CN109053831B - Novel compound in oldenlandia diffusa and application - Google Patents
Novel compound in oldenlandia diffusa and application Download PDFInfo
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- CN109053831B CN109053831B CN201811025778.2A CN201811025778A CN109053831B CN 109053831 B CN109053831 B CN 109053831B CN 201811025778 A CN201811025778 A CN 201811025778A CN 109053831 B CN109053831 B CN 109053831B
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Abstract
The invention relates to the field of natural compound separation, and relates to a novel compound in oldenlandia diffusa and application thereof. The invention provides a compound diffusoside C separated from water extraction of oldenlandia diffusa and application thereof in preparing anti-EV 71 virus medicaments. The invention carries out system separation aiming at the 30 percent ethanol elution part in the oldenlandia diffusa water extract, comprehensively uses 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 C in the separation process, and finds that the compound diffusoside C has good anti-EV 71 virus activity in the research process, the treatment window is wide and safe to use, and the application of the compound diffusoside C in preparing the anti-EV 71 virus medicine has important research significance.
Description
Technical Field
The invention relates to the field of natural compounds, in particular to a novel compound separated from oldenlandia diffusa and anti-EV 71 virus activity 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 pharmacological activities of oldenlandia diffusa starts in the 60 s, and about 80 compounds with different structural types are isolated and identified from the oldenlandia diffusa willd pharmacological activities of the oldenlandia diffusa willd pharmacological activities are more dispersed and more crude extract activities are reported according to literature, more research on chemical components of 60% ethanol extraction sites and less research on chemical components of water extraction sites according to literature reports, and the Yuexi Master thesis only isolates and identifies 5 compounds from water soluble sites, namely sitosterol, deacetyl asperulic acid, D-mannitol, p-coumaric acid and asperuloside; 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 research results, the research on the chemical components in the oldenlandia diffusa confirms that the antitumor active components of the oldenlandia diffusa have important significance for the research and development of innovative medicines of the oldenlandia diffusa. In addition, the monomeric compounds in the oldenlandia diffusa can have different functions from the oldenlandia diffusa, the prior art has less research on the separation and the drug effect of the monomeric components in the oldenlandia diffusa, and is blank about the separation of the compounds in the oldenlandia diffusa water extract, and the development of the separation and the activity identification of the monomeric substances in the oldenlandia water extract has important significance for the development of active drugs.
Disclosure of Invention
The invention carries out system separation on the 30 percent ethanol elution part in the oldenlandia diffusa water extract, obtains a novel compound diffusoside C in the separation process, and finds that the compound diffusoside C has good anti-EV 71 virus activity in the research process, and has wider treatment window and safe use. 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 C, 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, 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) 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 ② is diffusoside C.
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 elution procedure of 10-40% methanol, semi-preparative high performance liquid phase mobile phase of 7% acetonitrile-water, and chromatographic column of YMC-Pack ODS-A semi-preparative column (5 μm, 250 × 10 mmI.D.).
In a third aspect of the invention, a pharmaceutical composition is provided, which consists of compound diffusoside C and other components against EV71 virus.
In a fourth aspect of the invention, a pharmaceutical preparation is provided, which is prepared from compound diffusoside C and pharmaceutically acceptable excipients; preferably, compound diffusoside C is administered at a dose of 1.76-33.32. mu.g/mL.
In the fifth aspect of the invention, the compound diffusoside C, the pharmaceutical composition and the pharmaceutical preparation are applied to the preparation of anti-EV 71 virus medicaments.
The invention has the advantages of
The invention provides a novel compound diffusoside C separated from a water extract of oldenlandia diffusa, the compound has the activity of resisting EV71 virus, the therapeutic dose is 1.76-33.32 mu g/mL, the therapeutic window is wide, and the clinical use is safe. The research on diffusoside C provides a new research direction for the development of the oldenlandia diffusa monomeric 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 C;
FIG. 2 shows signal peak assignment of compound diffusoside C;
FIG. 3 is a 13CNMR spectrum (DMSO-d6) of compound diffusoside C;
FIG. 4 1HNMR spectrum of compound diffusoside C (DMSO-d 6);
FIG. 5 HSQC spectrum of compound diffusoside C (DMSO-d 6);
FIG. 6 HMBC spectrum of compound diffusoside C (DMSO-d 6);
FIG. 7 is a spectrum of H-HCOSY of compound diffusoside C (DMSO-d 6);
FIG. 8 ESI-MS spectrum (negative) of diffusoside C compound.
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 of the invention, the prior art is still blank about the separation of monomer components and activity research in the aqueous extract of the oldenlandia diffusa, and in order to solve the technical problems, the application provides a novel compound separated from the aqueous extract of the oldenlandia diffusa and the effect of the novel compound on resisting EV71 virus.
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 1100 LC/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 Shandong traditional Chinese medicine university college of medicine, is dry whole herb of Oldenlandiadiffusa (Willd.) Roxb. of oldenlandian diffusa of Rubiaceae, and 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
White powder, ESI-MS (positive) M/z 392.0[ M + NH ]4]+，396.9[M+Na]+Molecular weight 374, molecular formula C16H22O10. According to13C-NMR and DEPT spectra showed that this compound had 16 carbon atoms: 3 quaternary carbons, 9 methines, 3 methylenes, 1 methyl signal, including one double bond carbon: deltac152.14, 108.82; 8 continuous oxygen carbon number deltaC99.03, 94.83, 77.26, 76.57, 73.02, 69.96, 61.14, 51.01; two carbonyl groups deltaC215.96, 166.55. By HSQC and1the H-NMR spectrum assigns the hydrogen signal directly attached to the carbon.13C-NMR spectra show a set of sugar signals, deltaC99.03, 77.26, 76.57, 73.02, 69.96, 61.14; in HMBC spectra, deltaH7.51(1H, s) and δC166.66, 108.82, 94.83 and 29.56 have long-range correlation, and a structural fragment I is presumed to exist in the structure; deltaC215.96 and deltaH2.02, 2.25, 2.44, 2.61, 3.15 are all remotely related, and fragment II is presumed to be present in the structure; deltaH3.15 and deltaC152.14, 108.82 remote correlation, δH2.61 is remotely related to 94.83, 108.82; H-H COSY spectra: deltaH5.38 and deltaH2.61 Structure III of the related, therefore fragment-ligated compound, see FIG. 2, C signal data for the aglycone of Compound XVIII and H-15.45 (1H, br s), H-37.35 (1H, br s) determine the H-5, H-9 of the compound, consistent with the literature report of the relative configuration of Compound XVIIa. chemical shift of the sugar end group of 4.5, coupling constant J. 7.8Hz suggests the relative configuration of β -D-glucose. SciFinder network retrieves this compound as a new compound named Diffusoside C, and the assignment of the hydrocarbon signal is shown in Table 1.
TABLE 113C-NMR(400MHz，DMSO-d6)and1H-NMR(400MHz，DMSO-d6)data of compoundDiffusoside C
EXAMPLE 3 test of anti-EV 71 Virus Activity
3.1 cells and strains of viruses
The EV71 virus strain is a clinical isolate, the titer of the titrated strain is 107.2TCID50/mL, the virus is amplified in RD, the virus is frozen and thawed for 3 times, then the virus is centrifuged at 12000 Xg for 10min, and supernatant is taken and stored at-80 ℃ after being subpackaged. Culture solution: RPMI-1640 contains 10% fetal bovine serum, 100U/mL penicillin, 100U/mL streptomycin, 5% CO at 37 deg.C2Culturing in an incubator.
3.2 toxicity test of Compounds
RD cells were inoculated into a 96-well culture plate, grown into a monolayer, and the culture solution was discarded, and Diffusoside C prepared in example 1 was serially diluted at an initial concentration of 100. mu.g/mL 2-fold, and 10 wells were repeated for each dilution, while 3 wells of a normal cell control were set. At 37 ℃ 5% CO2After culturing for 96h, cytopathic effect (CPE) is observed under the mirror, the drug median intoxication concentration (TC50) is calculated by the Reed-Muench method, and the TC50 value of the compound Diffusoside C is 33.32 mug/mL.
3.3 test of the anti-EV 71 Activity of Compounds
RD cells are inoculated to a 96-well culture plate, culture solution is discarded after the RD cells grow into a monolayer, the compound Diffusoside C is serially diluted by 2 times according to the initial concentration of 50 mu g/mL according to the toxicity test of the medicine, 10 wells are repeated in each dilution, then 100TCID50 EV71 is added, and 6 wells of each of a normal cell control and a virus control are set. At 37 ℃ 5% CO2After culturing for 96h, cytopathic effect (CPE) is observed under the mirror, the half effective concentration of the drug (EC50) is calculated, and the EC50 value of the compound Diffusoside C is calculated to be 1.76 mu g/mL. 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 includedWithin the scope of protection of the present application.
Claims (5)
1. A method for separating a compound diffusoside C, wherein the compound has the following structural formula:
the separation steps are as follows:
(1) extracting herba Hedyotidis Diffusae with purified water under reflux for 1-3 times, concentrating under reduced pressure, passing through D101 type macroporous resin, eluting with water, 30% ethanol, 50% ethanol, and 95% ethanol, concentrating the eluate under reduced pressure, and vacuum drying to obtain 30% ethanol eluate A;
(2) performing gradient elution on the 30% ethanol elution part A by using silica gel column chromatography through an ethyl acetate-ethanol system, and obtaining part A6 when the volume ratio of ethyl acetate to ethanol is 1: 1;
(3) subjecting the A6 part to MCI gel column chromatography, and performing gradient elution with 5% -10% acetonitrile-water to obtain five parts A6-1-A6-5 in sequence;
(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) sequentially separating the part A6-5-3 by ODS medium pressure preparation liquid phase and semi-preparation high performance liquid phase separation to obtain a compound ① - ⑧, wherein the compound ② is diffusoside C;
the Sephadex LH-50 column chromatography mobile phase in the step (4) is 50% methanol;
the ODS medium-pressure preparation liquid phase elution mode in the step (5) is 10-40% of methanol-water; the mobile phase of the semi-preparative high performance liquid phase is 7% acetonitrile-water, and the semi-preparative high performance liquid chromatography column is YMC-Pack ODS-A semi-preparative column with specification of 5 μm and specification of 250 × 10mm I.D.
2. The separation method of claim 1, wherein the oldenlandia diffusa is extracted twice with water in the step (1), 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.
3. A pharmaceutical composition, which consists of a compound diffusoside C and other components against EV71 virus, wherein the diffusoside C has the following structural formula:
4. a pharmaceutical formulation, which is prepared from compound diffusoside C or the pharmaceutical composition of claim 3, and pharmaceutically acceptable excipients, wherein the diffusoside C has the following structural formula:
5. the pharmaceutical composition of claim 3, the pharmaceutical formulation of claim 4, for use in the preparation of a medicament against EV71 virus, wherein diffusoside C has the following structural formula:
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