CN111909021B - Sorbicillinoids compound and preparation method and application thereof - Google Patents

Sorbicillinoids compound and preparation method and application thereof Download PDF

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CN111909021B
CN111909021B CN202010621254.0A CN202010621254A CN111909021B CN 111909021 B CN111909021 B CN 111909021B CN 202010621254 A CN202010621254 A CN 202010621254A CN 111909021 B CN111909021 B CN 111909021B
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methanol
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杨献文
谢春兰
何志辉
鄢庆祥
邹正彪
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Third Institute of Oceanography MNR
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Abstract

The invention relates to a sorbieritoids compound, a preparation method and application thereof, wherein the compound is a compound shown as a formula (I) or a formula (II) or a salt thereof, wherein R is 1 、R 2 Each independently selected from methyl or hydrogen;
Figure DDA0002565236730000012
is a single bond or a double bond. The compound is separated from a fermentation product of Penicillium allii-sativi, achieves a remarkable anti-tumor effect by inhibiting tumor cell proliferation, has potential application in preparation and research and development of anti-cancer drugs, and has a good application prospect.
Figure DDA0002565236730000011

Description

Sorbicillinoids compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical compounds, and particularly relates to a sorbicinolids compound and a preparation method and application thereof.
Background
Tumors are one of the diseases that present serious threats to human health. According to statistics, 1810 ten thousand new tumor cases exist in 2018 all over the world, and 960 ten thousand patients die due to tumors. Drug resistance is a great problem in clinical tumor treatment, and enhancing treatment sensitivity or overcoming drug resistance is a problem which needs to be overcome urgently in the tumor field. However, these drugs often have single action target and large toxic and side effects, and secondary drug resistance and even multi-drug resistance are easily generated in the process of treating drug resistance, which further increases the difficulty of tumor treatment. Therefore, finding a high-efficiency, low-toxicity and broad-spectrum method or drug for reversing tumor resistance has become a research hotspot and difficulty in the tumor field at present.
Natural products refer to small chemical molecules with biological activity obtained from plants, animals and microorganisms in nature. Many active small molecules of natural product origin play an irreplaceable role as active precursor compounds in the process of new drug development. Marine microorganisms, because of their existence in special marine environments (high pressure, low temperature, oxygen deficiency, darkness), often have specific metabolic pathways in their bodies that produce secondary metabolites with novel structures. Some alkaloids, terpenoids, flavonoids, etc. from deep sea can exhibit strong antitumor activity.
Sorbicillinoids are a family of hexaketone metabolites with highly diverse biological activities isolated from fungi of marine and terrestrial origin. Many of these members have complex dimeric or trimeric structures, and another structural feature of these compounds is the C1 '-C6' sorbitol side chain. The compounds of sorbilinids have been extensively studied since the first report by Cram et al, 1948. The unique structural characteristics and biological activity of the compounds make them potential compounds for developing novel drugs. Over the past several decades, a number of sorbicillinoids compounds have been screened in different biological assays, most of which have focused on cytotoxic, antioxidant, antiviral and anticancer activity. Therefore, the isolation and screening of novel sorbieritoids compounds and the study of the antitumor activity thereof are of great significance in the development of anticancer drugs.
Disclosure of Invention
The invention aims to provide a sorbipoiids compound and a preparation method and application thereof.
To this end, the present invention provides, in a first aspect, a sorbicilinoids compound which is a compound represented by formula (I) or formula (II) or a salt thereof:
Figure BDA0002565236710000021
wherein, R is 1 、R 2 Each independently selected from methyl or hydrogen;
Figure BDA0002565236710000022
is a single bond or a double bond.
In a second aspect of the present invention, there is provided a process for preparing the sorbieritines compound, comprising the steps of:
s1, carrying out fermentation culture on Penicillium allii-sativi to obtain a fermentation product; the Penicillium allii-sativi is preserved in China Marine Culture Collection of China (MCCC) with the preservation number of MCCC 3A 00580;
s2, extracting the fermentation product obtained in the step S1, and separating and purifying the obtained extract to obtain the sorbicillinoids compound.
Further, step S2 includes:
s21, extracting the fermentation product obtained in the step S1 with ethyl acetate, and carrying out chromatography on the organic extract, wherein petroleum ether, dichloromethane and methanol are used for elution respectively; concentrating the dichloromethane layer to obtain crude extract;
s22, separating the crude extract obtained in the step S21 by normal phase silica gel column chromatography, and performing gradient elution by using a petroleum ether-ethyl acetate system to sequentially obtain 8 crude fractions: Fr.1-Fr.8;
s23, separating the crude fraction Fr.3 obtained in the step S22 by using ODS column chromatography, and then performing gradient elution by using a water-methanol system to sequentially obtain three crude fractions: fr.3-1, Fr.3-2 and Fr.3-3;
s24, separating the crude fraction Fr.3-2 obtained in the step S23 by normal phase column chromatography and sephadex column to obtain a compound of formula 1 and a compound of formula 2;
Figure BDA0002565236710000031
further, the mobile phase used in the normal phase column chromatography in step S24 is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 3: 1.
Further, the mobile phase used in the sephadex column in step S24 is methanol.
Further, the step S2 further includes the following steps:
s25, separating the crude fraction Fr.3-3 obtained in the step S23 by normal phase column chromatography and sephadex column to obtain a compound of formula 3;
Figure BDA0002565236710000032
further, the mobile phase used in the normal phase column chromatography in step S25 is dichloromethane-methanol, and the volume ratio of dichloromethane to methanol is 50: 1.
Further, the mobile phase used in the sephadex column in step S25 is methanol.
Further, the step 2 further comprises the following steps:
s26, separating and purifying the crude fraction Fr.8 obtained in the step S22 by ODS column chromatography and normal phase column chromatography to obtain a compound of formula 4 and a compound of formula 5;
Figure BDA0002565236710000041
further, the mobile phase used for ODS column chromatography in step S26 is methanol-water, in which the concentration gradient of methanol is 5% → 100%.
Further, the mobile phase used in the normal phase column chromatography in step S26 is dichloromethane-methanol, and the volume ratio of dichloromethane to methanol is 30: 1.
Further, in step S1, the conditions for fermentation culture of Penicillium allii-sativi include: inoculating mycelium to PDB-containing culture solution, and culturing to obtain seed solution; inoculating the seed solution into a fermentation culture medium, and statically culturing for 25-35 days at 28 ℃; the fermentation medium comprises 5-10% (w/v) of rice and 10-15% (v/v) of seawater.
Further, in step S1, the mycelium is prepared by the following steps: culturing Penicillium allii-sativi on a PDA (personal digital assistant) plate at 25 ℃ for 3-4 days to obtain the mycelium.
In a third aspect of the present invention, there is provided the use of said sorbicillinoid compound or a salt thereof for the preparation of: 1) an inhibitor of tumor cell proliferation; 2) a medicament for the prevention and/or treatment of neoplastic diseases.
Further, the tumor cells include breast cancer cells, lung cancer cells, liver cancer cells, esophageal cancer cells, colorectal cancer cells, and prostate cancer cells; preferably colorectal cancer cells and liver cancer cells.
Further, the tumor diseases include lung cancer, breast cancer, liver cancer, esophageal cancer, colorectal cancer and prostate cancer; preferably colorectal cancer and liver cancer.
Compared with the prior art, the invention has the following advantages:
the present invention provides novel sorbieritoids compounds isolated from fermentation broths of the deep sea Penicillium allii-sativi. The invention also provides a corresponding method for separating the compound from the fermentation liquor, and the preparation method has the advantages of environmental protection, simple steps, high product purity and the like. The anticancer effect of the sorbicillinoid compound is verified through a cytotoxicity experiment, and the anticancer effect of the compound is further proved to be achieved by inhibiting the proliferation of tumor cells through cell cycle analysis and main marker analysis. The sorbicillinoids compound provided by the invention has a good application prospect in the aspect of preparing anti-cancer drugs.
Drawings
Various other advantages and benefits will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the invention. In the drawings:
FIG. 1 shows the result of the proliferation inhibition of HT29 by the compounds provided by the present invention;
FIG. 2 is a graph showing the results of inhibition of HuH-7 proliferation by the compounds provided by the present invention;
FIG. 3 shows the results of flow analysis of the cell cycle of HT29 after the action of the compounds provided by the invention;
FIG. 4 shows the Western Blot assay of HT29 cells treated with a compound of formula 2;
FIG. 5 shows the Western Blot assay of HT29 cells treated with a compound of formula 5.
Detailed Description
Exemplary embodiments of the present disclosure will be described in more detail below with reference to the accompanying drawings. While exemplary embodiments of the present disclosure are shown in the drawings, it should be understood that the present disclosure may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.
Example 1 preparation of Sorbicillinoids
(1) Penicillium allii-sativi (accession number MCCC 3A00580) was cultured on PDA plates at 25 ℃ for 3 days; fresh mycelium was then inoculated into culture medium containing 400mL PDB; after 24h, 10mL of the seed solution was inoculated into a 1L Erlenmeyer flask (100 flasks) containing 80g of rice and 120mL of 3% seawater per flask and subjected to static culture at 28 ℃ for 30 days;
(2) extracting the fermented product obtained in the step (1) with ethyl acetate for three times, and evaporating the organic solvent under reduced pressure to obtain an organic extract (200 g); passing the extracts through normal phase column chromatography column, and eluting with petroleum ether, dichloromethane and methanol respectively; the dichloromethane layer was concentrated to give a crude extract (63.0 g);
(3) separating the crude extract obtained in the step (2) by using normal phase silica gel column chromatography, and performing gradient elution by using a petroleum ether-ethyl acetate system to obtain 8 crude fractions (Fr.1-Fr.8);
(4) the crude fraction Fr.3(5.5g) in step (3) was separated by ODS column chromatography, and gradient elution was carried out using a water-methanol system to obtain three crude fractions (Fr.3-1, Fr.3-2, Fr.3-3). Fr.3-2(211.4mg) was separated using normal phase column chromatography (petroleum ether-ethyl acetate, 3:1) and sephadex column (pure methanol) to give the compound of formula 1 (23.2mg) and the compound of formula 2 (4.5 mg). Fr.3-3(150.6mg) using normal phase column chromatography (dichloromethane-methanol, 50:1) and sephadex column (neat methanol) to give the compound of formula 3 (4.4 mg);
Figure BDA0002565236710000061
(5) the crude fraction Fr.8(15 g) in step (3) was separated and purified by ODS column chromatography (methanol-water: 5% → 100%) and normal phase column chromatography (dichloromethane-methanol, 30:1) to give the compound of formula 4 (20.3mg) and the compound of formula 5 (16.5 mg),
Figure BDA0002565236710000062
(6) the compounds of formulae 1, 2, 3, 4 and 5 obtained in the above steps are analyzed by 1D and 2D NMR spectra and high resolution mass spectrometry to determine the planar structure of the compound, and then the absolute configuration is determined by ECD calculation and the like, which are detailed as follows:
the compound of formula 1 is a yellow oil. Determining the molecular formula of the compound as C according to the main ion peak in the high-resolution mass spectrum 24 H 30 O 6 。 1 H、 13 C NMR data (Table 1) and DEPT and HMBC spectra show 24 carbon signals including 5 methyl groups, 3 methylene groups, 7 methines and 9 quaternary carbons, the planar structure of the compound was determined by detailed two-dimensional data, and finally the relative and absolute configurations of the compound of formula 1 were determined using NOE spectra and ECD calculations and named sorbiallostol A.
The compound of formula 2 has the molecular formula C 23 H 28 O 6 ， 1 H、 13 C NMR data (Table 1) showed 23 carbons, including 4Methyl, 3 methylene, 7 methine and 9 quaternary carbons. These signals are very close to the compound of formula 1, having only one methoxy group less than it. The structure of the compound of formula 2 was finally confirmed by detailed 1D and 2D NMR analysis, and was named sorbiallisol B.
The other three compounds are determined by comparing the physical and chemical data of NMR nuclear magnetism, optical rotation, mass spectrum and the like of the reference, and are respectively as follows: sohirnone A (compound of formula 3), 2',3' -dihydrosorbicilin (compound of formula 4) and sorbicilin (compound of formula 5).
TABLE 1 Compounds of formula 1 and formula 2 1 H NMR (400MHz, DMSO-d6) and 13 c NMR data (100MHz, DMSO-d) 6 )
Figure BDA0002565236710000071
Example 2 antitumor Activity assay
Two tumor cells, colorectal (HT29) and liver (HuH-7) cells, were selected for this example. Taking the compounds of formula 2 and 5 as examples, the compounds prepared in example 1 were tested for their anti-tumor activity by testing the inhibition rate of the compound samples on these tumor cells.
The present embodiment sets the following 3 groups:
negative control group: an equal amount of culture medium, one thousandth of DMSO, containing cells, without adding formula 2 or formula 5
A compound;
blank control group: an equivalent amount of culture medium, free of cells, and without the addition of a compound of formula 2 or formula 5;
experimental groups: adding the compounds of formula 2 and formula 5 to the cell culture medium, respectively;
the method comprises the following specific steps:
(1) after the cells are subjected to conventional digestion, the cells are resuspended in a culture medium and blown into a single cell suspension, and then the single cell suspension is inoculated into a 96-well plate with 2000-5000 cells per well, wherein the volume of each well is 200 mu l;
(2)37℃，5％CO 2 culturing for 24h in an incubator, and then adding compounds of formulas 2 and 5 with different concentrations to treat cells respectively;
(3) after further culturing for 48 hours, 10. mu.l of 5mg/mL MTT (3- (4,5) -dimethylthiohiazo (-z-y1) -3, 5-diphenyltetrazolium amide) was added to each well and reacted at 37 ℃ in the dark for 3 hours; carefully absorbing and removing the supernatant, adding 150 mu l DMSO into each hole, and oscillating for 10min to fully melt the crystal;
(4) measuring the light absorption value at 570nm by an enzyme-labeling instrument, then calculating the inhibition rate according to a formula (I),
Figure BDA0002565236710000081
the results are shown in FIG. 1 and FIG. 2( ** P<0.01， *** P<0.001， **** P<0.0001 compared with DMSO blank group), the compounds of the formula 2 and the compounds of the formula 5 have obvious inhibition effects on the growth of colorectal cancer cells HT29 and liver cancer cells HuH-7, and show obvious concentration dependence. These results show that the compounds prepared in example 1 have anti-tumor function and have very good prospect for developing anti-tumor drugs.
Example 3 cell cycle assay
HT29 cells were treated with Nocodazole (Nocodazole) (50ng/mL, 12h), a compound of formula 2 (50. mu.M, 48h), a compound of formula 5 (30. mu.M, 48h), respectively, then collected with trypsin and dried with 70% ethanol solution at 4 ℃ overnight. After removal of the ethanol solution, the cells were washed twice with PBS buffer and labeled with DAPI (purchased from Sigma-Aldrich, diluted with PBS at a ratio of 1:10000 for 10 min). Finally, the fluorescence was measured by PB450-A flow cytometer for cell cycle FCM analysis, and the results are shown in FIG. 3, where the first dark black peak indicates that the cells are in the G0-G1 phase, and the second light gray peak indicates that the cells are in the G2-M phase.
As can be seen from FIG. 3, the compound provided by the invention significantly inhibits the replication of tumor cells by blocking the cell cycle in the G2-M phase.
Example 4M-phase marker protein assay
HT29 cells were treated with Nocodazole (Nocodazole) (50ng/mL, 12h), compounds of formula 2 (5, 10, 30, 50. mu.M, 48h), and compounds of formula 5 (2.5, 5, 10, 30. mu.M, 48h), respectively, and then the cells were collected for Western Blot analysis, and the Western Blot results after treating HT29 cells with compounds of formula 2 are shown in FIG. 4, and the Western Blot results after treating HT29 with compounds of formula 5 are shown in FIG. 5.
Phosphorylation modification of histone H3(p-H3) occurs at specific stages of mitosis and meiosis and chromosomal location, and p-H3 can be used as one of M-phase marker proteins; the Cyclin B1 protein also plays an important role in cell cycle regulation, and overexpression of Cyclin B1 can promote G2/M phase transformation. As can be seen from FIGS. 4-5, the compounds provided by the present invention can significantly increase protein expression of p-H3 and Cyclin B1, and are dose-dependent, which further confirms that the compounds provided by the present invention indeed induce M phase block.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.

Claims (14)

1. A sorbicillinoids compound, which is a compound represented by the formula (I) or a salt thereof:
Figure 789837DEST_PATH_IMAGE001
，
wherein, R is 1 Selected from methyl or hydrogen.
2. A process for the preparation of the sorbicillinoids compound as claimed in claim 1, comprising the steps of:
s1 Penicillium notatumPenicillium allii-sativiPerforming fermentation culture to obtain a fermentation product; the PenicilliumPenicillium allii-sativiThe accession number of (1) is MCCC 3A 00580;
s2, extracting the fermentation product obtained in the step S1, and separating and purifying the obtained extract to obtain the sorbicillinoids compound.
3. The method of claim 2, wherein the step S2 includes:
s21, extracting the fermented product obtained in the step S1, extracting the fermented product with ethyl acetate, and carrying out chromatography on the organic extract, wherein petroleum ether, dichloromethane and methanol are used for elution respectively; concentrating the dichloromethane layer to obtain crude extract;
s22, separating the crude extract obtained in the step S21 by normal phase silica gel column chromatography, and performing gradient elution by using a petroleum ether-ethyl acetate system to sequentially obtain 8 crude fractions: Fr.1-Fr.8;
s23, separating the crude fraction Fr.3 obtained in the step S22 by using ODS column chromatography, and then performing gradient elution by using a water-methanol system to sequentially obtain three crude fractions: fr.3-1, Fr.3-2 and Fr.3-3;
s24, separating the crude fraction Fr.3-2 obtained in the step S23 by normal phase column chromatography and sephadex column to obtain a compound shown as a formula 1 and a compound shown as a formula 2;
Figure 972557DEST_PATH_IMAGE002
，
Figure 283452DEST_PATH_IMAGE003
。
4. the method according to claim 3, wherein the mobile phase used in the normal phase column chromatography in the step S24 is petroleum ether-ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 3: 1.
5. The method of claim 3, wherein the mobile phase used in the sephadex column of step S24 is methanol.
6. The method of claim 3, wherein the step S2 further comprises the steps of:
s25, separating the crude fraction Fr.3-3 obtained in the step S23 by normal phase column chromatography and sephadex column to obtain a compound of formula 3;
Figure 944241DEST_PATH_IMAGE004
。
7. the method of claim 6, wherein the mobile phase used for normal phase column chromatography in step S25 is dichloromethane-methanol, and the volume ratio of dichloromethane to methanol is 50: 1.
8. The method of claim 6, wherein the mobile phase of the sephadex column in step S25 is methanol.
9. The method of claim 3, wherein the step S2 further comprises the steps of:
s26, separating and purifying the crude fraction Fr.8 obtained in the step S22 by ODS column chromatography and normal phase column chromatography to obtain a compound of formula 4 and a compound of formula 5;
Figure 24192DEST_PATH_IMAGE005
，
Figure 377813DEST_PATH_IMAGE006
。
10. the preparation process according to claim 9, wherein the mobile phase used in the ODS column chromatography in step S26 is methanol-water, wherein the concentration gradient of methanol is 5% → 100%.
11. The method of claim 9, wherein the mobile phase used in the normal phase column chromatography in step S26 is dichloromethane-methanol, and the volume ratio of dichloromethane to methanol is 30: 1.
12. The method according to any one of claims 2 to 11, wherein the Penicillium notatum is produced in step S1Penicillium allii-sativiThe fermentation culture conditions of (a) include: inoculating mycelium to PDB-containing culture solution, and culturing to obtain seed solution; inoculating the seed solution into a fermentation culture medium, and statically culturing for 25-35 days at 28 ℃; the fermentation medium comprises 5-10% (w/v) of rice and 10-15% (v/v) of seawater.
13. The method of claim 12, wherein the mycelium is prepared by the following steps in step S1: penicillium notatumPenicillium allii-sativiAnd (3) culturing the mycelia on a PDA (personal digital assistant) plate at 25 ℃ for 3-4 days to obtain the mycelia.
14. Use of the sorbilinids compound or salt thereof according to claim 1 for the preparation of: 1) an inhibitor of tumor cell proliferation; 2) drugs for preventing and/or treating tumor diseases;
the tumor cell is a liver cancer cell or a colorectal cancer cell; the tumor disease is liver cancer or colorectal cancer.
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