CN115677471A - Rose alkyl diterpenoid compound, preparation method, pharmaceutical composition and anti-tumor application - Google Patents
Rose alkyl diterpenoid compound, preparation method, pharmaceutical composition and anti-tumor application Download PDFInfo
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Abstract
The invention discloses a rose alkyl diterpenoid compound, a preparation method, a pharmaceutical composition and an anti-tumor application thereof, and particularly discloses four rose alkyl diterpenoid compounds which are extracted and separated from euphorbia ebracteolata and have the same diterpenoid parent nucleus, and an application of the compounds in preparing anti-tumor drugs. Research shows that the compounds, euphelactenin C, euphelactenin D, euphelactenin E and euphelactenin F have obvious inhibiting effect on liver cancer cell HepG2, breast cancer cell T47D and MCF-7 and non-small cell lung cancer cell A549, especially have obvious activity on breast cancer cell T47D, and the activity of the compounds is superior to that of positive medicine cis-platinum (cissplatin), and can be used for developing antitumor medicines.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a rosettane diterpenoid compound, and preparation, a pharmaceutical composition and antitumor application thereof, and particularly discloses four rosettane diterpenoid compounds, namely eupolyhectalose C, eupolyhectalose D, eupolyhectalose E and eupolyhectalose F, which are extracted and separated from euphorbia pekinensis and have the same diterpenoid nucleus, and application of the compounds in preparing antitumor drugs.
Background
Cancer is currently a continuing public health challenge facing worldwide in common, and as the second most common cause of death worldwide, cancer is expected to be the most major obstacle to the expected life-span growth of the population in the 21 st century. In recent decades, the most common cancers are lung cancer, liver cancer, stomach cancer, esophageal cancer and breast cancer, which pose serious threats to public health and have heavy economic burden.
At present, the main treatment means for cancer clinically comprises surgical resection, radiotherapy and chemical drug therapy; however, all have some limitations, such as high recurrence rate, drug tolerance and various adverse reactions, which can be called 'one thousand damage to enemy and eight hundred damage to itself'. Traditional Chinese medicine has a long history of treating cancer, and is a characteristic and advantage of preventing and treating major diseases in traditional Chinese medicine. The effective way is to search natural compounds with obvious anticancer activity and small side effect from Chinese traditional medicines.
Euphorbia radix is one of the sources of Chinese traditional medicine radix Euphorbiae Fischerianae, and is recorded in Shen nong's herbal Jing, which uses root as medicine, has pungent taste, mild nature, enters liver and spleen meridians, has the effects of expelling water and eliminating phlegm, removing accumulation and killing parasites, and is clinically used for treating malignant tumors such as breast cancer, liver cancer and the like. Modern researches show that Euphorbia pekinensis has the effects of resisting tumor, resisting inflammation and the like, wherein diterpenoid compounds have good anti-tumor effect. Therefore, the diterpenoid compounds with anti-tumor activity from the euphorbia pekinensis have important practical value.
Disclosure of Invention
Aiming at the defects in the prior art, the invention discloses a rosette diterpenoid compound, a preparation method, a pharmaceutical composition and an anti-tumor application thereof, and particularly discloses four rosette diterpenoid compounds, namely euheperactine C, euheperactine D, euheperactine E and euheperactine F which are extracted from Euphorbia ebracteata and have the same diterpenoid parent nucleus, and an application thereof in preparing an anti-tumor medicament.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a rose bengal diterpenoid compound has the following structures shown in formulas I, II, III and IV:
I II
III Ⅳ。
the invention also provides a preparation method of the rose alkyl diterpenoid compound, wherein the rose alkyl diterpenoid compound is extracted and separated from euphorbia pekinensis.
In the above technical scheme, the preparation method of the rose bengal diterpenoid compound comprises the following steps:
s1, adding a solvent into dried Euphorbia pekinensis, carrying out reflux extraction, combining extracting solutions, and concentrating to obtain an extract;
s2, adding the extract into water with the mass of 8-12 times of that of the extract for suspension, extracting with petroleum ether, dichloromethane and ethyl acetate respectively, discarding dichloromethane extract and ethyl acetate extract, subjecting the petroleum ether extract to silica gel column chromatography, eluting with petroleum ether-ethyl acetate, collecting fractions, detecting with silica gel thin layer chromatography, and mixing to obtain fractions A, B, C, D, E, F, G, H and I in sequence;
s3, subjecting the fraction B to silica gel column chromatography, performing gradient elution by using petroleum ether-ethyl acetate, collecting 8 fractions B1-B8, subjecting the fraction B6 to ODS column chromatography, performing gradient elution by using methanol-water, collecting 60-70 fractions, performing silica gel thin layer chromatography, merging the fractions into 10 fractions J1-J10, subjecting the fraction J5 to Sephadex LH-20 gel column chromatography, performing gradient elution by using dichloromethane-methanol, collecting 50-60 fractions, performing silica gel thin layer chromatography, and merging the fractions into 5 fractions K1-K5;
s4, taking methanol-water as a mobile phase, adopting an HPLC method, and utilizing C 18 Separating with chromatographic column to obtain fraction K3, collecting fraction C, separating with HPLC, and separating with acetonitrile-water as mobile phase 18 The chromatographic column is used for preparing the roseidine diterpenoid compound with the structural formula shown in the formula II in the fraction J6.
In a specific embodiment of the present invention, in step S4, in the mobile phase used in the HPLC separation of fraction K3, the volume ratio of methanol to water is (55) - (60) depending on the polarity of the compound, in combination with the separation degree, and the like, and the retention time of the rosettane diterpenoid compounds represented by the formulae I, III and iv is 37-38 min, 39-41 min and 42-45 min, respectively.
In a specific embodiment of the present invention, in step S4, in the mobile phase used in the HPLC separation of fraction J6, the volume ratio of acetonitrile to water is (45) - (50), and the retention time of the rosettane diterpenoid of formula II is 36-38 min.
In the embodiment of the present invention, in step S3, when fraction B is subjected to silica gel column chromatography, gradient elution is performed using petroleum ether-ethyl acetate at a volume ratio of (100.
In the embodiment of the present invention, in step S3, when fraction B6 is subjected to ODS column chromatography, gradient elution is performed using methanol-water in a volume ratio of (30.
In the embodiment of the present invention, in step S3, when fraction J5 is subjected to Sephadex LH-20 gel column chromatography, dichloromethane-methanol at a volume ratio of (100.
In the embodiment of the present invention, in step S2, when the petroleum ether extract is subjected to silica gel column chromatography, elution is performed using petroleum ether-ethyl acetate in a volume ratio of (100.
In a specific embodiment of the present invention, in step S1, the solvent is 88-98 v% ethanol aqueous solution, and 8-10 times of Euphorbia radix by mass is added thereto, and the reflux extraction is performed for 2-3 times, each for 1-3 hours.
The invention also provides a pharmaceutical composition containing the rose benane diterpenoid.
Specifically, in the above technical scheme, the dosage form of the pharmaceutical composition is tablet, capsule, granule, oral liquid, syrup, paste, granule, dripping pill or pellet.
Specifically, in the above technical solution, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient. That is, pharmaceutical compositions containing the rose-bengal diterpenes of the present invention as an active ingredient and conventional pharmaceutical excipients or adjuvants or carriers are also encompassed by the present invention.
The invention also provides the application of the rose alkyl diterpenoid compound or the pharmaceutical composition in preparing antitumor drugs.
Compared with the prior art, the invention has the following advantages:
(1) The invention provides a rose alkyl diterpenoid compound which is not reported at present, and further provides a method for extracting the rose alkyl diterpenoid compound from euphorbia pekinensis, which has the advantages of simple and feasible operation, good reproducibility and high extraction purity;
(2) Test results show that the rose alkyl diterpenoid provided by the invention has obvious killing effect on breast cancer cells T47D and MCF-7, liver cancer cells HepG2 and non-small cell lung cancer cells A549, especially has obvious activity on the breast cancer cells T47D, and can be used for developing anti-tumor medicaments, especially medicaments for clinical chemotherapy stages.
Drawings
FIG. 1 is a HR-ESI-MS spectrum of Compound 1 prepared in example 1 of the present invention;
FIG. 2 shows the preparation of Compound 1 according to example 1 of the present invention 1 H NMR Spectroscopy (600MHz, CDCl) 3 ）；
FIG. 3 shows Compound 1 obtained in example 1 of the present invention 13 C NMR spectra (150MHz, CDCl) 3 ）；
FIG. 4 is an HMBC spectrum of compound 1 prepared in example 1 of the present invention;
FIG. 5 is a NOESY spectrum of Compound 1 obtained in example 1 of the present invention;
FIG. 6 is a HR-ESI-MS spectrum of Compound 2, prepared in example 1 of the present invention;
FIG. 7 shows the preparation of Compound 2 according to example 1 1 H NMR Spectroscopy (600MHz, CDCl) 3 ）；
FIG. 8 shows Compound 2 obtained in example 1 of the present invention 13 C NMR spectra (150 MHz, CDCl) 3 ）；
FIG. 9 shows HMBC spectra of compound 2 prepared in example 1 of the present invention;
FIG. 10 shows the NOESY spectrum of Compound 2 obtained in example 1 of the present invention;
FIG. 11 is an HR-ESI-MS spectrum of Compound 3 prepared in example 1 of the present invention;
FIG. 12 shows Compound 3 prepared in example 1 of the present invention 1 H NMR Spectrum (600MHz, CDCl) 3 ）；
FIG. 13 shows Compound 3 prepared in example 1 of the present invention 13 C NMR spectra (150 MHz, CDCl) 3 ）；
FIG. 14 shows HMBC spectra of compound 3 prepared in example 1 of the present invention;
FIG. 15 is a NOESY spectrum of Compound 3 obtained in example 1 of the present invention;
FIG. 16 is a HR-ESI-MS spectrum of Compound 4 prepared in example 1 of the present invention;
FIG. 17 shows the preparation of Compound 4 according to example 1 1 H NMR Spectrum (500MHz, CDCl) 3 ）；
FIG. 18 shows Compound 4 prepared in example 1 of the present invention 13 C NMR spectra (125 MHz, CDCl) 3 ）；
FIG. 19 shows an HMBC spectrum of compound 4 prepared in example 1 of the present invention;
FIG. 20 shows the NOESY spectrum of Compound 4 obtained in example 1 of the present invention.
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 do not 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 numerical ranges, each range between its endpoints and individual point values, and each individual point value can be combined with each other to give one or more new numerical ranges, and such numerical ranges should be construed as specifically disclosed herein.
In addition, the technical features involved in the respective 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 a rose benane diterpenoid compound comprises the following steps:
s1, weighing 67 Kg of dried Euphorbia pekinensis, adding 95 v% ethanol aqueous solution which is 10 times (670 Kg) of the Euphorbia pekinensis in mass as a solvent, performing reflux extraction for 3 times, extracting for 2 hours each time, combining the extracting solutions, and concentrating to obtain 6.47 Kg of extract;
s2, adding the extract (6.47 Kg) into water (64.7 Kg) with the mass being 10 times that of the extract to be suspended, respectively extracting with petroleum ether, dichloromethane and ethyl acetate with the volume being 1.5 times that of the suspension twice, respectively, obtaining 1500G of petroleum ether extract, 250G of ethyl acetate extract (waste) and 520G of dichloromethane extract (waste), subjecting the petroleum ether extract to silica gel column chromatography, eluting with petroleum ether-ethyl acetate with the volume ratios 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 fractions per 500 mL, detecting and combining fractions A, B, C, D, E, F, G, H and I in sequence, and collecting 50 fractions by silica gel thin layer chromatography;
s3, subjecting fraction B to silica gel column chromatography, gradient eluting with petroleum ether-ethyl acetate 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, and collecting 8 fractions B1-B8; subjecting fraction B6 to ODS column chromatography, gradient eluting with methanol-water at volume ratio of 30:70, 40: 60, 50:50, 60:40, 70: 30, 80: 20, 90: 10, and 100:0, collecting 68 fractions, detecting with silica gel thin layer chromatography, and mixing to obtain 10 fractions J1-J10; subjecting fraction J5 to Sephadex LH-20 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 55 fractions, detecting with silica gel thin layer chromatography, and mixing to obtain 5 fractions K1-K5;
s4, preparing the compound 1 (t R = 37-38 min）、3（t R = 39-41 min）、4（t R = 42-45 min), in a volume ratio of (45: 55) - (50: 50 Acetonitrile-water (most preferably 48: 52) as mobile phase in fraction J6 to obtain compound 2 (t) R = 36-38 min）。
Comparative example 1
Comparative example 1 of the present invention provides a process for the preparation of a rose bengal diterpenoid compound, which comprises steps similar to those of example 1 except that, in step S3, fraction B6 is subjected to ODS column chromatography using a solvent having a volume ratio of 15:85 of methanol-water.
As a result, it was not possible to prepare the compounds 1 to 4.
Comparative example 2
Comparative example 2 of the present invention provides a process for preparing a rose bengal diterpene compound, which is similar to example 1, except that in step S4, the ratio of methanol to water in the mobile phase used in the HPLC separation of fraction K3 was 35:65.
as a result, it was not possible to prepare the compounds 1 to 4.
Example 2
The embodiment of the invention provides physical properties and detection data of the compound 1 prepared in the embodiment 1, and the physical properties and the detection data are as follows:
white powder, easily soluble in chloroform and methanol;
+105.13 (c 0.10，MeOH)。
in the UV spectrum (not shown), λ max = 204nm (MeOH), suggesting a characteristic absorption of a rose benne diterpenoid; in the IR spectrum (not shown), 3442 cm -1 Indicating that the structure contains hydroxyl groups, 1595 cm -1 Suggesting that the structure contains a carbon-carbon double bond; according to high resolution mass spectrum (HR-ESI-MS, FIG. 1)m/z 303.2311[M+H] + (calculated 303.2319), the molecular weight was estimated to be 302, binding 1 H-NMR (FIG. 2), 13 C-NMR spectrum (FIG. 3), and the molecular formula was confirmed to be C 20 H 30 O 2 The unsaturation was calculated to be 6.
1 H NMR (600 MHz, CDCl 3 ) The spectrum (FIG. 2) shows that the region in the low field contains 4 alkene hydrogen signalsδ H 5.84 (1H, dd, J = 17.5, 10.8 Hz), 5.59 (1H, dt, J = 5.3, 2.5 Hz), 4.99 (1H, dd, J = 17.5, 1.2 Hz), 4.90 (1H, dd, J = 10.8, 1.2 Hz)](ii) a 4 single-peak methyl signals exist in the high field regionδ H 1.04, 0.96, 0.87，0.74 (each 3H, s)]。
13 C NMR (150 MHz, CDCl 3 ) The spectra (FIG. 3) show a total of 20 carbon signals, including 4 methyl carbon signals: (δ C 23.9, 23.0, 22.0, 13.1), 5 methylene carbon signals: (δ C 37.3, 35.4, 32.4, 32.0, 31.1), 2 methine carbon signals: (δ C 48.5, 43.1), 1 vicinal oxygen carbon signal(s) ((ii)δ C 74.6 4 signals of olefinic hydrogen and carbon: (δ C 150.3, 145.4 118.2, 109.7), 1 carbonyl carbon signal: (δ C 213.5 And 3 remaining quaternary carbon signals: (A)δ C 37.8, 35.6, 36.9)。
1 H NMR、 13 The signals of C NMR are shown in the following table.
| Position | δH (multi, J in Hz) | δC | Position | δH (multi, J in Hz) | |
| 1 | 5.59 (dt, J = 5.3, 2.5) | 118.2 | 11 | 1.69 (dd, J = 13.6, 3.9) 1.77 (ddd, J = 13.6, 4.2, 3.0) | 35.4 |
| 2 | 2.00 (m) 2.40 (dtd, J = 17.3, 5.3, 2.5) | 32.0 | 12 | 1.31 (m) 1.49 (dd, J = 13.6, 4.2) | 32.4 |
| 3 | 3.60 (dd, J =10.4, 6.0) | 74.6 | 13 | 35.6 | |
| 4 | 36.9 | 14 | 1.43 (m) 1.61 (dd, J = 3.6, 2.6) | 31.1 | |
| 5 | 2.59 (d, J =3.7) | 43.1 | 15 | 5.84 (dd, J = 17.5, 10.8) | 150.3 |
| 6 | 2.16 (dd, J = 18.8, 13.8) 2.53 (dd, J = 18.8, 4.9) | 37.3 | 16 | 4.90 (dd, J = 10.8, 1.2) 4.99 (dd, J = 17.5, 1.2) | 109.7 |
| 7 | 213.5 | 17 | 0.96 (s) | 22.0 | |
| 8 | 2.61 (d, J = 3.6 Hz) | 48.5 | 18 | 1.04 (s) | 23.9 |
| 9 | 37.8 | 19 | 0.74 (s) | 13.1 | |
| 10 | 145.4 | 20 | 0.87 (s) | 23.0 |
Bonding of 1 H NMR and 13 c NMR spectrum, presuming that Compound 1 may contain 1 carbonyl, 2 pairs of double bonds, presuming that the remaining 3 unsaturations are occupied by 3 rings, and, in addition, may contain 1 carbon signal attached to oxygen and 4 methyl groups; in combination with the above information, it is presumed that the compound 1 may be a rose bengal diterpene compound.
In the HMBC spectrum (figure 4), H-5 (can be observed: (δ H 2.59), H-6 (δ H 2.16, 2.53), H-8 (δ H 2.61), H-14 (δ H 1.43 And C-7 (δ C 213.5 Correlation between) and presuming the carbonyl is at the C-7 position; furthermore, H 3 -17 (δ H 0.96 And C-12 (δ C 32.4)、C-13 (δ C 35.6)、C-14 (δ C 31.1)、C-15 (δ C 150.3 Remote correlation between H, H 3 -18 (δ H 1.04 And C-3 (δ C 74.6)、C-4 (δ C 36.9)、C-5 (δ C 43.1)、C-19 (δ C 13.1 A remote correlation between the two or more remote correlations,H 3 -19 (δ H 0.74 And C-3 (δ C 74.6)、C-4 (δ C 36.9)、C-5 (δ C 43.1)、C-18 (δ C 23.9 Remote correlation between H, H 3 -20 (δ H 0.87 And C-8 (δ C 48.5)、C-9 (δ C 37.8)、C-10 (δ C 145.4)、C-11 (δ C 35.4 Remote correlation between the two groups, it is presumed that the methyl groups are at the C-17, C-18, C-19 and C-20 positions, respectively, in the structure.
In the NOESY spectra (figure 5), H-3 (δ H 3.60 And H-5 (δ H 2.59)、H-8 (δ H 2.61)、H 3 -18 (δ H 1.04 Has NOE correlation, H-8: (δ H 2.61 And H) 3 -17 (δ H 0.96 Have NOE correlation, thus determining the relative configuration of the compounds, i.e., H-3, H-5, H-8, H 3 -18 is in the alpha configuration towards one plane, 3-OH, H-15, H 3 -19 and H 3 -20 in the other plane, in the β configuration.
In summary, the structure of compound 1 (euphelacteolatin C) was determined as follows:
example 3
The embodiment of the invention provides physical properties and detection data of the compound 2 prepared in the embodiment 1, which are as follows:
white powder, which is easily soluble in chloroform and methanol;
+13.99 (c0.10,MeOH)。
in the UV spectrum (not shown), λ max = 203 nm (MeOH) suggesting a characteristic absorption of rose benne diterpenoids; in the IR spectrum (not shown), 3442 cm -1 Indicating that the structure contains hydroxyl groups at 1595 cm -1 Suggesting that the structure contains a carbon-carbon double bond; according to high resolution mass spectrometry (HR)ESI-MS, FIG. 6)m/z269.1893[M+H-H 2 O] + (calculated 269.1900) molecular weight was estimated to be 286, binding 1 H-NMR (FIG. 7), 13 C-NMR spectrum (FIG. 8), and it was confirmed that the molecular formula was C 19 H 26 O 2 The unsaturation degree was calculated to be 7.
1 H NMR (600 MHz, CDCl 3 ) The spectrum (FIG. 7) shows that 5 alkene hydrogen signals are present in the low field regionδ H : 7.08 (1H, d, J = 8.3 Hz), 6.65 (1H, d, J = 8.3 Hz), 5.87 (1H, dd, J = 17.5, 10.7 Hz), 4.97 (1H, dd, J = 17.5, 1.3 Hz), 4.90 (1H, dd, J = 10.7, 1.3 Hz)](ii) a There are two hydrogen signals associated with oxygenδ H : 3.78 (1H, d, J = 11.0 Hz), 3.63 (1H, d, J = 11.0 Hz)](ii) a The high field region contains 2 single-peak methyl hydrogen signalsδ H 2.13, 1.04 (each 3H, s)]。
13 C NMR (150MHz, CDCl 3 ) The spectrum (FIG. 8) shows a total of 19 carbon signals, including 2 methyl carbon signals: (δ C 22.9, 11.3), 5 methylene carbon signals (δ C 39.9, 32.7, 28.5, 27.1, 25.4), 1 methine carbon signal: (δ C 36.0 1 oxygen carbon linkage signal: (δ C 63.6 8 signals of olefinic hydrogen and carbon: (δ C 152.1, 150.9, 137.3, 135.1, 123.9, 122.9, 112.3, 109.3), and 2 quaternary carbon signals ((ii) ((iii))δ C 40.9, 36.5)。
1 H NMR、 13 The signals of C NMR are shown in the following table.
| Position | δH (multi, J in Hz) | δC | Position | δH (multi, J in Hz) | |
| 1 | 7.08 (d, J = 8.3) | 123.9 | 11 | 1.46 (dd, J = 13.6, 3.9) 2.42 (m) | 28.5 |
| 2 | 6.65 (d, J = 8.3) | 112.3 | 12 | 1.42 (d, J = 3.3) 1.65 (d, J = 4.0) | 32.7 |
| 3 | 152.1 | 13 | 36.5 | ||
| 4 | 122.9 | 14 | 1.28 (m) 1.53 (t, J = 13.3) | 39.9 | |
| 5 | 137.3 | 15 | 5.87 (dd, J = 17.5, 10.7) | 150.9 | |
| 6 | 2.77 (m) | 27.1 | 16 | 4.90 (dd, J = 10.7, 1.3) 4.97 (dd, J = 17.5, 1.3) | 109.3 |
| 7 | 1.62 (m) 1.83 (ddt, J = 13.3, 9.9, 6.6) | 25.4 | 17 | 1.04 (s) | 22.9 |
| 8 | 1.92 (tt, J = 13.3, 3.4) | 36.0 | 19 | 2.13 (s) | 11.3 |
| 9 | 40.9 | 20 | 3.63 (d, J = 11.0) 3.78 (d, J = 11.0) | 63.6 | |
| 10 | 135.1 |
Bonding with 1 H NMR and 13 c NMR spectrum, presuming that compound 2 may contain 1 benzene ring and 1 pair of terminal double bonds, presuming that the remaining 2 unsaturations are occupied by 2 rings; the compound 2 is presumed to be an aromatic rose alkyl diterpene compound by combining the spectrogram data.
In HMBC spectra (FIG. 9), H can be observed 2 -20 (δ H 3.78, 3.63) and C-8 (C: (C-C)δ C 36.0)、 C-9 (δ C 40.9)、C-10 (δ C 135.1)、C-11 (δ C 28.5 Remote correlation of) demonstrated that the hydroxyl group is attached to the C-20 position; furthermore, H-15 (δ H 5.87 And C-12 (δ C 32.7)、C-13 (δ C 36.5)、C-14 (δ C 39.9)、C-17 (δ C 22.9 Remote correlation of H), H 2 -16 (δ H 4.90 4.97) and C-13 (δ C 36.5)、C-15 (δ C 150.9 Remote correlation of) confirms the presence of a double bond between C-15 and C-16; h 3 -17 (δ H 1.04 And C-12 (δ C 32.7)、C-13 (δ C 36.5)、C-14 (δ C 39.9)、C-15 (δ C 150.9 Remote correlation of H), H 3 -19 (δ H 2.13 And C-3 (δ C 152.1)、C-4 (δ C 122.9)、C-5 (δ C 137.3 Remote correlation of the C-17 and C-19 methyl groups.
In the NOESY spectrum (FIG. 10), H-8 (C; (B;)δ H 1.92 ) and H 3 -17 (δ H 1.04 Has NOE correlation, H-15 (δ H 5.87 ) and H 2 -10 (δ H 3.63, 3.78) have NOE correlation; thus, the relative configuration of Compound 2, i.e., H-8 and H, was determined 3 17 are oriented in the same plane and are in the alpha configuration, H-15 and H 2 -20 towards the other plane, in β configuration.
In summary, the structure of compound 2 (euphelacteolatin D) was determined as follows:
example 4
The embodiment of the invention provides the physical properties and detection data of the compound 3 prepared in the embodiment 1, which are as follows:
white powder, which is easily soluble in chloroform and methanol;
+27.58(c 0.10,MeOH)。
lambda in UV (MeOH) spectrum (not shown) max = 204nm indicates that the compound 3 is a diterpenoid compound, and the IR spectrum (not shown) is 3442 cm −1 Indicating that the structure contains hydroxyl groups, 1595 cm −1 Suggesting that the structure contains a carbon-carbon double bond. According to high resolution mass spectrometry (HR-ESI-MS, FIG. 11)m/z269.1893 [M+H-H 2 O] + (calculated 269.1900), the molecular weight was estimated to be 286, and the molecular formula was determined to be C 19 H 26 O 2 The unsaturation degree was calculated to be 7.
1 H NMR (600 MHz, CDCl 3 ) The spectrum (FIG. 12) shows that 5 olefin hydrogen signals are present in the low field regionδ H : 7.08 (1H, d, J = 8.5 Hz), 6.67 (1H, d, J = 8.5 Hz), 5.92 (1H, dd, J = 17.5, 10.7 Hz), 5.02 (1H, dd, J = 17.5, 1.3 Hz), 4.93 (1H, dd, J = 10.7, 1.3 Hz)](ii) a There are 1 hydrogen signal [ alpha ] linked to oxygenδ H : 4.16 (1H, m)](ii) a The high field region has 3 methyl signalsδ H : 2.14 (3H, s), 1.26 (3H, s), 1.03 (3H, s)]。
13 C NMR (150MHz, CDCl 3 ) The spectrum (FIG. 13) shows a total of 19 carbon signals, including 3 methyl carbon signals: (δ C 24.1, 22.9, 11.5), 4 methylene carbon signals: (δ C 36.9, 36.7, 36.3, 33.0), 1 methine carbon signal: (δ C 40.2 1, oxygen-carbon linkage signal: (1)δ C 71.0 8 signals of olefinic hydrogen and carbon: (a)δ C 151.4, 150.9, 139.9, 132.7, 122.9, 122.1, 113.1, 109.4), and 2 quaternary carbon signals ((ii) ((iii))δ C 36.0, 36.0)。。
1 H NMR、 13 The signals of C NMR are shown in the following table.
| Position | δH (multi, J in Hz) | δC | Position | δH (multi, J in Hz) | |
| 1 | 7.08 (d, J = 8.5) | 122.9 | 11 | 1.62 (d, J = 3.5) 1.99 (dt, J = 12.8, 3.5) | 36.3 |
| 2 | 6.67 (d, J = 8.5) | 113.1 | 12 | 1.40 (m) 1.74 (d, J = 3.9) | 33.0 |
| 3 | 151.4 | 13 | 36.0 | ||
| 4 | 122.1 | 14 | 1.23 (s) 1.94 (d, J = 13.2) | 36.7 | |
| 5 | 132.7 | 15 | 5.92 (dd, J = 17.5, 10.7) | 150.9 | |
| 6 | 2.85 (d, J = 18.2) 3.15 (dd, J = 18.2, 6.6) | 36.9 | 16 | 4.93 (dd, J = 10.7, 1.3) 5.02 (dd, J = 17.5, 1.3) | 109.4 |
| 7 | 4.16 (m) | 71.0 | 17 | 1.03 (s) | 22.9 |
| 8 | 1.81 (dt, J = 13.5, 2.7) | 40.2 | 19 | 2.14 (s) | 11.5 |
| 9 | 36.0 | 20 | 1.26 (s) | 24.1 | |
| 10 | 139.9 |
Bonding of 1 H NMR and 13 c NMR spectrum, presuming that the compound 3 may contain 1 benzene ring and 1 pair of terminal double bonds, presuming that the remaining 2 unsaturations are occupied by 2 rings; the compound 3 is presumed to be an aromatic roseidine diterpene compound by combining the spectrum data.
In the HMBC spectrum (figure 14), H-7 (can be observed)δ H 4.16 And C-5 (δ C 132.7)、C-8 (δ C 40.2)、C-11 (δ C 36.3 Remote correlation of) demonstrated that the hydroxyl group is attached to the C-7 position; further, H 3 -17 (δ H 1.03 And C-12 (δ C 33.0)、C-14 (δ C 36.7)、C-15 (δ C 150.9 Remote correlation of H), H 3 -19 (δ H 2.14 And C-3 (δ C 151.4)、C-4 (δ C 122.1)、C-5 (δ C 132.7 Remote correlation of H), H 3 -20 (δ H 1.26 And C-8 (δ C 40.2)、C-10 (δ C 139.9)、C-11 (δ C 36.3 Remote correlation of) confirmed the presence of methyl groups at C-17, C-19 and C-20.
In the NOESY spectra (figure 15), H-8 (δ H 3.38 And H-7 (δ H 4.16)、H 3 -17 (δ H 1.08 Has NOE correlation, H-15 (δ H 5.92 And H) 3 -20 (δ H 1.26 Have NOE correlation; thus, the relative configuration of compound 3 is determined, with the hydrogen at position 7, the hydrogen at position 8, and the methyl at position 17 being in the same plane, substituted α, and the hydrogen at position 15 and the methyl at position 17 being in the other plane, substituted β.
In summary, the structure of compound 3 (euphelacteolatin E) was determined as follows:
example 5
The embodiment of the invention provides physical properties and detection data of the compound 4 prepared in the embodiment 1, which are as follows:
white powder, easily soluble in chloroform and methanol;
-69.98(c 0.10,MeOH)。
λ in UV (MeOH) spectrum (not shown) max = 206nm indicates that the compound 4 is a diterpenoid compound, and the IR spectrum (not shown) is 3442 cm −1 Suggesting that the structure contains a hydroxyl group. According to high resolution mass spectrometry (HR-ESI-MS, FIG. 16)m/z269.1892 [M+H-H 2 O] + (calculated 269.1900), the molecular weight was estimated to be 286, and the molecular formula was determined to be C 19 H 26 O 2 The unsaturation degree was calculated to be 7.
1 H NMR (500 MHz, CDCl 3 ) The spectrum (FIG. 17) shows that 5 alkene hydrogen signals are present in the low field regionδ H 7.09 (1H, d, J = 8.5 Hz), 6.75 (1H, d, J = 8.5 Hz), 5.88 (1H, dd, J = 17.5, 10.7 Hz), 4.98 (1H, dd, J = 17.5, 1.3 Hz), 4.90 (1H, dd, J = 10.7, 1.3 Hz)](ii) a There are 1 hydrogen signals associated with oxygenδ H 4.93 (1H, dd, J = 4.3, 1.7 Hz)](ii) a The high field region has 3 methyl signalsδ H 2.34, 1.08, 0.96 (each 3H, s)]。
13 C NMR (125 MHz, CDCl 3 ) The spectrum (FIG. 18) shows a total of 19 carbon signals, including 3 methyl carbon signals: (δ C 23.2, 21.2, 11.3), 4 methylene carbon signals: (δ C 39.2, 35.4, 33.9, 33.1), 1 methine carbon signal: (δ C 31.1 1 oxygen carbon linkage signal: (δ C 65.4 8 signals of olefinic hydrogen and carbon: (δ C 152.2, 151.1, 141.1, 136.0, 123.7, 123.4, 115.3, 109.1), and 2 quaternary carbon signals (b: (b)δ C 37.2, 36.7)。
1 H NMR、 13 C NMR informationThe number assignments are shown in the following table.
| Position | δH (multi, J in Hz) | δC | Position | δH (multi, J in Hz) | |
| 1 | 7.089 (d, J = 8.5) | 123.4 | 11 | 1.65 (m) 2.06 (d, J = 12.6) | 33.9 |
| 2 | 6.75 (d, J = 8.5) | 115.3 | 12 | 1.72 (d, J = 3.9) 1.42 (dd, J = 13.2, 2.9) | 33.1 |
| 3 | 152.2 | 13 | 36.7 | ||
| 4 | 123.7 | 14 | 1.22 (m) 1.51 (d, J = 13.2) | 39.2 | |
| 5 | 136.0 | 15 | 5.88 (dd, J = 17.5, 10.7) | 151.1 | |
| 6 | 4.93 (dd, J = 4.3, 1.7) | 65.4 | 16 | 4.90 (dd, J = 10.7, 1.3) 4.98 (dd, J = 17.5, 1.3) | 109.1 |
| 7 | 1.69 (t, J = 2.2) 1.92 (td, J = 13.7, 4.3) | 35.4 | 17 | 1.08 (s) | 23.2 |
| 8 | 2.17 (m) | 31.1 | 19 | 2.34 (s) | 11.3 |
| 9 | 37.2 | 20 | 0.96 (s) | 21.2 | |
| 10 | 141.1 |
Bonding of 1 H NMR and 13 c NMR spectrum, presume that this compound 4 may contain 1 benzene ring and 1 to terminal double bond, presume that the remaining 2 unsaturations are occupied by 2 rings; the compound 4 is presumed to be an aromatic rose alkyl diterpene compound by combining the spectrogram data.
In HMBC spectra (FIG. 19), H-6 (C.) (δ H 4.93 And C-4 (δ C 123.7)、C-5 (δ C 136.0)、C-10 (δ C 141.1 Long range correlation of) demonstrated that the hydroxyl group is attached to the C-6 position; furthermore, H 3 -17 (δ H 1.08 And C-12 (δ C 33.1)、C-14 (δ C 39.2)、C-15 (δ C 151.1 Remote correlation of H), H 3 -19 (δ H 2.34 And C-3 (δ C 152.2)、C-4 (δ C 123.7)、C-5 (δ C 136.0 Remote correlation of H), H 3 -20 (δ H 0.96 And C-8 (δ C 31.1)、C-9 (δ C 37.2)、C-10 (δ C 141.1 Remote correlation of C-17, C-19 and C-20 methyl groups.
In the NOESY spectrum (FIG. 20), H-15 (δ H 5.88 And H-6 (δ H 4.93)、H 3 -20 (δ H 0.96 Has NOE correlation, H-8: (δ H 5.92 And H) 3 -17 (δ H 1.08 Have NOE correlation; thus, the relative configuration of compound 4 is determined, with hydrogen at position 6, hydrogen at position 15 and methyl at position 20 in the same plane, being substituted at the alpha position, and with the hydroxyl at position 6, hydrogen at position 8 and methyl at position 17 in another plane, being substituted at the beta position.
In summary, the structure of compound 4 (euphelacteolatin F) was determined as follows:
test examples
This test example discloses the antitumor activity tests of compounds 1 to 4 (euphe-berletin C, euphe-berletin D, euphe-berletin E and euphe-berletin F).
1. Experimental materials and instruments
A test article: compound 1 (euphe berctaretin C), compound 2 (euphe berctaretin D), compound 3 (euphe berctaretin E) and compound 4 (euphe berctaretin F) obtained in example 1;
experimental cell lines and sources: liver cancer cell HepG2, breast cancer cell MCF-7 and non-small cell lung cancer cell A549 were purchased from the cell dictionary of Chinese academy of sciences (Shanghai).
2. Experimental methods
2.1 drug treatment
Dissolving compounds of euphe rhatolatin C, euphe rhatolatin D, euphe rhatolatin E and euphe rhatolatin F in DMSO to prepare a mother solution with the concentration of 0.01M, and storing the mother solution at-20 ℃; the test is carried out by diluting the extract into 200, 100, 50, 25, 12.5, 6.25 and 3.125 mu M at the moment of use.
Selecting Cisplatin (Cisplatin) as a positive control drug, and preparing a solution with a corresponding concentration according to the administration group by the method; meanwhile, a DMSO control group and a blank group containing no cells were set.
2.2 CCK-8 method of measurement
Taking cells in logarithmic growth phase, adjusting appropriate cell density, inoculating into 96-well plate, culturing at 37 deg.C and 5% CO in 100 μ L/well 2 The incubator of (1); after 24h of culture, the drug was diluted to five concentrations of 200, 100, 50, 25, 12.5, 6.25, 3.125. Mu.M, 100. Mu.L/well for 24h of action. A blank group and an administration group are respectively arranged, and each group is provided with 6 compound holes; adding 10 mu L of CCK-8 reagent in a dark place, and detecting the absorbance value (A) at 450 nm by using an enzyme-linked immunosorbent assay after 1.5 h; finally, the inhibition rate of each group of cells is calculated by taking the value of the blank group A as 100%.
Cell growth inhibition rate (%) = [ (a) Control of -A Sample(s) )/ (A Control -A Blank space )]×100%。
2.3 statistical methods
All data were examined and analyzed using SPSS (13.0) statistical software; data from each group are expressed as Mean ± standard error (Mean ± s.e.), global differences are assessed using One-Way ANOVA, and comparisons between groups are made using Dunnett or Dunnett's T3 test.
3. Results of the experiment
TABLE 1 IC of Compounds on tumor cells 50
The results in table 1 show that the compounds 1-4 (euphe-rhactin C, euphe-rhactin D, euphe-rhactin e and euphe-rhactin F) have better inhibitory effect on four cell strains after 24 hours of action, especially have obvious activity on breast cancer cell T47D, and the activity is better than that of the positive drug Cisplatin (cissplatin).
In conclusion, the rose alkyl diterpenoid compound has obvious inhibition effect on liver cancer cells HepG2, breast cancer cells T47D and MCF-7 and non-small cell lung cancer cells A549, and can be used for developing anti-tumor medicines, especially for clinical chemotherapy stage medicines.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed 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 (10)
1. A rose bengal diterpenoid compound is characterized in that,
has the structure shown in formulas I, II, III and IV:
I II
III Ⅳ。
2. the method for preparing the rose benane diterpene compound according to claim 1, wherein the rose bengal fruit extract is obtained by extracting the rose bengal fruit extract,
the rosenan diterpenoid compounds are extracted and separated from Euphorbia pekinensis.
3. The method for preparing a rosalkane-type diterpenoid compound according to claim 2,
the method comprises the following steps:
s1, adding a solvent into dried Euphorbia pekinensis, carrying out reflux extraction, combining extracting solutions, and concentrating to obtain an extract;
s2, adding the extract into water with the mass of 8-12 times that of the extract for suspension, respectively extracting with petroleum ether, dichloromethane and ethyl acetate, discarding dichloromethane extract and ethyl acetate extract, subjecting the petroleum ether extract to silica gel column chromatography, eluting with petroleum ether-ethyl acetate, collecting fractions, detecting and identifying by using silica gel thin layer chromatography, and combining to obtain fractions A, B, C, D, E, F, G, H and I in sequence;
s3, subjecting the fraction B to silica gel column chromatography, performing gradient elution by using petroleum ether-ethyl acetate, collecting 8 fractions B1-B8, subjecting the fraction B6 to ODS column chromatography, performing gradient elution by using methanol-water, collecting 60-70 fractions, performing silica gel thin-layer chromatography, merging the fractions into 10 fractions J1-J10, subjecting the fraction J5 to Sephadex LH-20 gel column chromatography, performing gradient elution by using dichloromethane-methanol, collecting 50-60 fractions, performing silica gel thin-layer chromatography, and merging the fractions into 5 fractions K1-K5;
s4, taking methanol-water as a mobile phase, adopting an HPLC method, and utilizing C 18 Separating with chromatographic column to obtain rosetane diterpene compounds with structural formulas shown as formula I, III and IV in fraction K3, and separating with acetonitrile-water as mobile phase by HPLC method using C 18 The chromatographic column is used for preparing the roseidine diterpenoid compound with the structural formula shown in the formula II in the fraction J6.
4. The method of preparing rosenan diterpenes according to claim 3, wherein the extract is a mixture of rosenan diterpenes,
in the step S4, the process is carried out,
in a mobile phase used for separating the fraction K3 by an HPLC method, the volume ratio of methanol to water is (55) - (60), and the retention time of the rosettane diterpenoid compounds shown in the structural formulas I, III and IV is respectively 37-38 min, 39-41 min and 42-45 min;
in the mobile phase used in HPLC separation of fraction J6, the volume ratio of acetonitrile to water is (45) - (55) and the retention time of the rosetane diterpene compound represented by the structural formula II is 36-38 min.
5. The method for preparing a rose bengal diterpenoid according to claim 3,
in the step S3, the process is carried out,
when fraction B was subjected to silica gel column chromatography, gradient elution was performed using petroleum ether-ethyl acetate at a volume ratio of (100) - (0;
subjecting fraction B6 to ODS column chromatography, gradient elution is performed using methanol-water in a volume ratio of (30;
when fraction J5 was subjected to Sephadex LH-20 gel column chromatography, dichloromethane-methanol was used in a volume ratio of (100.
6. The method for preparing a rose bengal diterpenoid according to claim 3,
in step S2, when the petroleum ether extract is subjected to silica gel column chromatography, petroleum ether-ethyl acetate is eluted using a volume ratio of (100;
in the step S1, the solvent is 88-98 v% of ethanol water, the added quantity of the solvent is 8-10 times of that of the Euphorbia radix, the reflux extraction frequency is 2-3, and each extraction time is 1-3 hours.
7. A pharmaceutical composition characterized by comprising, in combination,
contains the rose bengal diterpene compound according to claim 1.
8. The pharmaceutical composition of claim 7,
further comprises a pharmaceutically acceptable carrier or excipient.
9. The pharmaceutical composition of claim 7,
the dosage form of the pharmaceutical composition comprises any one of tablets, capsules, granules, oral liquid, syrup, paste, granules, dripping pills or pellets.
10. Use of a roseane diterpenoid according to claim 1 or a pharmaceutical composition according to any one of claims 7 to 9 for the preparation of an antitumor medicament.
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| CN109456149A (en) * | 2018-11-02 | 2019-03-12 | 大连医科大学 | Rose alkane type diterpene, preparation method containing aromatic group and preparing the application in antituberculotic |
| CN113336628A (en) * | 2021-04-16 | 2021-09-03 | 云南省中医中药研究院 | Diol rosalkane, preparation method and application thereof |
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| CN106866401A (en) * | 2016-12-23 | 2017-06-20 | 广州中大南沙科技创新产业园有限公司 | A kind of iron crab apple extract and preparation method thereof and the application in preventing and treating EBV virus infective medicaments are prepared |
| CN109456149A (en) * | 2018-11-02 | 2019-03-12 | 大连医科大学 | Rose alkane type diterpene, preparation method containing aromatic group and preparing the application in antituberculotic |
| CN113336628A (en) * | 2021-04-16 | 2021-09-03 | 云南省中医中药研究院 | Diol rosalkane, preparation method and application thereof |
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| LIU,ZG等: "Anti-inflammatory Diterpenoids from the Roots of Euphorbia ebracteolata" * |
| XINZHU KUANG等: "Euphorins A-H: bioactive diterpenoids from Euphorbia fischeriana" * |
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