CN107828663B - Indole diterpenoid compound crystal and application thereof as antitumor drug - Google Patents
Indole diterpenoid compound crystal and application thereof as antitumor drug Download PDFInfo
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Abstract
The invention relates to an indole diterpenoid crystal and application thereof as an antitumor drug, wherein X-ray single crystal diffraction data of the indole diterpenoid crystal are as follows: orthorhombic, space group P212121Cell parameter ofα=90°,β=90°,γ=90°,Z=4,Dx=1.142mg/mm3,F(000)=928,μ(Cu Kα)=0.540mm‑1Final deviation factor R1=0.05046,wR2=0.1067[I>2σ(I)]The Flack constant is 0.0 (2).
Description
Technical Field
The invention belongs to the field of marine medicines, and particularly relates to an indole diterpenoid compound crystal and application thereof as an anti-tumor medicine.
Background
Mangrove plants grow in the tropical and subtropical intertidal zones, the living environment has the characteristics of high pressure, high salt, low oxygen and the like, so that the endophytic fungi have unique metabolic pathways, and further have the capacity of generating compounds with novel structures and various biological activities, and the metabolic products of the mangrove plants have various medicinal values of antibiosis, antitumor, immunoregulation, enzyme inhibition and the like and are potential microbial drug development resources, so the endophytic fungi of the mangrove plants become one of important resources for developing new drugs.
The method for artificially culturing and fermenting is adopted to obtain the secondary metabolite with important antibacterial activity from mangrove endophytic fungi, has the characteristics of environmental friendliness, sustainable development and the like, and can effectively solve key problems of medicine sources and the like in the process of medicine development, thereby having unique advantages.
Disclosure of Invention
The invention provides a marine fungus Eupenicilium sp.HJ002, which is isolated from Melia azedarach, wherein the Melia azedarach is a natural protection zone of mangrove forest collected from Hongkong hong Kong in south China, Hainan, 2015 and 9 months. The strain preservation information of the marine fungus Eupenicillium sp.HJ002 of the invention is as follows: the name of the depository: china general microbiological culture Collection center; the address of the depository: western road No.1, north west city of township, beijing, institute of microbiology, china academy of sciences; the preservation date is as follows: 2016, 12 months, 21 days; the preservation number is: CGMCC No. 13373; and (3) classification and naming: penicillium orthopecium sp.
The invention provides an indole diterpenoid compound derived from mangrove plant xylocarpus melitensis fungi or pharmaceutically acceptable salt thereof, which is characterized in that the indole diterpenoid compound has a structure shown as the following compounds 1-3:
the invention provides a method for preparing the indole diterpenoid compounds 1-3, which is characterized by comprising the following steps:
(1) preparing a seed culture medium, inoculating a marine fungus Eupenicillium sp.HJ002 strain into the seed culture medium, and culturing at 26-28 ℃ for 3-4 days to obtain a seed culture solution;
(2) inoculating the seed culture solution obtained in the step (1) into a fermentation culture medium, and performing static culture at 26-28 ℃ for 21-28 days to obtain a fermented product;
(3) separating the fermentation liquor and the thalli in the fermentation product obtained in the step (2), extracting the fermentation liquor for 2-4 times by using ethyl acetate with the same volume, combining ethyl acetate phases, and then concentrating under reduced pressure to obtain an extract;
(4) subjecting the extract obtained in the step (3) to reduced pressure silica gel column chromatography, performing gradient elution by using petroleum ether-ethyl acetate as an eluent, wherein the elution gradient is respectively 100:0, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90 and 0:100, collecting two column volumes in each gradient, dividing the two column volumes into 6 components according to the polarity, wherein the elution with a gradient of 100: 0-90: 10 is a component 1, the elution with a gradient of 80: 20-70: 30 is a component 2, the elution with a gradient of 60: 40-50: 50 is a component 3, the elution with a gradient of 40: 60-30: 70 is a component 4, the elution with a gradient of 20: 80-10: 90 is a component 5, and the elution with a gradient of 0:100 is a component 6, wherein the component 4 is first subjected to normal phase silica gel column chromatography, and the eluent is petroleum ether: eluting with mixed solvent of ethyl acetate 5:1-2:1 for 2-5 column volumes, concentrating under reduced pressure, and performing Sephadex LH-20 gel column chromatography with CHCl as eluent3Eluting 3-6 column volumes with MeOH 1:1 mixed solvent, concentrating under reduced pressure, and performing High Performance Liquid Chromatography (HPLC) with Waters C18, 9.4 × 250mm, 7 μm, flow rate of 2mL/min, and mobile phase of MeOH H2O80: 30-75:25 to give compound 3 and compound 2 in that order; subjecting component 5 to Sephadex LH-20 gel column chromatography with MeOH as eluent, eluting for 3-6 column volumes, concentrating under reduced pressure, and subjecting to high performance liquid chromatography HPLC with Waters C18, 9.4 × 250mm, 7 μm, flow rate of 2mL/min, and MeOH as mobile phase2O72: 28, compound 1 was obtained.
Wherein the ratio of the eluent or the mobile phase is volume ratio; the seed culture medium contains 1.5-3.0% of glucose, 0.1-0.5% of yeast extract, 0.1-0.5% of peptone, 0.11-0.6% of crude sea salt and a proper amount of water; the fermentation culture medium contains 1.6-3.5% of glucose, 0.1-0.5% of yeast extract, 0.1-0.5% of peptone, 0.11-0.6% of crude sea salt and a proper amount of water; the percentages are weight percentages; the seed culture medium and the fermentation culture medium are both sterilized at 120 ℃ for 25-30 minutes.
Another embodiment of the present invention provides a crystal of compound 1, characterized by X-ray single crystal diffraction data of: orthorhombic, space group P212121Cell parameter of α=90°,β=90°,γ=90°,Z=4,Dx=1.142mg/mm3,F(000)=928,μ(Cu Kα)=0.540mm-1Final deviation factor R1=0.05046,wR2=0.1067[I>2σ(I)]The Flack constant is 0.0 (2).
Another embodiment of the present invention provides a crystal of compound 2, characterized by X-ray single crystal diffraction data of: orthorhombic, space group P212121Cell parameter of α=90°,β=90°,γ=90°,Z=4,Dx=1.155mg/mm3,F(000)=920,μ(Cu Kα)=0.548mm-1Final deviation factor R1=0.0323,wR2=0.0746[I>2σ(I)]The Flack constant was-0.01 (17).
The invention provides a preparation method of a compound 1 or 2 crystal, which is characterized in that the compound 1 or 2 is dissolved in a solvent and naturally crystallized to obtain the compound, wherein the solvent is one or more of methanol, ethanol, dichloromethane, petroleum ether or ethyl acetate.
The invention provides an antitumor drug which is characterized in that the indole diterpenoid compounds 1-3, the crystals thereof or the pharmaceutically acceptable salts thereof are used as effective components.
The anti-tumor medicament provided by the invention also comprises other anti-tumor medicaments; a pharmaceutically acceptable carrier or excipient may also be included.
In another embodiment of the invention, the indole diterpenoid compounds 1-3, the crystal thereof or the pharmaceutically acceptable salt thereof are used for preparing antitumor drugs. The tumor is preferably A549, Hela, HepG 2.
The term "pharmaceutically acceptable salts" as used herein refers to non-toxic inorganic or organic acid and/or base addition salts, as described in "Salt selection for basic drugs", int.J.pharm. (1986),33, 201-217.
Drawings
The XRD pattern of compound 1 of figure 1.
Figure 2 XRD pattern of compound 2.
Detailed Description
In order to facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the present invention and are not intended to limit the scope or the principle of the present invention, and the embodiments of the present invention are not limited to the following.
Example 1
(1) Culture of strain of marine fungus Eupenicillium sp.HJ002
Preparing a seed culture medium: 80g of glucose, 8g of peptone, 8g of yeast extract, 10g of crude sea salt and 4.0L of water are averagely distributed in 8 conical flasks with 1000mL and are sterilized at 120 ℃ for 25-30 minutes.
Inoculating a fungus Eupenicillium sp.HJ002 strain into a prepared seed culture medium, and culturing at 26-28 ℃ for 3 days to obtain a seed culture solution;
(2) fermentation of marine fungus Eupenicillium sp.hj002
Preparing a fermentation medium: 1.1kg of glucose, 100g of peptone, 100g of yeast extract, 125g of sea salt and 50L of water are averagely distributed in 75 conical flasks with 1000mL and are sterilized for 25-30 minutes at 120 ℃.
And (2) taking a proper amount of the seed culture solution obtained in the step (1) to be inoculated into a conical flask filled with a fermentation culture medium, and standing and culturing for 21 days at the temperature of 26-28 ℃.
(3) Isolation of Compounds 1-3
Filtering 15L of the fermentation product obtained in the step (2), separating the fermentation liquor and the thalli, and extracting the fermentation liquor for 2-3 times by using ethyl acetate with the same volume; mixing ethyl acetate phases, concentrating under reduced pressure to obtain extract, subjecting the extract to silica gel column chromatography under reduced pressure, performing gradient elution with petroleum ether-ethyl acetate as eluent, wherein the elution gradient is respectively 100:0, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90 and 0:100, collecting two column volumes per gradient, dividing into 6 components according to polarity, wherein the elution with a gradient of 100: 0-90: 10 is a component 1, the elution with a gradient of 80: 20-70: 30 is a component 2, the elution with a gradient of 60: 40-50: 50 is a component 3, the elution with a gradient of 40: 60-30: 70 is a component 4, the elution with a gradient of 20: 80-10: 90 is a component 5, and the elution with a gradient of 0:100 is a component 6, wherein the component 4 is first subjected to normal phase silica gel column chromatography, and the eluent is petroleum ether: eluting with mixed solvent of ethyl acetate 5:1-2:1 for 2-5 column volumes, concentrating under reduced pressure, and performing Sephadex LH-20 gel column chromatography with CHCl as eluent3Eluting 3-6 column volumes with MeOH 1:1 mixed solvent, concentrating under reduced pressure, and performing High Performance Liquid Chromatography (HPLC) with Waters C18, 9.4 × 250mm, 7 μm, flow rate of 2mL/min, and mobile phase of MeOH H2O80: 30-75:25 to give compound 3(1.5mg) and compound 2(6.4mg) in that order; subjecting component 5 to Sephadex LH-20 gel column chromatography with MeOH as eluent, eluting for 3-6 column volumes, concentrating under reduced pressure, and subjecting to high performance liquid chromatography HPLC with Waters C18, 9.4 × 250mm, 7 μm, flow rate of 2mL/min, and MeOH as mobile phase2O72: 28, yielding compound 1(7.2 mg).
The structure confirmation data for compounds 1-3 are as follows:
of compounds 1 to 3 of Table 11H(400MHz)and 13C(100MHz)NMR data (MeOD)
Compound 1: IR (KBr) vmax 3427,1636,1455,1377,1243,1121,731cm–1;1H and13C NMR is shown in Table 1; HRESIMS M/z 424.3204[ M + H ]]+(calcd for C28H42NO2,424.3210)。
Compound 2: lambda [ alpha ]max(logε)226(4.02),276(3.50),294(3.34)nm;IR(KBr)νmax 3420,1710,1602,1432,1366,1230,1110,738cm–1;1H and 13C NMR is shown in Table 1; HRESIMS M/z 422.3048[ M + H ]]+(calcd for C28H40NO2,422.3054)。
Compound 3: IR (KBr) vmax 3518,1712,1602,1272,1250,1230,1112,1082,1064,798cm–1;1H and 13C NMR is shown in Table 1; HRESIMS M/z 422.3050[ M + H ]]+(calcd for C28H40NO2,422.3054)。
Example 2
(1) Culture of fungus Eupenicillium sp.HJ002 strain
Seed medium (5.0L) was prepared: 1.5% of glucose (weight percentage, the same below), 0.5% of yeast extract, 0.1% of peptone, 0.11% of crude sea salt and the balance of water; the mixture is averagely distributed into 8 conical flasks with 1000mL, and is sterilized at 120 ℃ for 25-30 minutes.
Inoculating a fungus Eupenicillium sp.HJ002 strain into a prepared seed culture medium, and culturing at 26-28 ℃ for 4 days to obtain a seed culture solution;
(2) fermentation of the fungus Eupenicillium sp.HJ002
Preparing a fermentation medium (100L): 1.6% of glucose (weight percentage, the same below), 0.5% of yeast extract, 0.1% of peptone, 0.11% of crude sea salt and the balance of water; the mixture is averagely distributed into 150 conical flasks with the volume of 1000mL and is sterilized at 120 ℃ for 25-30 minutes.
And (2) taking a proper amount of the seed culture solution obtained in the step (1) to be inoculated into a conical flask filled with a fermentation culture medium, and standing and culturing for 28 days at the temperature of 26-28 ℃.
(3) Isolation of Compounds 1-3
Following a similar isolation procedure as in example 1, compounds 1-3 were obtained, and the structure confirmation data were in agreement with example 1.
Example 3
(1) Culture of fungus Eupenicillium sp.HJ002 strain
Seed medium (1.0L) was prepared: 3.0 percent of glucose (weight percentage, the same below), 0.1 percent of yeast extract, 0.5 percent of peptone, 0.6 percent of crude sea salt and the balance of water; the mixture is evenly distributed into 3 500mL conical bottles and is sterilized for 25 to 30 minutes at 120 ℃.
Inoculating a fungus Eupenicillium sp.HJ002 strain into a prepared seed culture medium, and culturing at 26-28 ℃ for 4 days to obtain a seed culture solution;
(2) fermentation of the fungus Eupenicillium sp.HJ002
Preparing a fermentation medium (20L): 3.5 percent of glucose (weight percentage, the same below), 0.1 percent of yeast extract, 0.5 percent of peptone, 0.6 percent of crude sea salt and the balance of water; the mixture is evenly distributed into 30 conical flasks of 1000mL and is sterilized at 120 ℃ for 25-30 minutes.
And (2) taking a proper amount of the seed culture solution obtained in the step (1) to be inoculated into a conical flask filled with a fermentation culture medium, and standing and culturing for 24 days at the temperature of 26-28 ℃.
(3) Isolation of Compounds 1-3
Following a similar isolation procedure as in example 1, compounds 1-3 were obtained, and the structure confirmation data were in agreement with example 1.
Example 4
Dissolving 2.0mg of compound 1 in 2mL of methanol, standing for natural crystallization, and obtaining colorless crystals after 4 days (figure 1), wherein the crystal structure of the colorless crystals adopts Cu K alpha ray by a Gemini super diffractometer (Xcalibur, Atlas, Gemini ultra diffractometer)Diffraction data was collected by scanning at 120.01(10) K.
Crystals of compound 1: orthorhombic, space group P212121Cell parameter of α=90°,β=90°,γ=90°,Z=4,Dx=1.142mg/mm3,F(000)=928,μ(Cu Kα)=0.540mm-1Final deviation factor R1=0.05046,wR2=0.1067[I>2σ(I)]The Flack constant is 0.0 (2).
In addition, the compound 1 is dissolved in one or more of ethanol, dichloromethane, petroleum ether or ethyl acetate, and the mixture is kept still for 3 to 7 days to obtain the crystal.
Example 5
Dissolving 1.0mg of compound 1 in 1mL of methanol, standing for natural crystallization, and obtaining colorless crystals after 5 days (figure 2), wherein the crystal structure of the colorless crystals adopts Cu K alpha ray by a Gemini ultra diffractometer (Xcalibur, Atlas, Gemini ultra diffractometer)Diffraction data was collected by scanning at 120.01(10) K.
Crystals of compound 2: orthorhombic, space group P212121Cell parameter of α=90°,β=90°,γ=90°,Z=4,Dx=1.155mg/mm3,F(000)=920,μ(Cu Kα)=0.548mm-1Final deviation factor R1=0.0323,wR2=0.0746[I>2σ(I)]The Flack constant was-0.01 (17).
In addition, the compound 2 is dissolved in one or more of ethanol, dichloromethane, petroleum ether or ethyl acetate, and the mixture is kept still for 3 to 7 days to obtain the crystal.
Example 6 antitumor Activity assay
The MTT method is adopted to carry out cytotoxic activity test on tumor cells A549, Hela and HepG2, and 5-Fu and Adriamycin (Adriamycin) are used as positive control drugs.
Test results show that the crystals of the compounds 1-3 and the compounds 1 and 2 of the invention all show certain inhibitory activity on tumor cells A549, Hela and HepG2, and IC501-25. mu.g/mL, wherein the specific activity of compounds 1-2 is shown in the following table.
Claims (5)
1. A marine fungus Eupenicillium sp.hj002 characterized by the following strain preservation information: the name of the depository: china general microbiological culture Collection center; the address of the depository: western road No.1, north west city of township, beijing, institute of microbiology, china academy of sciences; the preservation date is as follows: 2016, 12 months, 21 days; the preservation number is: CGMCC No. 13373; and (3) classification and naming: penicillium orthopecium sp.
2. A crystal of an indole diterpenoid compound, characterized in that the indole diterpenoid compound has the following structure:the X-ray single crystal diffraction data are as follows: orthorhombic, space group P212121Cell parameter ofα=90°,β=90°,γ=90°,Z=4,Dx=1.142mg/mm3,F(000)=928,μ(Cu Kα)=0.540mm-1Final deviation factor R1=0.05046,wR2=0.1067[I>2σ(I)]The Flack constant is 0.0 (2).
3. A crystal of an indole diterpenoid compound, characterized in that the indole diterpenoid compound has the following structure:the X-ray single crystal diffraction data are as follows: orthorhombic, space group P212121Cell parameter ofα=90°,β=90°,γ=90°,Z=4,Dx=1.155mg/mm3,F(000)=920,μ(Cu Kα)=0.548mm-1Final deviation factor R1=0.0323,wR2=0.0746[I>2σ(I)]The Flack constant was-0.01 (17).
4. A method for producing the crystal according to any one of claims 2 to 3, characterized by comprising the steps of: dissolving 1 or 2 in a solvent, standing and naturally crystallizing to obtain the product, wherein the solvent is one or more of methanol, ethanol, dichloromethane, petroleum ether or ethyl acetate.
5. Use of a crystal according to any one of claims 2 to 3 for the preparation of a medicament for inhibiting tumor cells selected from the group consisting of a549, Hela, HepG 2.
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