CN115626932A - Novel diterpene compound, preparation method thereof, pharmaceutical composition and application thereof in antitumor drugs - Google Patents
Novel diterpene compound, preparation method thereof, pharmaceutical composition and application thereof in antitumor drugs Download PDFInfo
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Abstract
The invention discloses a novel diterpenoid compound, a preparation method thereof, a pharmaceutical composition and application thereof in antitumor drugs. The abietane diterpenoid compound Fischer iabietane F provided by the invention has obvious inhibitory activity on liver cancer cells BEL-7402 and breast cancer cells MDA-MB-231, the pimararene diterpenoid compound Fischeripimiaaranane A has obvious inhibitory activity on breast cancer cells MDA-MB-231 and leukemia cells U937, the activity of the pimarane diterpenoid compound Fischerianarane A is obviously superior to that of a positive medicine cis-platinum Cisplatin, and the rosine diterpenoid compound Fischer iabietane F can be used for developing anti-tumor medicines.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a novel diterpene compound, a preparation method thereof, a pharmaceutical composition and application thereof in antitumor drugs; more particularly, relates to abietane type and pimarane type diterpenoid compounds, a preparation method thereof, a pharmaceutical composition and application thereof in antitumor drugs.
Background
Euphorbia fischeriana Kitag (root of Euphorbia fischeriana)E. fischeriana) Is a perennial herb of Euphorbiaceae (Euphorbiaceae) euphorbia, the root of which is used as the medicine is Chinese wolfsbane, which has pungent and mild taste and enters liver and spleen channels. Modern pharmacological research shows that various diterpene compounds in euphorbia stellera have the effects of resisting tumor, inflammation, bacteria and the like. In order to search for new anti-tumor candidate drugs, the inventor isolated novel abietane-type and pimarane-type diterpenoid compounds from the root of euphorbia stellera and found that the diterpenoid compounds can inhibit the growth of various tumor cells.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides novel abietane type and pimarane type diterpenoid compounds, and a preparation method, a pharmaceutical composition and application thereof.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention discloses a novel abietane diterpenoid compound which has a structure shown as a formula (1);
（1）。
the second aspect of the invention discloses a pimarane type diterpenoid compound, which has a structure shown in the following formula (2):
（2）。
the invention also provides a preparation method of the abietane-type and/or pimarane-type diterpenoid compounds, and the abietane-type and pimarane-type diterpenoid compounds are extracted and separated from euphorbia chamaejasme.
In the above technical scheme, the preparation method of the abietane-type and pimarane-type diterpenoid compounds comprises the following steps:
s1, taking the root of dried euphorbia stellera, adding a solvent for reflux extraction, combining extracting solutions and concentrating to obtain an extract;
s2, adding the extract into water with the mass of 8-15 times, suspending, sequentially extracting with petroleum ether and dichloromethane, discarding the petroleum ether extract, subjecting the dichloromethane extract to silica gel column chromatography, eluting with petroleum ether-ethyl acetate, collecting fractions, detecting with a silica gel thin layer, and combining fluorescence spots with Rf values of 0.82-0.84, 0.78-0.80, 0.74-0.76, 0.65-0.68, 0.57-0.62, 0.53-0.55, 0.45-0.47 and 0.35-0.39 and spots with 10% vanillin sulfate color being gray purple respectively according to observation under 254 nm and 365 nm to obtain 8 fractions respectively named as A, B, C, D, E, F, G, H and I;
s3, subjecting the fraction D to ODS column chromatography, performing gradient elution by using methanol-water, collecting 60-70 fractions, performing silica gel thin-layer chromatography, and combining the fractions into 6 fractions D1-D6; subjecting the fraction D3 to ODS column chromatography, performing gradient elution with methanol-water, collecting 30-40 fractions, detecting with silica gel thin layer chromatography, and combining into 4 fractions J1-J4;
subjecting the fraction C to silica gel column chromatography, performing gradient elution by using dichloromethane-methanol, collecting 50-60 fractions, performing silica gel thin layer chromatography, and combining the fractions into 5 fractions C1-C5;
s4, taking methanol-water as a mobile phase, adopting an HPLC method, and utilizing C 18 The chromatographic column isPreparing a abietane diterpenoid compound with a structural formula shown in a formula (1) from the fraction J3;
or using methanol-water as mobile phase, HPLC method, and using C 18 The chromatographic column is used for preparing the pimarane diterpenoid compounds with the structural formula shown in the formula (2) in the fraction C5.
In a specific embodiment of the present invention, in step S4, in the mobile phase used in the HPLC separation of fraction J3, the volume ratio of methanol to water is (65) to (68) 32, and the retention time of the abietane-type diterpenoid compound represented by the formula (1) is 28 to 30 min.
In a specific embodiment of the present invention, in step S4, in the mobile phase used in the HPLC separation of fraction C5, the volume ratio of methanol to water is (69) - (72).
In the embodiment of the present invention, in step S3,
subjecting the fraction D to ODS column chromatography, eluting with a methanol-water gradient with a volume ratio of (30;
and/or subjecting fraction D3 to ODS chromatography, eluting with methanol-water gradient of (50) - (0);
and/or subjecting fraction C to silica gel column chromatography, eluting with a dichloromethane-methanol gradient at a volume ratio of (100.
In a specific embodiment of the present invention, in step S2, the dichloromethane extract is subjected to silica gel column chromatography, eluted with petroleum ether-ethyl acetate at a volume ratio of (100;
in the specific embodiment of the invention, in the step S1, the solvent is 88-98V% aqueous ethanol, and the mass of the ethanol added is 8-10 times of that of euphorbia fischeriana, and the reflux extraction times are 2-4, and each extraction time is 1-3h.
The invention also provides a pharmaceutical composition of the abietane-type or pimarane-type diterpenoid compound.
Specifically, in the above technical scheme, the pharmaceutical composition comprises a synergist and a pharmaceutically acceptable carrier or excipient. That is, pharmaceutical compositions containing the abietane-type and pimarane-type diterpenoid compounds of the present invention as an active ingredient and conventional pharmaceutical excipients or adjuvants or carriers are also encompassed by the present invention.
Specifically, in the above technical solution, the synergist is any one of the following substances:
<xnotran> , , , , , , , , (DDP), , , 5- , , , , , , , , 6- , , , C1-C20 , , , , , , , , , , 5' - -5- , 5' - -5- , 2' - -5- , , , , , , , , 3236 zxft 3236, , , , , , , , , 5262 zxft 5262 , 3763 zxft 3763 , , , , , , , , , , , , , , , , , , 6- , , , , , , , , , , , . </xnotran>
Specifically, in the above technical scheme, the dosage form of the pharmaceutical composition is tablet, capsule, granule, oral liquid, granule, dripping pill or pellet.
The invention also provides application of the diterpenoid compound in preparing a medicament for preventing or treating malignant tumors, in particular to a medicament for clinical chemotherapy stages.
Specifically, the invention provides an application of abietane diterpenoid compounds in preparing a medicament for preventing or treating liver cancer or breast cancer.
Specifically, the invention also provides application of the pimarane diterpenoid compound in preparation of a medicament for preventing or treating breast cancer or leukemia.
Compared with the prior art, the invention has the following advantages:
(1) The invention provides a abietane-type and pimaric alkane-type diterpenoid compound which is not reported at present, and further provides a method for extracting and obtaining the abietane-type and pimaric alkane-type diterpenoid compound from euphorbia chamaejasme with simple operation, good reproducibility and high extraction purity;
(2) Test results show that the abietane-type and pimarane-type diterpenoid compounds provided by the invention have obvious killing effects on liver cancer cells BEL-7402, breast cancer cells MDA-MB-231 and leukemia cells U937, and can be used for developing anti-tumor and anti-cancer drugs, especially drugs in clinical chemotherapy stages.
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FIG. 1 shows the preparation of Compound 1 according to example 1 of the present invention 1 H NMR Spectrum (500MHz, CDCl) 3 ）；
FIG. 2 shows the preparation of Compound 1 according to example 1 of the present invention 13 C NMR spectra (125 MHz, CDCl) 3 ）；
FIG. 3 shows the preparation of Compound 2 according to example 2 of the present invention 1 H NMR Spectrum (400 MHz, CDCl) 3 ）；
FIG. 4 shows the preparation of Compound 2 according to example 2 of the present invention 13 C NMR spectrum (100 MHz, CDCl) 3 ）。
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments.
It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the examples, the means used are conventional in the art unless otherwise specified.
The terms "comprises," "comprising," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from regular distributors, not indicated by the manufacturer.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and these ranges or values should be understood to encompass values close to these ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
A preparation method of abietane diterpenoid compounds comprises the following steps:
s1, weighing 46 kg of euphorbia stellera roots, adding 95% ethanol water solution which is 10 times of the euphorbia stellera roots in mass as a solvent, performing reflux extraction for three times, extracting for 2 hours each time, combining extracting solutions, and concentrating to obtain 2.0 kg extract;
s2, adding the extract (2.0 kg) into 10 times of water (20L) for suspension, sequentially extracting with petroleum ether and dichloromethane in an amount which is 1.5 times of the volume of the suspension for 3 times to obtain 1000 g petroleum ether extract (reject) and 560 g dichloromethane extract, subjecting the dichloromethane extract to silica gel column chromatography, eluting with petroleum ether-ethyl acetate gradient at a volume ratio of 100:0, 90: 10, 80: 20, 70:30, 60:40, 50:50, 40:60, 30:70, 20: 80, 10: 90 and 0:100, 1 fraction is obtained in volume per 500 mL, 50 fractions are collected in total, and according to the results of observation of Rf values of 0.82-0.84, 0.78-0.80, 0.74-0.76, 0.65-0.68, 0.57-0.62, 0.53-0.55, 0.45-0.47 and 0.35-0.39 under 254 nm and 365 nm by using silica gel thin layer chromatography, similar fractions are combined to obtain 8 fractions which are named as A, B, C, D, E, F, G, H and I respectively;
s3, subjecting fraction D to ODS column chromatography, performing gradient elution with methanol-water at a volume ratio of 30:70, 40:60, 50:50, 60:40, 70:30, 80: 20, 90: 10 and 100:0, collecting 60 fractions, performing detection with silica gel thin-layer chromatography, combining into 6 fractions D1-D6, subjecting fraction D3 to ODS column chromatography, performing gradient elution with methanol-water at a volume ratio of 50:50, 60:40, 70:30, 80: 20, 90: 10 and 100:0, collecting 30-40 fractions, performing detection with silica gel thin-layer chromatography, and combining into 4 fractions J1J 4.
S4, compound 1 (t) R = 28-30 min）。
Physical properties and test data of compound 1 prepared in example 1 are as follows:
white amorphous powder, easily soluble in chloroform and methanol. Molecular weight 332, presumed by high resolution mass spectrometry, bound 1 HNMR (fig. 1)、 13 CNMR spectra (FIG. 2) and determination of molecular formula C 20 H 28 O 4 The unsaturation degree was calculated to be 7.
1 HNMR (500 MHz, CDCl 3 ) The spectrum (FIG. 1) shows that the signal of hydrogen on 4 oxocarbons is contained in the low field regionδ H 4.94 (s), 4.63 (s), 4.28 (d,J = 8.5 Hz),3.39 (d,J = 8.5 Hz)](ii) a The high field region has 4 methyl signalsδ H 1.98, 0.94, 0.93 (each 3H, s)]。
13 CNMR (125 MHz, CDCl 3 ) The spectrum (FIG. 2) shows a total of 20 carbon signals, including 3 methyl carbon signals: (δ C 32.9, 21.6, 9.6), 6 methylene carbon signals: (δ C 41.8, 33.9, 32.3, 26.2, 20.8, 20.5), 2 methine carbon signals: (δ C 51.9, 51.3), 4 vicinal oxygen carbon signals (δ C 85.8, 78.0, 74.1, 70.7), 2 alkene hydrogen carbon signals: (δ C 162.6, 124.7), 1 carbonyl carbon signal: (δ C 174.9 And 2 remaining quaternary carbon signals: (a)δ C 48.8,34.0)。
1 H NMR、 13 The signals of C NMR are shown in the following table.
| Position of Position | Chemical shift of hydrogen δ H (Multi, J) in Hz) | Chemical grade of carbon Shift delta C | Position of Position | Chemical shift of hydrogen δ H (Multi, J) in Hz) | Chemical position of carbon Shift delta C |
| 1 | 1.86 (overlap) 1.37 (overlap) | 32.3 | 11 | 2.42 (m) 1.46 (overlap) | 26.2 |
| 2 | 1.58 (m) 1.26 (m) | 20.5 | 12 | 4.94 (s) | 78.0 |
| 3 | 1.44 (overlap) 1.16 (m) | 41.8 | 13 | 162.6 | |
| 4 | 34.0 | 14 | 4.63 (s) | 70.7 | |
| 5 | 1.25 (m) | 51.9 | 15 | 124.7 | |
| 6 | 1.88 (overlap) 1.73 (m) | 20.8 | 16 | 174.9 | |
| 7 | 1.76 (m) | 33.9 | 17 | 1.98 (s) | 9.6 |
| 8 | 85.8 | 18 | 0.93 (s) | 32.9 | |
| 9 | 1.82 (m) | 51.3 | 19 | 0.94 (s) | 21.6 |
| 10 | 48.8 | 20 | 4.28 (d, 8.5) 3.39 (d, 8.5) | 74.1 |
Bonding of 1 H NMR and 13 c NMR spectrum, presuming that compound 1 may contain 1 α, β -unsaturated lactone moiety, presuming that the remaining 4 unsaturations are occupied by 4 rings, and, in addition, 4 oxygen-bonded carbon signals and 3 methyl groups; in combination with the above information, it is presumed that the compound 1 may be an ent-abietane-type diterpene compound.
In HMBC spectra, H-12 (C: (A) (B))δ H 4.94 And C-11 (δ C 26.2)、C-13 (δ C 162.6 A correlation between (a) and (b), H-14: (δ H 4.63 And C-8 (δ C 85.8)、C-9 (δ C 51.3)、C-12 (δ C 78.0)、C-13 (δ C 162.6 And C-14 (δ C 70.7 A correlation between) indicates that the C-12 position and the C-14 position are substituted by oxygen; furthermore, H-20a (δ H 4.28 And C-8 (δ C 85.8)、C-10 (δ C 48.8)、C-5 (δ C 51.9 Remote correlation between H-20 b: (δ H 3.39 And C-5 (δ C 51.9)、C-10 (δ C 48.8 Long range correlation between) demonstrated the formation of an oxygen bridge between the C-8 and C-20 positions.
In the NOESY spectrum, H-5 (δ H 1.25 And H-9 (δ H 1.82)，H-12 (δ H 4.94 And H-20 b: (δ H 3.39 Has no NOE correlation, H-9 is not related to H-14, and thus the relative configuration of the compound is determined, i.e., H-12, H-20 is in the α configuration toward one plane, and H-5, H-9, and 14-OH is in the β configuration toward the other plane.
In summary, the structure of the novel compound 1 (Fischer iabietane F) was determined as follows:
（1）。
comparative example 1
Comparative example 1 of the present invention provides a method for preparing abietane-type diterpenoid compounds, which comprises the steps similar to those of example 1, except that, in step S3, the fraction D3 is subjected to ODS column chromatography using a solvent having a volume ratio of 40:60 methanol-water elution.
The results show that compound 1 could not be prepared.
Comparative example 2
Comparative example 2 of the present invention provides a process for preparing abietane-type diterpenoid compounds, which comprises the steps similar to those of example 1 except that, in step S4, the volume ratio of methanol to water in the mobile phase used in the HPLC separation of fraction J3 was 50:50.
the results show that compound 1 could not be prepared.
Example 2
A preparation method of a pimarane diterpenoid compound comprises the following steps:
s1, weighing 46 kg of euphorbia stellera roots, adding 95% ethanol water solution which is 10 times of the euphorbia stellera roots in mass as a solvent, performing reflux extraction for three times, extracting for 2 hours each time, combining extracting solutions, and concentrating to obtain 2.0 kg extract;
s2, adding the extract (2.0 kg) into 10 times of water (20L) for suspension, sequentially extracting with petroleum ether and dichloromethane in an amount which is 1.5 times of the volume of the suspension for 3 times to obtain 1000 g petroleum ether extract (reject) and 560 g dichloromethane extract, subjecting the dichloromethane extract to silica gel column chromatography, eluting with petroleum ether-ethyl acetate gradient at a volume ratio of 100:0, 90: 10, 80: 20, 70:30, 60:40, 50:50, 40:60, 30:70, 20: 80, 10: 90 and 0:100, 1 fraction is obtained in volume per 500 mL, 50 fractions are collected in total, and according to the results of observation of Rf values of 0.82-0.84, 0.78-0.80, 0.74-0.76, 0.65-0.68, 0.57-0.62, 0.53-0.55, 0.45-0.47 and 0.35-0.39 under 254 nm and 365 nm by using silica gel thin layer chromatography, similar fractions are combined to obtain 8 fractions which are named as A, B, C, D, E, F, G, H and I respectively;
s3, subjecting fraction C to silica gel column chromatography, gradient eluting with dichloromethane-methanol at volume ratio of 100:0, 90: 10, 80: 20, 70:30, 60:40, 50:50, 40:60, 30:70, 20: 80, 10: 90 and 0:100, collecting 50-60 fractions, performing silica gel thin layer chromatography, and mixing to obtain 5 fractions C1-C5;
s4, compound 2 (t) was prepared in fraction C5 by HPLC using methanol-water as the mobile phase at a volume ratio of 70 R = 17-20 min）。
The physical properties and the test data of compound 2 prepared in example 2 are as follows:
white amorphous powder; molecular weight 346, estimated by high resolution mass spectrometry, bound 1 HNMR (FIG. 3), 13 CNMR spectra (FIG. 4) and determination of molecular formula C 22 H 34 O 3 The unsaturation was calculated to be 6.
1 HNMR (400 MHz, CDCl 3 ) The spectrum (FIG. 3) shows that the region in the low field contains 4 alkene hydrogen signalsδ H 5.72 (1H, dd,J = 17.2, 10.4 Hz),5.26 (1H, d, J = 1.6 Hz), 5.15 (1H, dd,J = 17.2, 2.0 Hz), 5.04 (1H, dd,J = 10.4, 1.6 Hz)](ii) a Contains 3 hydrogen signals on the continuous oxygen carbonδ H 3.27 (1H, dd,J = 11.6, 4.1 Hz),3.76 (1H, d, J = 10.6 Hz), 3.97 (1H, d, J = 10.6 Hz)](ii) a The high field region has 4 methyl signalsδ H 2.05, 1.02, 0.83,0.74 (each 3H, s)]。
13 C-NMR (100 MHz, CDCl 3 ) The spectrum (FIG. 4) shows a total of 22 carbon signals, of which there are 4 methyl carbon signals: (δ C 28.7, 21.2, 15.9, 15.0), 6 methylene carbon signals: (δ C 37.3, 35.9, 30.5, 27.7, 22.3, 18.3), 2 methine carbon signals: (δ C 54.2, 51.6), 2 vicinal oxygen carbon signals (δ C 79.3, 71.8), 4 alkene hydrogen carbon signals (Cδ C 142.6, 141.1, 122.7, 116.8), 1Carbonyl carbon signal (C:)δ C 171.5 And 3 remaining quaternary carbon signals: (a)δ C 43.1,39.2, 38.5). Bonding of 1 HNMR spectrogram, supposing it may be diterpenoid, structure may contain 1 acetyl, 2 pairs of double bonds, 1 hydroxyl and 3 methyl.
1 HNMR、 13 The signals of C NMR are shown in the following table.
| Position of Position | The chemical shift of hydrogen δ H (multi, J in Hz) | chemical grade of carbon Shift delta C | Position of Position | Chemical shift of hydrogen δ H (Multi, J in) Hz) | Chemical potential of carbon Shift delta C |
| 1 | 1.69 (m) 1.17 (m) | 37.3 | 12 | 1.38 (m) 1.32 (m) | 30.5 |
| 2 | 1.65 (m) 0.93 (m) | 27.7 | 13 | 43.1 | |
| 3 | 3.27 (dd, 11.6, 4.1) | 79.3 | 14 | 5.26 (d, 1.6) | 122.7 |
| 4 | 39.2 | 15 | 5.72 (dd, 17.2, 10.4) | 142.6 | |
| 5 | 1.07 (dd, 12.3, 2.6) | 54.2 | 16 | 3.15 (dd, 17.2, 2.0) 5.04 (dd, 10.4, 1.6) | 116.8 |
| 6 | 1.64 (m) 1.43 (m) | 22.3 | 17 | 3.76 (d, 10.6) 3.97 (d, 10.6) | 71.8 |
| 7 | 2.39 (m) 2.09 (m) | 35.9 | 18 | 1.02 (s) | 28.7 |
| 8 | 141.1 | 19 | 0.83 (s) | 15.9 | |
| 9 | 1.71 (m) | 51.6 | 20 | 0.74 (s) | 15.0 |
| 10 | 38.5 | Ac-CO | 171.5 | ||
| 11 | 1.55 (m) 1.31 (m) | 18.3 | Ac-Me | 2.05 (s) | 21.2 |
According to combination with known compoundsThe comparison of the data shows that it should be an ent-pimarane diterpene, except that the chemical shift at the C-17 position is shifted in low field and a group of acetyl signals are added, and it is inferred that the acetyl group is connected with the C-17 position by an ester bond. In HMBC spectra, H 2 -17 (δ H 3.76, 3.97) and acetylcarbonyl group: (δ C 171.5 Remote correlation of (a) demonstrated an acetoxy substitution at the C-17 position.
In summary, the structure of the novel compound 2 (fisheripimiaarane a) was determined as follows:
（2）。
comparative example 3
Comparative example 3 of the present invention provides a preparation method of a pimarane type diterpenoid compound, which has the steps similar to example 2 except that, in step S3, fraction C is gradient-eluted using petroleum ether-ethyl acetate at a volume ratio of 100:0, 90: 10, 80: 20, 70:30, 60:40, 50:50, 40:60, 30:70, 20: 80, 10: 90 and 0:100 when subjected to silica gel column chromatography.
The results show that compound 2 could not be prepared.
Comparative example 4
Comparative example 4 of the present invention provides a process for preparing a pimarane-type diterpenoid compound, which has the similar procedure as in example 2 except that in step S4, in the mobile phase used in the HPLC separation of fraction C5, the volume ratio of methanol to water is 60:40.
the results show that compound 2 could not be prepared.
In order to better understand the essence of the present invention, the following will be described the new application of the diterpenoid compounds in the pharmaceutical field by combining the pharmacological test and the results.
Test examples
This test example discloses experiments of inhibiting the activity of tumor cells with the above-mentioned compounds Fischer iabietane F and Fisheripimiarane A.
(1) Experimental materials and instruments
BEL-7402, MDA-MB-231 and U937 cell lines were purchased from the cell dictionary of Chinese academy of sciences (Shanghai);
DMEM medium, RPMI 1640 medium, PBS buffer, fetal Bovine Serum (FBS) and trypsin were purchased from Gibco, USA;
CCK-8 cell activity assay kit (MCE, USA);
DMSO (Sigma, usa);
96-well plates (corn corporation, usa);
carbon dioxide cell culture chamber (Thermo Fisher Scientific, usa);
a full-wavelength microplate reader (Thermo Fisher Scientific, USA);
BIOFUGE STRATOS centrifuge (Thermo Fisher Scientific, USA);
IX73 inverted electron microscope (Olympus, japan);
pipettors (Eppendorf, germany);
related consumables such as superclean bench, centrifuging tube, straw.
(2) Cell recovery and culture
Taking out the marked BEL-7402, MDA-MB-231 and U937 cell freezing tube in liquid nitrogen, immediately putting into a water bath kettle at 37 ℃, and quickly thawing and thawing within 1 min as much as possible; after the frozen tube is disinfected by alcohol, transferring the frozen liquid in the tube into a 15 mL sterile centrifuge tube, adding a corresponding culture medium, uniformly mixing, and centrifuging to remove a supernatant; washing by repeating the above steps once, adding 10 mL culture fluid, mixing, resuspending the cells, transferring to 10 mL petri dish, placing at 37 deg.C, 5% 2 The culture is carried out in a constant temperature incubator.
When the cell density reaches 70% -80%, the cells are passaged; sucking out old culture medium, adding PBS to wash for 2 times, adding trypsin containing EDTA into a culture dish, placing the culture dish in an incubator at 37 ℃ for 3min, then adding the culture medium to stop digestion, centrifuging the culture dish at 1000 rpm for 5min, sucking out digestion liquid, adding the culture medium containing serum again, repeatedly blowing and beating cells to form cell suspension, and finally transferring the cell suspension into a new culture dish according to the number of the cells to finish cell passage.
(3) CCK-8 method for evaluating cell activity
BEL-7402, MDA-MB-231 and U937 cells were treated at 1X 10 cells, respectively 4 The cells/well are plated on a 96-well plate, each group comprises 6 multiple wells, the cells are plated and cultured for 24 hours, compounds of Fischer iabietane F and Fischer ipimiarane A are dissolved and then are respectively diluted to 100, 50, 25, 12.5, 6.25 and 3.125 mu M for treating the cells, then 48 h is treated at 37 ℃,10 mu L of CCK-8 kit and 2h are added, an enzyme labeling instrument is used for detecting the absorbance value at 450nm, and the cell proliferation inhibition rate is calculated.
Cell proliferation inhibition (%) = [ (control-a sample)/(control-a blank) ] × 100%;
the results are shown in the table
TABLE 1 screening test results of diterpenoid compounds for inhibiting tumor cells
The results of experiments on the inhibition of the tumor cell activity of Fischer iabietane F and Fischeripimaanane A show that the compounds Fischer iabietane F and Fischeripimaanane A have significant inhibitory effects on human liver cancer cell BEL-7402, human breast cancer cell MDA-MB-231 and human leukemia cell U937, wherein Fischer iabietane F has significant inhibitory activity on liver cancer cell BEL-7402 and breast cancer cell MDA-MB-231, and Fischeripimaanane A has significant inhibitory activity on breast cancer cell MDA-MB-231 and leukemia cell U937, and the activities of the Fischer iabietane F and the Fischeripimaanane A are significantly superior to that of positive drug Cisplatin (Cisplatin). The diterpenoid compound is shown to be an anti-tumor candidate prodrug with development prospect in natural products.
In conclusion, the two diterpenoid compounds can be applied as the prodrugs for treating malignant tumors.
Application example 1
The application example of the invention discloses a capsule taking Fischer iabietane F as a raw material medicine, which comprises the following components:
Fischeriabietane F 18.0 mg
starch 6.0 g
Sodium metabisulfite 0.2 g
Magnesium stearate 0.2 g
Proper amount of absolute ethyl alcohol
Making into 100 granules.
The preparation method comprises the following specific steps:
mixing Fischer iabietane F, starch and sodium metabisulfite, adding anhydrous alcohol to obtain soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and making into capsule.
Application example 2
The application example of the invention discloses a granule taking a compound Fisheripamaranane A as a raw material medicine, which comprises the following components:
Fisheripimaarane A 35.0 mg
starch 6.0 g
Sodium bisulfite 0.2 g
Magnesium stearate 0.2 g
Absolute ethyl alcohol 0.1 mL;
100 bags are made.
The preparation process comprises the following steps:
mixing Fisheripamaranane A with starch and sodium bisulfite, adding anhydrous ethanol to obtain soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and packaging.
Application example 3
The application example of the invention discloses an oral liquid taking a compound Fischer iabietane F as a raw material medicine, which comprises the following components:
Fischeriabietane F25.0 mg
sucrose 3.0 g
Sodium bisulfite 0.2 g
Methylparaben 0.2 g
Sodium bicarbonate 0.1 mL
1000mL of water for injection;
100 pieces are made.
The preparation process comprises the following steps:
mixing the above materials, and packaging by conventional method.
Application example 4
The invention discloses an injection taking a compound Fisheripamaranane A as a raw material medicine, which comprises the following components:
Fisheripimaarane A45.0 mg
vitamin C0.2 g
Sodium chloride 6.0 g
Sodium bicarbonate 0.1 mL
1000mL of water for injection;
100 pieces are made.
The preparation process comprises the following steps:
mixing the above materials, and making into 100 pills by conventional injection preparation method.
Application example 5
The application example of the invention discloses a tablet taking Fischer iabietane F and cyclophosphamide as raw material medicines, which comprises the following components:
Fischeriabietane F20.0 mg
cyclophosphamide 5 g
Hydroxypropyl methylcellulose 18 g
Talc powder 0.4 g
Lactose 0.2 g
Magnesium stearate 0.2 g
Absolute ethyl alcohol 0.1 mL;
100 pieces were prepared.
The preparation process comprises the following steps:
mixing Fischer iabietane F, cyclophosphamide, hydroxypropyl methylcellulose, talcum powder, lactose and magnesium stearate, adding anhydrous ethanol to obtain soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and tabletting.
Application example 6
The application example of the invention discloses a capsule taking Fisheripamaranane A and lenalidomide as raw material medicines, which comprises the following components:
Fisheripimaarane A18.0 mg
lenalidomide 2.0 g
Starch 6.0 g
Sodium metabisulfite 0.2 g
Magnesium stearate 0.2 g
Absolute ethyl alcohol 0.1 mL;
making into 100 granules.
The preparation process comprises the following steps:
mixing Fisheripamaarane A, lenalidomide, starch and sodium pyrosulfite, adding anhydrous ethanol to obtain soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and making into capsule.
Application example 7
The invention discloses an injection taking Fischer iabietane F and vinorelbine as raw material medicines, which comprises the following components:
Fischeriabietane F30.0 mg
vinorelbine 2.0 g
Vitamin C0.2 g
Sodium chloride 6.0 g
Sodium bicarbonate 0.1 mL
1000mL of water for injection;
100 pieces are made.
The preparation process comprises the following steps:
mixing the above materials, and making into 100 pills by conventional injection preparation method.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is specific and detailed, but not to be understood as limiting the scope of the invention.
It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (12)
1. A preparation method of a novel diterpenoid compound is characterized in that the novel diterpenoid compound is obtained by extracting and separating euphorbia stellera from euphorbia lathyris.
2. The preparation method of the novel diterpenoid compound according to claim 1, which comprises the following steps:
s1, taking the root of the dried euphorbia ebracteolata hance, adding a solvent for reflux extraction, combining extracting solutions and concentrating to obtain an extract;
s2, adding the extract into water with the mass of 8-15 times that of the extract for suspension, sequentially extracting with petroleum ether and dichloromethane, discarding the petroleum ether extract, subjecting the dichloromethane extract to silica gel column chromatography, eluting with petroleum ether-ethyl acetate, collecting fractions, detecting with a silica gel thin layer, combining similar fractions according to the spot Rf value and the vanillin sulfate color development result to sequentially obtain 8 fractions which are named as A, B, C, D, E, F, G, H and I respectively;
s3, subjecting the fraction D to ODS column chromatography, performing gradient elution by using methanol-water, collecting 60-70 fractions, performing silica gel thin layer chromatography, and combining the fractions into 6 fractions D1-D6; subjecting the fraction D3 to ODS column chromatography, performing gradient elution with methanol-water, collecting 30-40 fractions, detecting with silica gel thin layer chromatography, and combining into 4 fractions J1-J4;
subjecting the fraction C to silica gel column chromatography, performing gradient elution by using dichloromethane-methanol, collecting 50-60 fractions, performing silica gel thin layer chromatography, and combining the fractions into 5 fractions C1-C5;
s4, taking methanol-water as a mobile phase, adopting an HPLC method, and utilizing C 18 Preparing a abietane diterpenoid compound with a structural formula shown in the following formula (1) in the fraction J3 by using a chromatographic column;
（1）
or using methanol-water as mobile phase, and HPLC method using C 18 The chromatographic column produces a pimarane diterpenoid compound represented by the following formula (2) in fraction C5:
（2）。
3. the method for preparing diterpenoids according to claim 2, wherein, in step S4,
in a mobile phase used for separating the fraction J3 by an HPLC method, the volume ratio of methanol to water is (65) to (68) 32, and the retention time of the abietane-type diterpenoid compound represented by the formula (1) is 28-30 min;
or in a mobile phase used for separating the fraction C5 by an HPLC method, the volume ratio of methanol to water is (69).
4. The method for preparing diterpenoids according to claim 2, wherein, in step S3,
subjecting the fraction D to ODS column chromatography, eluting with a methanol-water gradient with a volume ratio of (30;
and/or subjecting fraction D3 to ODS chromatography, eluting with methanol-water gradient of (50) - (0);
and/or subjecting the fraction C to silica gel column chromatography, performing gradient elution by using dichloromethane-methanol at a volume ratio of (100.
5. The method for preparing novel diterpenoids according to claim 2, wherein in step S2, the dichloromethane extract is subjected to silica gel column chromatography, eluted with petroleum ether-ethyl acetate at a volume ratio of (100) - (0) to 50-60 fractions, collected and identified by silica gel thin layer chromatography, and combined to obtain fractions A, B, C, D, E, F, G, H and I in sequence;
and/or in the step S1, the solvent is 88-98V% ethanol water solution, 8-10 times of the euphorbia lantana is added, the reflux extraction frequency is 2-4 times, and the extraction time is 1-3h each time.
6. A novel diterpenoid compound is characterized in that,
the novel diterpenoid compound is a novel abietane diterpenoid compound with a structure shown in a formula (1);
（1）
or the novel diterpenoid compound is a novel pimarane diterpenoid compound with the structure shown in the formula (2);
（2）。
7. a pharmaceutical composition comprising the novel diterpenoid compound according to claim 6.
8. The pharmaceutical composition of claim 7, further comprising a pharmaceutically acceptable carrier or excipient.
9. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises a potentiating agent;
the synergist is any one or more of the following substances: hydroxycamptothecin, paclitaxel, vincristine, vindesine, vinorelbine, mitoxantrone, mechlorethamine, cyclophosphamide, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, capecitabine, raltitrexed, cytarabine, gemcitabine, methotrexate, pemetrexed, hydroxyurea, 6-mercaptopurine, doxorubicin, gemcitabine, C 1 -C 20 Acylamino gemcitabine, flutolterone, cladribine, fluorouracil, tegafur, carmofur, difurofluorouracil, doxifluridine, eicilabine, capecitabine, 5' -deoxy-5-fluorocytidine, 5' -deoxy-5-fluorouridine, 2' -deoxy-5-fluorouridine, aliskirineCytosine, cytidine, troxacitabine, sapatatinib, decitabine, bosutinib, tafitinib, E Luo Tini, dacomitinib, lenatinib, dovirtinib, pasatinib, panatinib, semetinib, cazatinib, ruxotinib, lu Zuoti ni, ai Leti ni, cabletinib, levatinib, ceritinib, afatinib, sunitinib, lapatinib, crizotinib, apatinib, erlotinib, ematinib, carnitinib, axitinib, bosutinib, nilotinib, gefitinib, dasatinib, sitagliptin, imatinib, 6-mercaptopurine, methotrexate, aminopterin, hydroxyurea, dialdehyde, adenosine, ibrutinib, trumetinib, runtitinib, azacitiib, cytarabine, lorantib, lolidine, loratabine, and Alfatin.
10. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is in the form of tablet, capsule, granule, oral liquid, granule, dripping pill or pellet.
11. The use of the novel diterpenoid compound according to claim 6 for the preparation of a medicament for preventing or treating liver cancer or breast cancer, wherein the novel diterpenoid compound is a abietane-type diterpenoid compound.
12. The use of a novel diterpenoid according to claim 6 for the preparation of a medicament for the prevention or treatment of breast cancer or leukemia, wherein the novel diterpenoid is a pimarane-type diterpenoid.
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