2.25 (m, 2H, H-8'a),2.14-2.02 (m, 6H, H-8a, H-9a, H-8b), 1.87-1.76 (m, 4H, H-9b, H-8'b), 1.60 (s,6H, H-15), 1.51 (s, 6H, H-15), 1.47-1.41 (m, 4H, H-3a, H-3b). 13 C NMR (100MHz, CDCl3) δ150.4 (C-1), 44.5 (C-2), 56.8 (C-3), 63.1 (C-4), 140.3 (C-5),82.9 (C-6), 47.4 (C-7), 24.0 (C-8), 38.7 (C-9), 72.0 (C-10), 139.4 (C-11),170.2 (C-12), 119.1 (C-13), 29.2 (C-14), 21.3 (C-15), 153.0 (C-1', C-5'),125.8 (C-2', C-4'), 138.4 (C-3'), 204.7 (C-6'), 50.0 (C-7'), 35.0 (C-8').

[0146] Compound 24

[0147] Yield: 52%

[0148] Molecular formula: C 41 H 45 NO8

[0149] HRMS (ESI, m / z): [M + Na] + [C 41 H 45 NO8Na] + Calcd 691.2878, Found 691.2897.

[0150] 1 H NMR (400 MHz, CDCl3) δ 7.21 (s, 2H, H-2', H-3'), 6.09 (d, 2H, J =3.6 Hz, H-13a), 5.41 (d, 2H, J = 3.6 Hz, H-13b), 4.80 (d, 2H, J = 10.0 Hz, H-6), 3.73-3.70 (m, 2H, H-6'), 3.15 (brs, 2H, H-2), 2.76-2.70 (m, 2H, H-7),2.24-2.18 (m, 2H, H-7'a), 2.10-2.05 (m, 2H, H-8a), 2.02-1.96 (m, 2H, H-9a),1.92-1.71 (m, 6H, H-8b, H-9b, H-7'b), 1.60 (s, 6H, H-15), 1.44 (s, 6H, H-14),1.40-1.31 (m, 4H, H-3a, H-3b). 13 C NMR (100 MHz, CDCl3) δ151.0 (C-1), 44.3 (C-2), 56.4 (C-3), 62.5 (C-4), 139.7 (C-5), 82.5 (C-6), 47.2 (C-7), 23.6 (C-8),38.8 (C-9), 72.0 (C-10), 139.5 (C-11), 170.0 (C-12), 119.0 (C-13), 28.7 (C-14), 20.9 (C-15), 154.4 (C-1', C-4'), 118.3 (C-2', C-3'), 193.2 (C-5'), 53.4(C-6'), 34.4 (C-7').

[0151] Compound 25

[0152] Yield: 58%

[0153] Molecular formula: C 40 H 44 O8S

[0154] HRMS (ESI, m / z): [M + Na] + [C 40 H 44 O8SNa] + Calcd 707.2649, Found 707.2635.

[0155] 1 H NMR (400 MHz, CDCl3) δ 7.75 (s, 2H, H-2', H-3'), 6.11 (d, 2H, J =3.2 Hz, H-13a), 5.43 (d, 2H, J = 3.2 Hz, H-13b), 4.86 (d, 2H, J = 9.6 Hz, H-6), 3.68-3.65 (m, 2H, H-6'), 3.17(br s, 2H, H-2), 2.79-2.72 (m, 2H, H-7),2.29-2.23 (m, 2H, H-7'a), 2.13-1.91 (m, 5H, H-8a, H-8b, H-9a), 1.84-1.74 (m,4H, H-9b, H-7'b), 1.59 (s, 6H, H-15), 1.46 (s, 6H, H-14), 1.42-1.40 (m, 2H,H-3a), 1.33-1.31 (m, 2H, H-3b). 13 C NMR (100 MHz, CDCl3) δ 151.0 (C-1), 44.3(C-2), 56.4 (C-3), 62.1 (C-4), 139.9 (C-5), 82.6 (C-6), 47.2 (C-7), 23.6 (C-8), 38.8 (C-9), 72.0 (C-10), 139.6 (C-11), 170.1 (C-12), 118.9 (C-13), 28.7(C-14), 20.8 (C-15), 150.9 (C-1', C-4'), 132.7 (C-2', C-3'), 196.9 (C-5'),53.9 (C-6'), 35.1 (C-7').

[0156] Example 2:

[0157] To evaluate the cytotoxic activity of dimeric guaiane sesquiterpene lactones 1-25 on hepatoma cell lines.

[0158] 1. Materials and methods

[0159] 1.1 Materials

[0160] Hepatoma cell lines (HepG2, Huh7 and SK-Hep-1) were purchased from Shanghai Jinin Biotechnology Co., Ltd.; culture medium (Dulbecco's Modified Eagle Medium, DMEM) was purchased from Thermo Fisher Scientific (Suzhou, China); serum (fetal bovine serum, FBS) was purchased from Life Technologies (NY, USA); RPMI-1640 was purchased from Thermo Fisher Biochemical Products (Beijing, China).

[0161] 1.2 Instruments

[0162] Flex Station 3 benchtop multifunctional microplate reader (Bio-RAD 680, USA); analytical balance (AG135, Metler Toledo, China); incubator (DHP-9082, Shanghai).

[0163] 1.3 Experimental process

[0164] 1). Take the logarithmic phase growth of hepatoma cells, discard the old culture medium, wash twice with PBS, and discard the PBS;

[0165] 2). Digest the cells with 0.25% trypsin, and when the cell outline is observed under the microscope and has a tendency to round, quickly aspirate the trypsin;

[0166] 3) Stop digestion with DMEM complete medium containing 10% FBS and resuspend the cells, take 10 μL of cell suspension, count with a cell counter, and adjust the cell concentration to 1 × 10 4 / mL with medium, inoculate in a 96-well plate, add 100 μL of cell suspension per well, incubate in a 37 ℃, 5% CO2 incubator for 24 h, and make the cells adhere;

[0167] 4). Aspirate the culture medium, add the diluted sample to the plate, add 100 μL per well, set 3 replicate wells for each concentration, and continue incubation in the incubator for 48 h;

[0168] 5). Remove the culture medium, add the prepared MTT solution (1 mg / mL), 100 μL per well, incubate in the incubator for 4 h;

[0169] 6). Remove the MTT solution, add DMSO, 100 μL per well, incubate in the incubator for 10 min;

[0170] 7). Use the microplate reader to measure the absorbance value at 490 nm wavelength, calculate the cell inhibition rate by the formula: inhibition rate = (negative - experimental group) / (negative - blank group) x 100%, and use the statistical software GraphPad prism 5 to calculate IC 50 , and the experiment is repeated 3 times.

[0171] 2. Results

[0172] Compounds 1-25 have strong inhibitory activity on three strains of liver cancer cells (HepG2, SK-Hep-1 and Huh7), with IC 50 values between 1.1-18.7 μM. In particular, compound 17 shows obvious inhibitory activity, with IC 50 values of 1.5 (HepG2), 1.1 (Huh7) and 1.1 μM (SK-Hep-1), stronger than the positive drug sorafenib.

[0173] Table 1. Inhibitory activity of compounds 1-25 on three strains of liver cancer cells

[0174]

[0175] 3. Conclusion

[0176] The above results show that the new dimerization guaiane sesquiterpene lactone 1-25 has cytotoxicity on three strains of liver cancer cells (HepG2, Huh7 and SK-Hep-1), and can be used as a drug for the treatment of liver cancer related diseases.

[0177] Example 3:

[0178] Inhibitory effect of compound 17 on the growth of xenotransplant tumor in nude mice.

[0179] (1) Experimental method: Huh7 liver cancer cells were cultured routinely, and the cells were counted after trypsin digestion, and the cell concentration was adjusted to 10 6 / mL. 5-6 week old BALB / C male nude mice were selected, and the treated tumor cells were inoculated subcutaneously in the left inguinal, and raised for about two weeks until the tumor volume grew to 100 mm 3The drug administration was started from left to right. 24 tumor-bearing nude mice were randomly divided into five groups, 6 in each group, namely positive control group (sorafenib 30 mg / kg) and model control group (drug solvent group) and compound 17 high (60 mg / kg), low (30 mg / kg) dose groups. Intraperitoneal injection was given once a day, and the tumor size was measured with a vernier caliper and the body weight change of tumor-bearing nude mice was recorded, and the administration was continuously given for 50 days. After the end of the experiment, the mice were executed by decapitation, dissected, the tumors were peeled off and weighed. The anti-tumor activity was evaluated according to the tumor diameter method and the tumor weight method, respectively.

[0180] Experimental results Figure 2

[0181] Compared with the control group, the tumor size and weight of the compound 17 intervention group decreased in a dose-dependent manner, indicating that compound 17 delayed the progression of the tumor. After administration of 30 and 60 mg / kg of compound 17, the inhibition rate of tumor weight was as high as 76%, 84% compared with the control group.

[0182] Preparation examples

[0183] In the following preparation examples, conventional reagents are selected, and the preparation is prepared according to the existing conventional method, and the application example only embodies that at least one of the compounds 1-25 described in the application can be prepared into different preparations, and the specific reagents and operations are not specifically limited:

[0184] 1. At least one of the compounds 1-25 is dissolved in DMSO, and then water for injection is added according to the conventional method, and the injection solution is prepared by precision filtration, filling and sterilization, and the concentration of the injection solution is 0.5-5 mg / mL.

[0185] 2. At least one of the compounds 1-25 is dissolved in DMSO, and then dissolved in sterile water for injection, stirred to dissolve, filtered with a sterile suction filter funnel, and then sterilely filtered, and then packaged in ampoules, and then low-temperature freeze-dried and sterilely sealed, to obtain a powder injection.

[0186] 3. At least one of the compounds 1-25 is added to the excipient at a mass ratio of 9:1 to prepare a powder.

[0187] 4. At least one of the compounds 1-25 is added to the excipient at a mass ratio of 5:1 to prepare granules for tabletting.

[0188] 5. At least one of the compounds 1-25 is prepared into an oral solution according to the conventional oral solution preparation method.

[0189] ​6. At least one of compounds 1-25 is added to excipients in a mass ratio of 5:1 to prepare capsules.

[0190] 7. At least one of compounds 1-25 is added to excipients in a mass ratio of 5:1 to prepare granules.

[0191] From the above examples, the application provides a guaiane-eudesmane sesquiterpene dimer, a preparation method and application thereof, a pharmaceutical composition and application thereof. The dimerized guaiane sesquiterpene lactone 1-25 provided by the application has different degrees of inhibitory activity on liver cancer cells, can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition, and can be used for preparing an anti-liver cancer drug.

[0192] The above only describes the preferred embodiments of the application, and it should be noted that, for those skilled in the art, without departing from the principles of the application, a number of improvements and refinements can be made, and these improvements and refinements should also be considered as the protection scope of the application.

Claims

1. The dimerized guaiacol sesquiterpene lactone 1-25 shown in the following structural formula, 。 2. The method for preparing the dimerized guaiacolone lactone 1-25 as shown in claim 1, characterized in that, This method involves preparing dimerized guaiacol sesquiterpene lactones 1-25 by reacting guaiacol dienes with divinyl ketones of different structures via a Diels-Alder reaction / dedimethylamine removal. 。 3. The use of the dimerized guaiacol sesquiterpene lactone 1-25 as shown in claim 1 in the preparation of an anti-liver cancer drug.

4. A pharmaceutical composition comprising at least one of the dimerized guaiacol sesquiterpene lactones 1-25 as shown in claim 1 and a pharmaceutically acceptable carrier.

5. The use of the pharmaceutical composition of claim 4 in the preparation of an anti-liver cancer drug.

6. The method for preparing the pharmaceutical composition according to claim 4, characterized in that, The method includes the following steps: Dimericated guaiacol sesquiterpene lactones 1-25 were first prepared by reacting guaiacol dienes with divinyl ketones of different structures via a Diels-Alder reaction / demethylamine grouping.

7. Then, take any one or more of the dimerized guaiacol sesquiterpene lactones 1-25 prepared in the above steps and add them to a pharmaceutically acceptable carrier.

Images