Steroid-indole alkaloid hybrid dimer compound as well as preparation method and application thereof in preparation of anti-tumor chemotherapeutic drug sensitizer

Abstract

The invention discloses a steroid-indole alkaloid hybrid dimer compound, a preparation method of the steroid-indole alkaloid hybrid dimer compound and application of the steroid-indole alkaloid hybrid dimer compound in preparation of an anti-tumor chemotherapeutic drug sensitizer. The steroid indole diketopiperazine alkaloid hybrid compound is prepared from a fungus Aspergillus sp.EGF15-0-3 rice culture medium for the first time; the compound is a novel skeleton compound found for the first time in nature. It is found for the first time that the heterocomplex has Tdp1 inhibitory activity and can be applied as a tyrosine-DNA phosphodiesterase 1 (Tdp1) inhibitor. The chemosensitization activity of the heterocomplex on the tumor chemotherapeutic drug topotecan TPT is found for the first time, drug source molecules and data support are provided for developing a novel natural anti-tumor combined inhibitor, and the heterocomplex has important significance on development and utilization of marine aspergillus fungus resources.

Description

Technical field:

[0001] The invention relates to a steroid-indole alkaloid hybrid dimer compound, a preparation method thereof and an application thereof in preparing an anti-tumor chemotherapy drug sensitizer. Background technology:

[0002] Malignant tumors have always been an important killer threatening human health. Although research on tumor treatment is constantly progressing and deepening, the current clinical treatment method for malignant tumors is still mainly to use chemotherapy drugs to induce tumor cell DNA damage and thus kill tumor cells. Topoisomerase 1 (Top1) inhibitors are often widely used in clinical practice as chemotherapy drugs for the treatment of lung cancer, colon cancer, bladder cancer, etc., such as topotecan (TPT), irinotecan (IRT) and hydroxycamptothecin (HCPT). These drugs usually achieve significant therapeutic effects in the early stage of treatment, but as the treatment time increases, tumor cells are prone to develop resistance to these drugs, which greatly reduces the therapeutic effect of the drugs. Studies have shown that TPT administration will lead to an increase in the expression of the DNA repair enzyme tyrosine-DNA phosphodiesterase 1 (Tdp1), resulting in the body's tolerance to the same dose of drugs after a period of treatment. Marine fungi have gradually become an important drug source molecule supply station due to their high species diversity. Searching for Tdp1 inhibitors from marine fungi that are highly effective, low-toxic, and can work synergistically with cancer chemotherapy drugs is expected to become an important strategy to overcome tumor resistance and provide more possibilities for cancer treatment. Summary of the invention:

[0003] The purpose of the present invention is to provide a steroid-indole alkaloid hybrid dimer compound and a preparation method thereof and use thereof in the preparation of an anti-tumor chemotherapy drug sensitizer.

[0004] The present invention is achieved through the following technical solutions:

[0005] Steroidal-indole alkaloid hybrid dimer compound, its structural formula is as follows:

[0006]

[0007] The preparation method of the steroid-indole alkaloid hybrid dimer compound is to prepare it from the rice culture medium of marine soft coral Aspergillus sp. EGF 15-0-3 with a deposit number of GDMCC60476, and the specific steps are as follows:

[0008] 1) Strain activation: Inoculate the strain onto a plate containing PDA medium, place in a constant temperature incubator at 28°C for 2-3 days, and after a single colony grows on the plate, pick up the single colony with an inoculation loop and transfer it to a triangular flask containing PDB medium, and culture it in a full-temperature shaker at 28°C at 165 r / min for 2-3 days to obtain the activated seed culture solution of Aspergillus sp. EGF15-0-3;

[0009] 2) Strain fermentation: The activated seed solution was taken and added into a conical flask filled with rice culture medium, and cultured at 28° C. for 35 days. The strain was compared with the blank culture medium to observe whether there was obvious growth of the strain. After the growth was completed, the fermentation was stopped, and the strain was inactivated with EtOAc, extracted by shaking on a shaker, and then concentrated under reduced pressure to obtain an EtOAc phase extract;

[0010] 3) The EtOAc phase extract obtained in step 2) was subjected to silica gel column chromatography to obtain V PE :V EtOAc =50:1~1:1 petroleum ether-ethyl acetate system gradient elution, then ethyl acetate and pure methanol system flushing, TLC thin layer tracking, combined with NMR and LC-MS joint analysis to obtain 8 fractions Fr.1-Fr.8, among which Fr.6 was the steroidal indole diketopiperazine heterocompound enrichment site according to NMR and LC-MS analysis, and was selected for further MCI column chromatography to V 甲醇 :V 水 =40%-100% methanol-water system was used as the eluent for crude separation to obtain 8 sub-fractions: Fr.6-1-Fr.6-8, among which Fr.6-8 was subjected to gel column chromatography to obtain V 甲醇 :V 二氯甲烷 =7:3 methanol-dichloromethane system as eluent, and then silica gel column chromatography, V PE :V EtOAc =50:1-10:1 petroleum ether-ethyl acetate system was used as eluent to obtain Fr.6-8-1-Fr.6-8-10, among which Fr.6-8-9 was repeatedly prepared by HPLC liquid phase to obtain compound 1-4.

[0011] PDA culture medium: glucose 2.0%, potato juice 200g / L, agar 10%, potato juice is prepared with aged sea water as solvent, salinity 3.5%, pH natural.

[0012] PDB is a medium without agar added to PDA.

[0013] Rice culture medium: 100 g rice, 0.3% peptone, 100 mL saline water.

[0014] The inventors prepared steroidal indole diketopiperazine alkaloid hybrid compounds from the fungus Aspergillus sp. EGF15-0-3 rice culture medium for the first time, and compounds 1-4 are new skeleton compounds discovered for the first time in nature. It is also the first time that such hybrids have Tdp1 inhibitory activity. Therefore, the present invention also protects the use of the compounds as tyrosine-DNA phosphodiesterase 1 (Tdp1) inhibitors.

[0015] The present invention discovers for the first time the chemosensitizing activity of the heterocomplex on tumor chemotherapy drugs.

[0016] Therefore, the present invention also protects the use of the compound in the preparation of anti-tumor chemotherapy drug sensitizers.

[0017] The tumors include human lung cancer, human breast cancer and human cervical cancer.

[0018] Anti-tumor chemotherapy drugs include topotecan (TPT), irinotecan (IRT) and hydroxycamptothecin (HCPT).

[0019] The present invention also protects a composition comprising the steroid-indole alkaloid hybrid dimer compound and the tumor chemotherapy drug TPT.

[0020] The beneficial effects of the present invention are as follows:

[0021] 1) For the first time, a steroidal indoledione piperazine alkaloid hybrid compound was prepared from the rice culture medium of the fungus Aspergillus sp. EGF15-0-3. This compound is a new skeleton compound discovered in nature for the first time.

[0022] 2) It was discovered for the first time that this type of hybrid has tyrosine-DNA phosphodiesterase 1 (Tdp1) inhibitory activity and can be used as a Tdp1 inhibitor.

[0023] 3) For the first time, the chemosensitizing activity of this type of heterocomplex on the tumor chemotherapy drug topotecan TPT was discovered, which provides drug source molecules and data support for the development of new natural anti-tumor combination inhibitors, and is of great significance for the development and utilization of marine Aspergillus fungal resources.

[0024] The marine soft coral Aspergillus sp. EGF15-0-3 with the deposit number of GDMCC 60476 of the present invention has been disclosed in CN 111139185 B, Aspergillus sp. and application thereof. Description of the drawings:

[0025] Figure 1 is compound 1 1 H- 1 Schematic diagram of H COSY, key HMBC and NOE correlation;

[0026] Figure 2 is the single crystal X-diffraction structure diagram of compounds 1 and 2;

[0027] Figure 3 It is compound 2 1 H- 1 Schematic diagram of H COSY, key HMBC and NOE correlation;

[0028] Figure 4 is compound 3 1 H- 1 Schematic diagram of H COSY, key HMBC and NOE correlation;

[0029] Figure 5 is the single crystal X-diffraction structure diagram of compounds 3 and 4;

[0030] Figure 6 are the measured and calculated ECD spectra of compounds 3 and 4;

[0031] Figure 7 is compound 4 1 H- 1 Schematic diagram of H COSY, key HMBC and NOE correlation;

[0032] Figure 8 The Tdp1 enzyme inhibitory activity of compounds 1-4 (A) and the reproductive inhibition curve of compound 1 on different tumor cells (B);

[0033] Fig. 9 The anti-tumor effects of different concentrations of compound 1 combined with gradient concentrations of TPT are shown in Figure 1. (A) Cell survival curves of MCF-7, Hela and H460; (B) H460 cell effect synergy index; (C) H460 cell clone formation. Specific implementation method:

[0034] The following is a further description of the present invention, rather than a limitation of the present invention.

[0035] Example 1: Preparation and structural identification of compounds 1-4

[0036] Source of microorganisms: The strain EGF15-0-3 in the patent was isolated from soft corals collected in the Sanya waters of the South China Sea. The species was identified as Aspergillus fungus and preserved in the Guangdong Microbial Culture Collection Center with the preservation number GDMCC 60476.

[0037] Culture medium formula:

[0038] PDA culture medium: 2.0% glucose, 200g / L potato juice, 10% agar, potato juice is prepared with aged sea water as solvent, salinity is 3.5%, pH is natural, PDB is the culture medium without agar in PDA.

[0039] Rice culture medium: 100 g rice, 0.3% peptone, 100 mL saline water.

[0040] Strain activation: After the culture tube is taken out of the refrigerator and thawed, use an inoculation loop to dip an appropriate amount of bacterial solution and inoculate it onto a plate containing PDA culture medium, a total of 5 plates, and culture them in a constant temperature incubator at 28°C for 2-3 days. After a single colony grows on the plate, use an inoculation loop to pick up a single colony and transfer it to a 1000mL Erlenmeyer flask containing 200mL PDB culture medium, activate a total of 1000mL, and culture it in a full-temperature shaking cabinet at 28°C at 165r / min for 2-3 days to obtain the activated EGF15-0-3 seed culture solution.

[0041] Strain fermentation: 5.0 mL of the activated seed solution was added to a 1000 mL Erlenmeyer flask containing 100 g of rice culture medium, and a total of 900 L was fermented. The culture was kept at 28°C for 35 days, and compared with the blank culture medium to observe whether there was obvious strain growth. The fermentation was stopped when the growth was complete.

[0042] Post-treatment of secondary metabolites: After the strains were grown, they were directly inactivated with EtOAc (250 mL / 100 g rice medium) and then extracted by shaking on a shaker (165 r / min) for 3 times, each time for 8 hours. The EtOAc solutions were combined and concentrated under reduced pressure to obtain an EtOAc phase extract (900.0 g).

[0043] Separation of steroidal indole alkaloids hybrid compounds: The crude extract of EtOAc fraction was purified by silica gel column chromatography with V PE :V EtOAc =50:1~1:1 petroleum ether-ethyl acetate system gradient elution, then ethyl acetate and pure methanol system flushing, TLC thin layer tracking, combined with NMR and LC-MS joint analysis to obtain 8 fractions Fr.1-Fr.8, among which Fr.6 was the steroidal indole diketopiperazine heterocompound enrichment site according to NMR and LC-MS analysis, and was selected for further MCI column chromatography to V 甲醇 :V 水 =40%-100% methanol-water system was used as the eluent for crude separation to obtain 8 sub-fractions (Fr.6-1-Fr.6-8). Fr.6-8 was subjected to gel column chromatography and then to silica gel column chromatography to obtain Fr.6-8-1-Fr.6-8-10. Gel column chromatography was performed with V 甲醇 :V 二氯甲烷 =7:3 methanol-dichloromethane system was used as eluent, and silica gel column chromatography was performed with V PE :VEtOAc = 50:1~10:1 petroleum ether-ethyl acetate system was used as the eluent, wherein Fr.6-8-9 was repeatedly prepared by HPLC liquid phase to obtain compounds 1-4, respectively, with the following structural formulas:

[0044]

[0045] Structure identification:

[0046] Compound 1, white-brown powder, according to its high-resolution mass spectrum HRESIMS, the quasi-molecular ion peak m / z: 712.4463 [M+H] + (The calculated value is C 47 H 58 N 3 O 3 712.4478), indicating that its molecular formula is C 47 H 57 N 3 O 3 , the molecule contains 21 unsaturated atoms. The UV spectrum shows that its maximum absorption wavelength is λ max =224, 293 and 336 nm. Infrared spectra showed the presence of amino groups in the structure (3358, 3192 and 3050 cm -1 ), carbonyl (1681 and 1635 cm -1 ) and benzene rings (1583, 1456 and 1373 cm -1 ) group. Comprehensive analysis of 1D NMR and HSQC of compound 1 (Table 1) revealed that there were three amino proton signals in the structure [δ H 8.52 (1H, s), 7.51 (1H, s) and 6.10 (1H, s)], an isolated ketone carbonyl signal (δ C =199.7), two amide carbonyl signals (δ C = 168.2 and 159.4), a quaternary substituted double bond signal (δ C =154.0 and 125.4), three triple-substituted double bond signals [δ H 7.18(1H,m,overlapped), 5.76(1H,s) and 5.51(1H,s); δ C =164.3, 135.1, 124.7, 123.4, 122.5 and 122.4], a cis-disubstituted double bond signal [δ H 6.61(1H,d,J=9.6Hz) and 6.07(1H,m,overlapped); δ C =133.7 and 125.0], a terminal single and double bond signal [δ H6.05(1H,m,overlapped) and 5.20(2H,m); δ C =144.4 and 113.4], a 2,3-disubstituted indole fragment [δ H 7.36(1H,d,J=8.0Hz), 7.23(1H,d,J=8.0Hz), 7.18(1H,t,J=8.0Hz) and 7.13(1H,t,J=8.0Hz); δ C =143.8, 134.5, 126.3, 121.0, 118.8, 111.5, 111.5 and 103.0], four quaternary carbons, five methines, eight methylenes and seven methyl signals. Based on the above information, it was found that compound 1 also had characteristic signals of indole diketopiperazine (i.e. Figure 1 In addition, the remaining fragments (i.e., Figure 1 1b) is a known steroid compound (22E)-ergosta-4,6,8(14),22-tetraen-3-one [ See J. Nat. Prod. 2011, 74, 1281-1283.]. Based on the key correlations between H-20 and C-21′ / C23′ and H-23′ and C-12 / C13 / C20 / C20′ in HMBC, it is inferred that the indole diketopiperazine fragment 1a and the steroidal fragment 1b are connected via C-20-C-12′, C-12-C-9′ and N-11-C-7′ bonds ( Figure 1 ), thus concluding that the planar structure of compound 1 is the first hybrid dimer compound of indoledione piperazine alkaloid and steroid skeleton.

[0047] The relative configuration of compound 1 was inferred based on its NOESY spectrum data. For the steroidal core fragment (I-1), H 3 -19′ / H 3 -18′ and H-11′a, H 3 -18′ and H-16′a, H-17′ and H-16′b, and H-9′ and H-11′b are correlated, suggesting that H 3 -19′, H 3-18′, H-11′a and H-16′a are in the same plane of the molecule, while H-9′, H-16′b and H-17′ are in another plane of the molecule, which leads to the conclusion that the relative configuration of the steroidal core fragment is 9′R*, 10′R*, 13′R*, 17′R*. For the indoledionepiperazine fragment (II-1), another set of key information about H-23′ and H-20 suggests that H-23′ and NH-11 are in different planes of the molecule ( Figure 1 ). According to the NOE correlation between 14-NH and H-4, Δ 8,9 The double bond configuration is also Z. The absolute configuration of compound 1 was further determined by single crystal data to be 12S, 9′S, 10′R, 13′R, 17′S, 23′R, 24′R ( Figure 2 ).

[0048] Table 1. Compound 1 1 H(400MHz) and 13 C (100MHz) NMR data (δ in ppm, J in Hz, solvent CDC1 3 ) a

[0049]

[0050]

[0051] Compound 2, light yellow-brown powder, according to its high-resolution mass spectrum HRESIMS gives the quasi-molecular ion peak m / z: 712.4406 [M+H] + (The calculated value is C 47 H 58 N 3 O 3 712.4478), indicating that its molecular formula is C 47 H 57 N 3 O 3 The molecule contains 21 unsaturated groups. Comprehensive analysis of the 1D and 2D NMR spectra of compound 2 (Table 2) and combined with its molecular weight information show that compound 2 and compound 1 have the same planar structure. The main difference between the two spectra is that C-12[δ C =60.6 (Compound 2), 62.1 (Compound 1)], C-20 [δ C =29.5 (Compound 2), 34.4 (Compound 1)] and C-23′[δ C =49.9 (compound 2), 41.1 (compound 1)] signal difference, and the correlation between H-23′ and NH-11 / H-20 can be clearly observed in the NOESY spectrum of compound 2 ( Figure 3), suggesting that compound 2 may be a C-12 spiro ring diastereomer of compound 1. Similarly, through single crystal data, we also determined that the absolute configuration of compound 2 is 12R, 9′S, 10′R, 13′R, 17′S, 23′R, 24′R ( Figure 2 ), which is the C-12 spiro ring diastereomer of compound 1.

[0052] Table 2. Compound 21 1 H(400MHz) and 13 C (100MHz) NMR data (δ in ppm, J in Hz, solvent CDC1 3 )

[0053]

[0054]

[0055] Compound 3, white-brown powder, according to its high-resolution mass spectrum HRESIMS gives the quasi-molecular ion peak m / z: 712.4453 [M+H] + (The calculated value is C 47 H 58 N 3 O 3 712.4478), indicating that its molecular formula is C 47 H 57 N 3 O 3 The molecule contains 21 unsaturated groups. Comprehensive analysis of the 1D and 2D NMR spectra of compound 3 (Table 3) and combined with its molecular weight information show that compound 3 and compound 2 also have the same planar structure. The main difference between the two spectra is that C-20[δ C =34.3 (Compound 3), 29.5 (Compound 2)], C-23′[δ C =43.5 (Compound 3), 49.9 (Compound 2)], C-24′[δ C =40.7 (Compound 3), 39.4 (Compound 2)] and C-25′[δ C =28.2 (compound 3), 33.3 (compound 2)] signal differences, and only the correlation between NH-11 and H-20 was observed in the NOESY spectrum of compound 3 ( Figure 4 ), suggesting that compound 3 may be the C-23′ diastereomer of compound 2. The relative configuration of compound 3 was determined to be 12R*, 9′S*, 10′R*, 13′R*, 17′S*, 23′S*, 24′R* based on its single crystal data. Figure 5), and its absolute configuration was determined by quantum chemical ECD calculation method as 12R, 9′S, 10′R, 13′R, 17′S, 23′S, 24′R ( Figure 6 ), which is the C-23′ diastereomer of compound 2.

[0056] Table 3. Compound 3 1 H(400MHz) and 13 C (100MHz) NMR data (δ in ppm, J in Hz, solvent CDC1 3 )

[0057]

[0058] Compound 4, light yellow powder, according to its high resolution mass spectrum HRESIMS gives the quasi-molecular ion peak m / z: 712.4429 [M+H] + (The calculated value is C 47 H 58 N 3 O 3 712.4478), indicating that its molecular formula is C 47 H 57 N 3 O 3 The molecule contains 21 unsaturated groups. Comprehensive analysis of the 1D and 2D NMR spectra of compound 4 (Table 4) and combined with its molecular weight information show that compound 4 and compound 3 also have the same planar structure. The main difference between the two spectra is that C-20[δ C =27.3 (Compound 4), 34.3 (Compound 3)] and C-23′[δ C =51.3 (compound 4), 43.5 (compound 3)] signal differences, and the correlation between NH-11 and H-23′ can be clearly observed in the NOESY spectrum of compound 4 ( Figure 7 ), suggesting that compound 4 may be a C-12 spiro ring diastereomer of compound 3. Similarly, the relative configuration of compound 4 was determined based on its single crystal data to be 12S*, 9′S*, 10′R*, 13′R*, 17′S*, 23′S*, 24′R*( Figure 5 ), and its absolute configuration was determined by the same quantum chemical ECD calculation method as 12S, 9′S, 10′R, 13′R, 17′S, 23′S, 24′R ( Figure 6 ), which is the C-12 spiro ring diastereomer of compound 3.

[0059] Table 4. Compound 4 1 H(400MHz) and 13C (100MHz) NMR data (δ in ppm, J in Hz, solvent CDC1 3 )

[0060]

[0061] Physical constants and spectral data:

[0062] Compound 1: pale white powder, UV(MeOH)λ max (logε)223(0.60),282(0.47),347(0.54)nm; IR(KBr)ν max 3358,3192,2958,2926,1670,1635,1583,1419,1219,1191,966,742cm -1 ; HRESIMS (ESI-TOF) m / z [M+H] + 712.4453(Calcd for C 47 H 58 N 3 O 3 712.4478); CD(MeOH):λ max (Δε)210(-22.61),256(8.49),318(-16.29); 1 H NMR and 13 C NMR see Table 1.

[0063] Compound 2: light yellow powder, UV(MeOH)λ max (logε)224(1.36),283(0.52),348(1.26)nm; IR(KBr)ν max 3325,3273,2960,2918,1681,1583,1456,1354,1261,1193,1099,1020,800,742cm -1 ; HRESIMS (ESI-TOF) m / z [M+H] + 712.4406 (Calcd for C 47 H 58 N 3 O 3 712.4478); CD(MeOH):λ max (Δε)215(28.69),262(-12.26),364(38.60); 1 HNMR and 13 C NMR see Table 2.

[0064] Compound 3: pale white powder, UV(MeOH)λ max (logε)222(1.05),282(0.38),348(0.66)nm; IR(KBr)ν max 3327,3215,2960,2914,1670,1668,1583,1417,1219,871,738cm -1 ; HRESIMS (ESI-TOF) m / z [M+H] + 712.4432(Calcd for C 47 H 58 N 3 O 3 ); CD(MeOH):λ max (Δε)242(18.33),317(-9.83); 1 H NMR and 13 C NMR see Table 3.

[0065] Compound 4: light yellow powder, UV(MeOH)λ max (logε)224(1.33),284(0.52),346(1.20)nm; IR(KBr)ν max 3334,3199,2960,2924,1670,1662,1583,1417,1219,964,742cm -1 ; HRESIMS (ESI-TOF) m / z [M+H] + 712.4429 (Calcd for C 47 H 58 N 3 O 3 712.4478); CD(MeOH):λ max (Δε)223(4.83),284(-3.02),364(12.58); 1 H NMR and 13 CNMR is shown in Table 4.

[0066] Example 2: Tyrosine-DNA phosphodiesterase 1 (Tdp1) enzyme inhibitory activity of compounds 1-4

[0067] The Tdp1 enzyme inhibitory activity of steroidal indole diketopiperazine hybrid compounds (compounds 1-4) was evaluated by a fluorescence quantitative detection method. The results showed that (see Figure 8), steroidal indole diketopiperazine hybrid compounds showed different degrees of inhibitory activity against Tdp1 enzyme, among which compound 1 had the best activity (IC 50 =5.04±0.48 μM).

[0068] Example 3: Application of Compound 1-4 in the Preparation of Topotecan (TPT) Sensitizer for Anti-tumor Chemotherapy

[0069] Single dose

[0070] The CCK-8 method was used to evaluate the inhibitory effect of compound 1 on the proliferation of human lung cancer cells H460, human breast cancer cells MCF-7 and human cervical cancer cells Hela. The study found that compound 1 had a weak cytotoxic effect on these three cell lines and had no obvious cytotoxicity at a concentration of 100 μM ( Fig. 9 ). For the study of the synergistic lethal anti-tumor effect of two drugs, the combination with compounds with weak cytotoxic activity can achieve the chemotherapy sensitization effect at low doses without increasing drug toxicity. Therefore, it has certain advantages in the development of anti-tumor sensitizers.

[0071] Combination therapy

[0072] In order to further evaluate whether compound 1 can be used as a sensitizer for clinical anti-tumor drugs, we selected the Top1 inhibitor topotecan (TPT) as a combined drug to test the synergistic anti-tumor effect in the above three cells. The results showed (see Fig. 9 In Figure AB), TPT has a weak killing ability against the lung cancer cell line H460; but when TPT is combined with compound 1, it can selectively enhance the sensitivity of H460 cells to TPT, indicating that the two have a significant synergistic effect. Studies have shown that as the administration time of Top1 inhibitors increases, the expression level of Tdp1 will gradually increase, thereby causing tumor cells to develop drug resistance, which is a self-protection mechanism of tumor cells. In order to further investigate the long-term (10 days) anti-proliferation ability of active compounds on tumor cells, we used a clone formation experiment to evaluate the synergistic effect of active compound 1 on TPT. Fig. 9 As shown in C, at non-toxic concentrations, the combined administration of compound 1 and TPT can significantly reduce the formation of H460 cell clones in a concentration-dependent manner.

Claims

1. A steroidal-indole alkaloid heterodimer compound, characterized in that: Its structural formula is as follows:

2. The method for preparing the steroidal-indole alkaloid heterodimer compound according to claim 1, characterized in that: It is prepared from the rice culture medium of marine soft coral Aspergillus sp. EGF 15-0-3 with the deposit number of GDMCC 60476, and the specific steps are as follows: 1) Inoculate the strain onto a plate containing PDA medium, place it in a constant temperature incubator at 28°C for 2-3 days, and after a single colony grows on the plate, pick up the single colony with an inoculation loop and transfer it to a triangular flask containing PDB medium, and culture it in a full-temperature shaking cabinet at 28°C at 165r / min for 2-3 days to obtain the activated seed culture solution of Aspergillus sp.EGF15-0-3; 2) the activated seed solution was taken and added into a conical flask filled with rice culture medium, and statically cultured at 28° C. for 35 days, inactivated with EtOAc, extracted by shaking on a shaker, and then concentrated under reduced pressure to obtain an EtOAc phase extract; 3) The EtOAc phase extract obtained in step 2) was subjected to silica gel column chromatography to obtain V PE :V EtOAc =50:1~1:1 petroleum ether-ethyl acetate system gradient elution, then ethyl acetate and pure methanol system flushing, TLC thin layer tracking, combined with NMR and LC-MS joint analysis to obtain 8 fractions Fr.1-Fr.8, among which Fr.6 was the steroidal indole diketopiperazine heterocompound enrichment site according to NMR and LC-MS analysis, and was selected for further MCI column chromatography to V 甲醇 :V 水 =40%-100% methanol-water system was used as the eluent for crude separation to obtain 8 sub-fractions: Fr.6-1-Fr.6-8, among which Fr.6-8 was subjected to gel column chromatography to obtain V 甲醇 :V 二氯甲烷 =7:3 methanol-dichloromethane system as eluent, and then silica gel column chromatography, V PE :V EtOAc =50:1-10:1 petroleum ether-ethyl acetate system was used as eluent to obtain Fr.6-8-1-Fr.6-8-10, among which Fr.6-8-9 was repeatedly prepared by HPLC liquid phase to obtain compound 1-4.

3. The preparation method according to claim 2, characterized in that: PDA culture medium: glucose 2.0%, potato juice 200g / L, agar 10%, potato juice is prepared with aged sea water as solvent, salinity 3.5%, pH natural.

4. The preparation method according to claim 2, characterized in that: PDB is a medium without agar added to PDA.

5. The preparation method according to claim 2, characterized in that: Rice culture medium: 100 g rice, 0.3% peptone, 100 mL saline water.

6. Use of the steroidal-indole alkaloid hybrid dimer compound according to claim 1 as a tyrosine-DNA phosphodiesterase 1 inhibitor.

7. Use of the steroidal-indole alkaloid hybrid dimer compound according to claim 1 in the preparation of an anti-tumor chemotherapy drug sensitizer.

8. The use according to claim 7, characterized in that: The tumors include human lung cancer, human breast cancer and human cervical cancer.

9. The use according to claim 7, characterized in that: The anti-tumor chemotherapy drugs were topotecan, irinotecan and hydroxycamptothecin.

10. A composition comprising the steroid-indole alkaloid hybrid dimer compound according to claim 1 and a tumor chemotherapy drug topotecan.

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