CN108948108B - Compound separated from oldenlandia diffusa - Google Patents
Compound separated from oldenlandia diffusa Download PDFInfo
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- CN108948108B CN108948108B CN201811026624.5A CN201811026624A CN108948108B CN 108948108 B CN108948108 B CN 108948108B CN 201811026624 A CN201811026624 A CN 201811026624A CN 108948108 B CN108948108 B CN 108948108B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
- C07H1/08—Separation; Purification from natural products
Abstract
The invention relates to the field of natural compound separation, in particular to a novel compound separated from oldenlandia diffusa. The invention discloses a compound diffusoside D extracted and separated from oldenlandia diffusa water and application thereof in preparing anti-endometritis medicaments. The invention carries out system separation aiming at the elution part of 30 percent ethanol in the water extract of the oldenlandia diffusa, comprehensively uses the separation technologies such as silica gel column chromatography, MCI gel column, Sephadex LH-20 gel column chromatography, ODS medium pressure liquid chromatography and reversed phase semi-preparative HPLC, obtains a novel compound diffusoside D in the separation process, and finds that the compound diffusoside D has good activity of resisting endometritis in the research process, and has important research significance when being applied to the preparation of medicines for resisting endometritis.
Description
Technical Field
The invention relates to the field of natural compounds, in particular to a novel compound separated from a hedyotis diffusa water extract and an endometritis treatment effect thereof.
Background
The development of lead compounds from traditional Chinese medicine extracts is a research means commonly used by technicians in the field, such as docetaxel, paclitaxel, vincristine, irinotecan and the like, and has a remarkable curative effect clinically. Oldenlandia diffusa is used as a common medicine of Chinese medicinal anticancer drugs, the antitumor effect of oldenlandia diffusa is basically verified, and oldenlandia diffusa injection which is already on the market is also used as an antitumor auxiliary medicine; the research on the chemical components and the pharmacological activity of the oldenlandia diffusa begins in the 60 s, and about 80 compounds with different structural types are isolated and identified so far, but the exact anti-tumor chemical components of the oldenlandia diffusa willd are still unclear, according to the literature reports, particularly from the aspects of the quantity, the structure, the biological activity and the like of the chemical components of the oldenlandia diffusa willd, the research contents of the chemical components and the pharmacological activity of the oldenlandia diffusa willd are more dispersed, the activity of crude extracts is more reported, the literature reports on the chemical components of 60% ethanol extraction positions are more. The Yue Jun Wei Master thesis only isolated and identified 5 compounds from the water-soluble part, which are sitosterol, deacetyl asperulosic acid, D-mannitol, p-coumaric acid, asperuloside respectively; no other reports of chemical components of the water extraction part of the oldenlandia are found, which are not mutually assisted with the traditional clinical application of the oldenlandia. In the aspect of pharmacological activity, the oldenlandia diffusa aqueous extract is reported to have anti-leukemia activity on WEHI-3 cell induced leukemia mice, can inhibit the proliferation of human liver cancer HepG2 cells, and enhances the effect of low-dose 5-fluorouracil on inhibiting cdk2-e2f1 signal pathways, thereby enhancing the anti-cancer activity of the oldenlandia diffusa aqueous extract. Ever-growing reports that the oldenlandia diffusa aqueous extract HD-1 can obviously inhibit the proliferation of HepG2 and HCT-116 cells in vitro and can inhibit the growth of sarcoma S180 of tumor-bearing mice in vivo. In addition, the oldenlandia water extract has obvious inhibition effect on the growth of leukemia K562 and CEM cells and has strong inhibition effect on the growth of multidrug resistant leukemia HL-60/ADR.
From the above results, it can be seen that the study of chemical components in oldenlandia diffusa confirms that monomer components having antitumor and antioxidant effects are of great significance for the development of novel compounds. In addition, the monomeric compounds in the oldenlandia diffusa can have different effects from those of the oldenlandia diffusa, the separation and the pharmacodynamic study of the monomeric components in the oldenlandia diffusa are less in the prior art, the separation of the compounds in the oldenlandia diffusa water extract is more blank, the separation and the activity identification of the monomeric substances in the oldenlandia diffusa water extract are developed, and the method has important significance for the development of active medicaments.
Disclosure of Invention
The invention performs systematic separation on the elution part of 30 percent ethanol in the water extract of the oldenlandia diffusa, and separates to obtain a novel compound diffusoside D. The structure of the compound is as follows:
aiming at the technical problems, the technical scheme of the invention is as follows:
the first invention of the invention provides a novel compound, namely diffusoside D, wherein the structural formula of the compound is as follows:
in a second aspect of the present invention, there is provided a method for isolating the above compound, comprising the steps of:
(1) extracting herba Hedyotidis Diffusae with water, subjecting the water extract to macroporous resin enrichment, eluting with water, 30% ethanol, 50% ethanol, and 95% ethanol, respectively, concentrating the eluate under reduced pressure, and vacuum drying to obtain 30% ethanol eluate A.
(2) And adding the 30% ethanol elution part A into an ethyl acetate-ethanol solvent system for gradient elution to sequentially obtain six parts A1-A6.
(3) The part A6 is subjected to MCI gel column chromatography to obtain five parts A6-1-A6-5.
(4) Eluting the A6-5 part with Sephadex LH-50 column chromatography to obtain three parts, A6-5-1, A6-5-2, and A6-5-3.
(5) And sequentially carrying out ODS medium-pressure preparation liquid phase and semi-preparation high-performance liquid phase separation on the part A6-5-3 to obtain a compound ① - ⑧, wherein the compound ③ is diffusoside D.
Preferably, the oldenlandia diffusa is added into purified water for reflux extraction for 1-3 times in the step (1), the oldenlandia diffusa is concentrated under reduced pressure and then passes through a D101 type macroporous resin column, elution is respectively carried out by water, 30% ethanol, 50% ethanol and 95% ethanol, the eluent is concentrated under reduced pressure, and vacuum drying is carried out to obtain the 30% ethanol elution part A.
More preferably, the oldenlandia diffusa is extracted twice with water, the first time is 2 hours, the second time is 1 hour, and the extracting solutions are combined and concentrated under reduced pressure until the amount of the oldenlandia diffusa is five times.
Preferably, in the step (2), the 30% ethanol elution part A is subjected to gradient elution by an ethyl acetate-ethanol system, and when the volume ratio of ethyl acetate to ethanol is 1:1, the part A6 is obtained.
Preferably, the part A6 is subjected to MCI gel column chromatography, and is eluted by a 5-10% acetonitrile-water gradient to sequentially obtain five parts A6-1-A6-5.
Preferably, the A6-5 part is eluted by Sephadex LH-50 column chromatography to obtain three parts, namely A6-5-1, A6-5-2 and A6-5-3, wherein the mobile phase is 50% methanol.
Preferably, part A6-5-3 is separated into ① - ⑧ by ODS medium pressure preparative liquid phase with elution procedure of 10-40% methanol, semi-preparative high performance liquid phase with mobile phase of 7% acetonitrile-water, and chromatographic column YMC-Pack ODS-A semi-preparative column (5 μm, 250 × 10mmI.D.) sequentially.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising compound diffusoside D and a further anti-endometritis agent.
In a fourth aspect of the invention, a pharmaceutical preparation is provided, which is prepared from compound diffusoside D and pharmaceutically acceptable excipients; preferably, compound diffusoside D is administered at a dose of 10-50 mg/kg.
In the fifth aspect of the invention, the compound diffusoside D, the pharmaceutical composition and the pharmaceutical preparation are applied to the preparation of the anti-endometritis drug.
The invention has the advantages of
The invention provides a novel compound diffusoside D separated from a water extract of oldenlandia diffusa, wherein the compound has the activity of resisting endometritis, and the treatment dose is 10-50 mg/kg. The research on diffusoside D provides a new research direction for the development of the oldenlandia diffusa monomer compound.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application.
FIG. 1 is a flow chart of a method for isolating diffusoside D;
FIG. 2 shows signal peak assignment for compound diffusoside D;
FIG. 3 is a 13CNMR spectrum (DMSO-D6) of compound diffusoside D;
FIG. 41 HNMR spectrum of compound diffusoside D (DMSO-D6);
FIG. 5 HSQC spectrum of compound diffusoside D (DMSO-D6);
FIG. 6 HMBC spectrum of compound diffusoside D (DMSO-D6);
FIG. 7 is a spectrum of H-HCOSY of compound diffusoside D (DMSO-D6);
FIG. 8 ESI-MS spectrum (positive) of diffusoside D;
FIG. 9 ESI-MS spectrum (negative) of diffusoside D.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As described in the background art, the prior art is still blank about the separation of monomer components and the activity research of the oldenlandia diffusa aqueous extract, and in order to solve the technical problems, the application provides a novel compound separated from the oldenlandia diffusa aqueous extract and the effect of the compound on resisting endometritis.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific examples and comparative examples.
The apparatus and material sources in the present invention are as follows:
BRUKER 400MHz FT NMR nuclear magnetic resonance apparatus
Agilent 1100LC/MSD Trap ion Trap LC MS (Agilent Co., Ltd.)
LC-10AD HPLC, SPD-10A ultraviolet detector (Shimadzu Japan)
SENCO rotary evaporator (Shanghai Shensheng science and technology Co., Ltd.)
YMC-Pack ODS-A semi-preparative columns (5 μm, 250X 10 mmI.D.); d101 type macroporous adsorbent resin (chemical plant of tianjin nan kaiki university); ODS filler (YMC) MCI GEL reversed-phase Polymer filler (Beijing Whidery technologies, Ltd.); column chromatography silica gel (200-300 mesh), thin layer chromatography silica gel (Qingdao ocean factory); sephadex LH-20 (Pharmacia); the column chromatography reagents are analytically pure, and the high performance liquid chromatography reagents are chromatographically pure.
Ultrasonic cleaner: KQ5200B model ultrasonic cleaner.
The Oldenlandia diffusa used in the invention is provided by the department of pharmacy of subsidiary hospitals of Shandong traditional Chinese medicine university, is identified by professor Lifeng of the college of medicine of Shandong traditional Chinese medicine university, is dry whole herb of Oldenlandia diffusa (Willd.) Roxb. of rubiaceae, and the specimen is stored in the college of medicine of Shandong traditional Chinese medicine university.
Isolation of the Compound of example 1
20kg of spreading hedyotis herb is extracted twice by adding water for 2h for the first time and 1h for the second time, the mixture is concentrated to about 100kg under reduced pressure, the mixture passes through a D101 type macroporous absorption resin column, and is respectively eluted by water, 30% ethanol, 50% ethanol and 95% ethanol, the eluent is concentrated under reduced pressure and dried under vacuum, and about 650g of 30% ethanol elution part (A) and about 170g of 50% ethanol elution part (B) are obtained. Separating and purifying 470g of crude extract A by silica gel column chromatography, MCI gel, Sephadex LH-20 column chromatography, ODS medium pressure liquid chromatography, HPLC high pressure liquid phase semi-preparative chromatography, etc., wherein the separation process is shown in figure 1.
EXAMPLE 2 identification of Compounds
Diffusoside D
White powder, ESI-MS (positive) M/z 399.3[ M + Na [ ]]+，ESI-MS(negaitive)m/z 751.4[2M-H]-Molecular weight 376 and molecular formula C16H24O10. According to13C-NMR gave a 16-carbon signal, analyzed1H-NMR and HSQC spectra attribute and combine hydrogen signals attached to carbon atoms1Hydrogen signal in H-NMR, determination of one carbonyl, one quaternary carbon and 4 CH in the compound210 CH; in HMBC spectra, δH3.17(1H, overlapped), 4.01(2H, m), 5.31(1H, d, J ═ 7.2), 5.74(1H, s) and δ, respectivelyC153.0 remote correlation, δH3.49, 4.01 and deltaC46.65 has a remote correlation, as shown in FIG. 2, presumably with structural fragment I; deltaH2.82, 3.65, 3.27, 5.31 and deltaC178.89 has a remote correlation, δH3.27 and δC44.21 and 61.66 are related remotely, presumably with structural fragment ii; i and II share deltaC41.68, 86.09, thus the extension structural fragment is iii; deltaCSugar carbon signals with a component glycoside: 103.03, 77.40, 77.18, 73.88, 70.54, 61.00, δ in HMBC spectraH3.49, 4.01 and sugar end group carbon deltaC103.3 are remotely related, so the structure of compound 22 is presumed to be iv; in the H-HCOSY spectrum, δH: 5.31 is related to 3.27, 3.14 is related to 3.49, 2.82 is related to 3.65, 5.71 is related to 3.14, and 2.82 is related to 3.27, and further verifying the correctness of the structure; the SciFinder searches that the compound is a new compound, named DifLysoside D, hydrocarbon signal assignment is shown in table 1.
TABLE 113C-NMR(400MHz，DMSO-d6)and1H-NMR(400MHz，DMSO-d6)data ofDiffusoside D
EXAMPLE 3 Activity test of Compounds
3.1 model building
60 healthy SD female rats were taken, and 50 of them were used to prepare an animal model of chronic endometritis. Pentobarbital sodium is injected into abdominal cavity to anaesthetize rat, then expose uterus, needle is inserted into right side of uterus bifurcation towards ovary direction by No. 4 scalp needle, 250mL/L phenol mucilage is injected slowly for 0.05mL (liquefied phenol 5mL, tragacanth 1g, glycerin 4mL, distilled water is added to prepare for 20 mL); the left uterus was not injected as a self control. In addition, 10 SD rats are a sham operation group, only abdominal surgery is performed, and phenol mucilage is not injected for molding.
3.2 grouping and administration
After the model is built, all animals are normally fed for 1 week, and on day 8, the rats are randomly divided into 6 groups, namely ① sham operation group (10 mL/kg of distilled water is given), ② model group, ③ levofloxacin group (40mg/kg), ④ compound low dose group (10mg/kg), ⑤ compound medium dose group (30mg/kg) ⑥ compound high dose group (50mg/kg), wherein the intragastric administration volume of the rats is 1mL/100g of body weight, and the rats are continuously administered for 7 days.
3.3 detection of inflammatory factors
After 7 days of administration, blood was collected from the abdominal aorta under intraperitoneal injection of pentobarbital sodium under anesthesia, and the serum was centrifuged and the contents of tumor necrosis factor (TNF- α), interleukin-2 (IL-2), and interleukin-10 (IL-10) in the serum were determined by radioimmunoassay (see Table 2).
Table 2 effect of compounds on serum inflammatory factors (,
n is 10, unit: ng/mL)
P < 0.05 compared to sham group; in comparison with the set of models,△P＜0.05。
3.4 measurement of uterine ovarian body ratio and uterine swelling ratio
After anesthesia and blood sampling, uterine ovaries on both sides of a rat are picked up and weighed, the weight difference value of the left side and the right side of the uterus is the inflammatory swelling degree, and the change of the swelling rate and the uterine ovary body ratio value is solved. The results are shown in Table 3.
TABLE 3 Effect of Compounds on uterine ovarian volume fraction and uterine swelling Rate: (
n＝10)
P < 0.05, P < 0.01, compared to sham group; in comparison with the set of models,△P＜0.05，△△P＜0.01。
the above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (12)
1. A compound, designated diffusoside D, having the formula:
2. the method for isolating diffusoside D according to claim 1, comprising the steps of:
(1) extracting herba Hedyotidis Diffusae with water, enriching the water extractive solution with macroporous resin, eluting with water, 30% ethanol, 50% ethanol and 95% ethanol respectively, concentrating the eluate under reduced pressure, and vacuum drying to obtain 30% ethanol eluate A;
(2) separating by silica gel column chromatography, and gradient eluting the 30% ethanol elution part A with ethyl acetate-ethanol solvent system to obtain six parts A1-A6;
(3) separating the part A6 by MCIgel column chromatography to obtain five parts A6-1-A6-5;
(4) eluting the A6-5 part by Sephadex LH-50 column chromatography to obtain three parts of A6-5-1, A6-5-2 and A6-5-3;
(5) and sequentially carrying out ODS medium-pressure preparation liquid phase and semi-preparation high performance liquid phase separation on the part A6-5-3 to obtain a compound ① - ⑧, wherein the compound ③ is diffusoside D.
3. The separation method of claim 2, wherein the dried oldenlandia diffusa in step (1) is added with purified water for reflux extraction for 1-3 times, and the extract is concentrated under reduced pressure and then passes through D101 type macroporous resin, and is eluted with water, 30% ethanol, 50% ethanol and 95% ethanol respectively, and the eluate is concentrated under reduced pressure and dried under vacuum to obtain 30% ethanol elution part A.
4. The separation method of claim 3, wherein the dried oldenlandia diffusa is extracted twice with water, 2h for the first time and 1h for the second time, and the extracts are combined and concentrated under reduced pressure to five times the amount of the dried oldenlandia diffusa.
5. The separation method according to claim 2, wherein in the step (2), the 30% ethanol elution part A is subjected to gradient elution by an ethyl acetate-ethanol system by using silica gel column chromatography, and when the volume ratio of ethyl acetate to ethanol is 1:1, the part A6 is obtained.
6. The separation method of claim 2, wherein the fraction a6 is subjected to MCI gel column chromatography and eluted sequentially with a 5% to 10% acetonitrile-water gradient to give five fractions a6-1 to a 6-5.
7. The separation method of claim 2, wherein the Sephadex LH-50 column chromatography mobile phase is 50% methanol.
8. The separation method according to claim 2, wherein the ODS medium-pressure preparative liquid-phase elution mode is 10% to 40% methanol-water; the mobile phase of the semi-preparative high-performance liquid phase is 7% acetonitrile-water, the semi-preparative high-performance liquid chromatographic column is A YMC-Pack ODS-A semi-preparative column, and the specification is as follows: 5 μm, 250 × 10mmI.D.
9. A pharmaceutical composition comprising the compound diffusoside D according to claim 1 and other anti-endometritis agents.
10. A pharmaceutical preparation, which is prepared from the compound diffussided according to claim 1 or the pharmaceutical composition according to claim 9, and a pharmaceutically acceptable excipient.
11. The pharmaceutical formulation according to claim 10, wherein the compound diffussided is administered in a dose of 10-50 mg/kg.
12. Use of the compound diffusoside D according to claim 1, the pharmaceutical composition according to claim 9 or the pharmaceutical formulation according to claim 10 for the manufacture of a medicament for the treatment of endometritis.
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| CN101129521A (en) * | 2007-09-11 | 2008-02-27 | 浙江大学 | Effective component of hedyotis diffusa and method of preparing the same and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101129521A (en) * | 2007-09-11 | 2008-02-27 | 浙江大学 | Effective component of hedyotis diffusa and method of preparing the same and application |
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| Iridoids and iridoid glucosides from fruits of Crescentia cujete;Kaneko, Tetsuo，等;《Phytochemistry》;19971231;第46卷(第5期);第907-910页 * |
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