CN114957272A - Chromane dimer and preparation method and application thereof - Google Patents
Chromane dimer and preparation method and application thereof Download PDFInfo
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- trigochromene
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 125000003016 chromanyl group Chemical class O1C(CCC2=CC=CC=C12)* 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- -1 chromane dimer compound Chemical class 0.000 claims abstract description 15
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- 238000000034 method Methods 0.000 claims description 7
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- 150000001930 cyclobutanes Chemical group 0.000 description 1
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- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical compound C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention relates to the field of medical biotechnology, in particular to a novel chromane dimer compound in long-sequence Sanbao wood, a preparation method thereof, application of the compound in preparing a medicament for preventing or treating tumor diseases or health care products for preventing tumor diseases.
Description
Technical Field
The invention relates to a novel chromane dimer in Sanbao wood, a preparation method and application thereof, belonging to the technical field of medical biology.
Background
Long-sequence sanbao (Trigonostemon howii Merr. & Chun) is a plant of the genus Trigonostemon (Euphorbiaceae), an evergreen shrub, a specific plant of the south of the sea. The research finds that the extract contains various chemical components of diterpene, alkaloid, isoflavone, lignan and other compounds, and the pharmacological activity of the long-sequence Sanbao wood extract or monomer shows the aspects of antivirus, antitumor, antibacterial, anti-inflammatory, antioxidation and the like.
Chromane derivatives, including coumarin and flavone, from natural sources and artificially synthesized have a great deal of medicinal development value and become important sources of novel medicaments. However, the reports of novel chromane dimers from natural sources are less, only individual coumarin dimers are available, and products which can be developed by related applications are rare.
Disclosure of Invention
The present invention provides a novel chromane dimer, a trigochromene a, a preparation method thereof and an application thereof in the preparation of drugs with anti-tumor effects aiming at the problems of the prior art.
The invention aims to realize the following technical scheme, and provides a chromane dimer compound, the chemical name of which is trigochromene A, and the structural formula of which is shown as the formula (I):
a preparation method of a chromane dimer compound trigochromene A comprises the following steps:
a. taking dry branches and leaves powder of the long-order Sanbao wood, performing reflux extraction by using an ethanol water solution, and recovering a solvent to obtain an ethanol total extract;
b. dispersing the ethanol total extract in water, suspending, sequentially extracting with dichloromethane, ethyl acetate and n-butanol to obtain different polar parts, collecting dichloromethane phase, concentrating under reduced pressure, and removing organic solvent to obtain extract;
c. and (3) taking the dichloromethane part for gradient elution and column chromatography separation and purification, and separating to obtain the compound trigochromene A.
The specific steps of the step c are as follows: performing silica gel column chromatography on dichloromethane part, and gradient eluting with petroleum ether-ethyl acetate as eluent at volume ratio of 100: 0 to 0: 100 (30: 1, 15: 1, 8: 1, 5: 1, 3: 1, 1: 1, 0: 1) to obtain 11 components Fr.1-Fr.11; taking Fr.9, adopting a silica gel column, using petroleum ether-ethyl acetate as an eluent, and carrying out gradient elution with the volume ratio of 100: 5 to 0: 100 (20: 1, 15: 1, 10: 1, 8: 1, 5: 1, 2: 1 and 0: 1) to obtain 4 subfractions Fr.9.1-Fr.9.4; and Fr.9.3 is taken, and is subjected to chromatography separation and pigment removal by a small-hole adsorption resin MCI column, wherein the volume ratio of methanol to water is 30: 70-100: 0 (30: 70, 50: 50, 70: 30, 100: 0), combining Fr.9.3.2-Fr.9.3.4, performing ODS reversed phase column chromatography, performing gradient elution with a methanol-water volume ratio of 30: 70-100: 0 (30: 70, 50: 50, 70: 30, 100: 0) to obtain 4 subfractions Fr.9.3.2.1-Fr.9.3.2.4, performing semi-preparation on the component Fr.9.3.2.2, performing methanol-water volume ratio of 83: and 17, isocratic elution and separation to obtain the compound trigochromene A.
The invention provides an application of a chromane dimer compound trigochromene A or an analogue, a tautomer, a regioisomer, a stereoisomer, an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating tumor diseases or preparing a health-care product for preventing tumor diseases.
The term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts are described in detail by Berge et al in J.pharmaceutical Sciences (1977)66: 1-19.
The compounds of the invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.
The invention has the following beneficial effects: 1. the novel chromane dimer trigochromene A is obtained by separating a dichloromethane part extract of branches and leaves of Trigonostemon Horwii Merr & Chun for the first time, and is separated and purified by alcohol extraction, silica gel column chromatography, MCI column chromatography and semi-preparative HPLC (high performance liquid chromatography), so that a novel compound is successfully obtained, and the operation method is simple, convenient and rapid.
2. The new chromane dimer trigochromene A of the invention is proved to have good anti-tumor activity and IC thereof by in vitro cell experiments 50 The value is 30.27 + -3.17 to 81.84 + -1.66 mu M (37.60 + -1.90 to 49.93 + -3.51 mu M for the positive drug cis-platin). The chromane dimer trigochromene A or the analogue, the tautomer, the regioisomer, the stereoisomer, the enantiomer, the diastereoisomer or the pharmaceutically acceptable salt thereof can be used for preparing antitumor drugs or health care products for preventing tumor diseases.
3. The novel chromane dimer trigochromene A or tautomer, stereoisomer or pharmaceutically acceptable salt can be combined with an excipient or carrier allowed by a preparation or a medicament to prepare the medicament or medicinal composition with the antitumor activity. The medicine or pharmaceutical composition can be made into tablet, granule, capsule, oral liquid, dripping pill, injection, aerosol, etc.; controlled or sustained release formulations or nano-formulations well known in the modern pharmaceutical industry may also be employed.
Drawings
FIG. 1 of trigochromene A 1 H-NMR Spectrum (CDCl) 3 )。
FIG. 2 of trigonochromene A 13 C-NMR Spectrum (CDCl) 3 )。
FIG. 3 HMBC spectrum of trigochromene A (CDCl) 3 )。
FIG. 4 HSQC spectrum (CDCl) of trigochromene A 3 )。
FIG. 5 NOESY spectrum (CDCl) of trigochromene A 3 )。
FIG. 6 of trigochromene A 1 H- 1 H COSY spectrogram (CDCl) 3 )。
FIG. 7 UV spectrum of trigochromene A.
FIG. 8 is an IR spectrum of trigochromene A.
FIG. 9 is a HR-ESI-MS spectrum of trigochromene A.
Detailed Description
The present invention will be described in further detail with reference to the following detailed description and accompanying drawings.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.
Example 1: preparation method of chromane dimer compound trigochromene A
Pulverizing 20kg dried branches and leaves of Sambucus nigra, extracting with 50-100L 95% ethanol under reflux for 3 times (each for 3 hr), and recovering solvent to obtain total ethanol extract 1667.2 g. Adding 10L of distilled water for suspension, sequentially extracting with 4L of dichloromethane, 4L of ethyl acetate and 4L of n-butanol for 4 times respectively, and recovering the extractive solutions to dryness to obtain 196.3g of dichloromethane extract, 130.2g of ethyl acetate extract and 280.5g of n-butanol extract.
1600g of silica gel (100-200 mesh) is taken for wet column packing, 196.3g of the dichloromethane part extract is subjected to sample mixing by 260g of silica gel (100-200 mesh), and dry-method sample loading is carried out after drying. Gradient elution is carried out on petroleum ether-ethyl acetate mixed solvents (v/v 30: 1, 15: 1, 8: 1, 5: 1, 3: 1, 1: 1 and 0: 1) with different proportions, comparison and combination are carried out by TLC and ultraviolet color development methods, and 11 components (Fr.1-Fr.11) are obtained in total.
Fr.9(9.8g) was subjected to gradient elution with a silica gel column using petroleum ether-ethyl acetate (volume ratio 20: 1, 15: 1, 10: 1, 8: 1, 5: 1, 2: 1, 0: 1) to give 4 subfractions Fr.9.1-Fr.9.4).
Fr.9.3 is separated by a small-hole adsorption resin (MCI) column chromatography and pigment is removed, after methanol-water (volume ratio of 30: 70, 50: 50, 70: 30 and 100: 0) is subjected to gradient elution, Fr.9.3.2-Fr.9.3.4 are combined and then subjected to gradient elution by an ODS column and methanol-water (volume ratio of 30: 70, 50: 50, 70: 30 and 100: 0) to obtain 4 subfractions Fr.9.3.2.1-Fr.9.3.2.4, and the component Fr.9.3.2.2 is subjected to semi-preparative high performance liquid phase and methanol-water (210nm, 254nm, volume ratio of 83: 17 and 2mL/min) to obtain a compound trigochromene A (26.0 mg).
Example 2: structure identification of compounds
The modern structure identification technology is applied to determine the chemical structure of the obtained active ingredient and discover the active ingredient with a novel structure. The results are shown in FIGS. 1 to 8.
Compound trigonchromene a: white solid powder of formula C 30 H 36 O 8 (HR-ESI-MS m/z 547.2304 [M+Na] + (calculated 547.2302) and has 13 unsaturations. The UV spectrum shows maximum absorption peaks at 207, 220 and 275 nm. The infrared spectrum shows at v max 1685cm -1 ，ν max 1600，1575，1458cm -1 There is infrared absorption.
By 13 C-NMR， 1 H-NMR and HSQC comparison analysis of the compound 1 H and 13 c NMR spectrum and molecular formula of C 15 H 18 O 4 Of isoevodionol methyl ether 1 H and 13 the C NMR spectra are very similar (. delta.) C 74.4, 158.0, 156.2, 119.2, 96.5, 155.8, 111.4) in addition to the signals for H-3 and H-4, C-3 and C-4. The compound isoevodionol methyl ether has a double bond at C-3 and C-4, and contains two alkene methyl groups (. delta.) H 5.53 and 6.47, each 1H, d, J ═ 9.6 Hz). the H-3 and H-4 of trigochromene A are two sp 3 Methyl group (delta) H 2.60 and 3.11,1H, dd, J ═ 6.0,1.8Hz, respectively). This indicates that trigochromene A is a dimer of isoevodol methyl ether.
In the HMBC experiment, H-3 is related to C-2, C-3 '(HSQC related carbon, no satellite peak), C-4 and C-10, and H-4 is related to C-2, C-3, C-4' (HSQC related carbon, no satellite peak), C-5, C-9 and C-10. These data indicate that a symmetric dimer, bonded by carbon C-3 and carbon C-4 of two isoevodolol methyl ether molecules, forms a cyclobutane ring. Further HMBC correlations (FIG. 2) are from H-11 or H-12 to C-2, C-3; from H-8 to C-6, C-7, C-9, C-10; from H 3 -14 to C-13; from H 3 -15 to C-5 and C-6; h 3 -16 toC-7 can establish a planar structure of the compound isoevodol methyl ether, with two possible ring closure modes, head-to-tail or head-to-head. By comparing the coupling constants of such cyclobutane-type structures, 1 h NMR spectrum showed that H-3 and H-4 are at delta H At 2.60 and 3.11 for dipole resonance with coupling constants of 6.0 and 1.8Hz, respectively, indicating that 1 is a trans-trans fusion head-to-tail mode with a typical AA 'XX' symmetrically substituted cyclobutane ring.
The configuration of trigochromene a was further determined by ROESY experiments. The ROESY correlation between H-8'/H-16' and H-14'/H-15' confirms the partial steric structure of the trigochromene A, consistent with isoevodinol methyl ether, and further evidence is that a unit of ROESY correlation was chosen between H-3 'and H-4', H-11', H-12'; from H-4' to H-3', H-15', H-11' (from H-4 to H-11 '), and designated H-3 and H-4 on one side of the cyclobutane annulus and H-3' and H-4' on the other side of the cyclobutane annulus. the Chem 3D molecular model structural analysis of trigochromene a is consistent with the relative configuration shown below, thus establishing the entire structure except for the absolute configuration.
Structure analysis:
TABLE 1 NMR data (CDCl) of the compound trigochromene A 3 )
Example 3: screening for antitumor Activity
The CCK-8 method is adopted to research the proliferation inhibition effect of the compound trigochromene A on human cervical cancer cells (HeLa) and human colon cancer cells (HepG 2). Human cervical cancer HeLa, human liver cancer HepG2 and human colon cancer HCT116 cells were purchased from Shanghai cell bank of Chinese academy of sciences, and completely cultured in DMEM containing 10% fetal bovine serum, 1% penicillin and streptomycin at 37 deg.C and 5% CO 2 Culturing and subculturing in an incubator. Taking HeLa in logarithmic growth phase,HepG2, HCT116 cells were seeded in 96-well plates at approximately 5X 10 cells per well 4 Culturing the cells for 24h, adding medicine, adding 1 μ L of samples with concentration of 0.1mg/mL, 1mg/mL, 2mg/mL and 5mg/mL into each well of the experimental group, adding cisplatin with corresponding concentration into the positive control group, adding 1 μ L of DMSO into the negative control group, setting 3 multiple wells in each group, placing at 37 deg.C, and placing at 5% CO 2 Culturing in an incubator. After 24 hours of action, 10. mu.L of CCK-8 solution was added to each well, incubated in an incubator for 2 hours, and the absorbance (OD value) was measured at a wavelength of 450nm in a microplate reader. The experiment was repeated three times and the IC was further calculated 50 The value is obtained. Cisplatin (cissplatin) was used as a positive control drug.
The inhibition rate was [1- (OD administration group/OD control group) ] × 100%. Wherein the OD administration group is OD value of administration group with trigochromene A, and the OD control group is OD value of control group without trigochromene A.
The experimental results show that the novel compounds of the invention have IC values on HepG2, HeLa and HCT116 cells 50 The values are respectively 30.27 +/-3.17 mu M, 59.32 +/-2.41 mu M and 81.84 +/-1.66 mu M, and the IC of positive control drug cis-platinum on HepG2, HeLa and HCT116 cells 50 The values were 44.66. + -. 0.33. mu.M, 37.60. + -. 0.57. mu.M, and 49.93. + -. 1.05. mu.M, respectively. Indicating that the trigochromene A has cytotoxic activity on the three tumor cells and can be used for preparing medicaments for resisting colon cancer, cervical cancer and liver cancer. See table below:
TABLE 2 tumor inhibition Rate (IC) of the Compound trigochromene A 50 ，μM)
While the invention has been described in connection with specific embodiments thereof, it will be understood that these should not be construed as limiting the scope of the invention, which is defined in the following claims, and any variations which fall within the scope of the claims are intended to be embraced thereby.
Claims (7)
1. A chromane dimer compound, having the chemical name of trigochromene A, and having the structural formula shown in formula (I):
2. a method for preparing the chromane dimer compound trigochromene a of claim 1, characterized in that: the method comprises the following steps:
a. taking dry branches and leaves powder of the long-order Sanbao wood, performing reflux extraction by using an ethanol water solution, and recovering a solvent to obtain an ethanol total extract;
b. dispersing the ethanol total extract in water, suspending, sequentially extracting with dichloromethane, ethyl acetate and n-butanol to obtain different polar parts, collecting dichloromethane phase, concentrating under reduced pressure, and removing organic solvent to obtain extract;
c. and (3) taking the dichloromethane part to carry out silica gel column chromatography, MCI column chromatography and semi-preparative HPLC for separation and purification, and separating to obtain the compound trigochromene A.
3. The method for producing a chromane dimer compound, trigochromene a, according to claim 2, characterized in that: the specific steps of the step c are as follows:
taking a dichloromethane part, carrying out silica gel column chromatography, using petroleum ether-ethyl acetate as an eluent, and carrying out gradient elution with the volume ratio of 100: 0 to 0: 100 to obtain 11 components Fr.1-Fr.11;
taking Fr.9, adopting a silica gel column, using petroleum ether-ethyl acetate as an eluent, and carrying out gradient elution with the volume ratio of 100: 5 to 0: 100 to obtain 4 subfractions Fr.9.1-Fr.9.4;
and Fr.9.3 is taken, and is subjected to chromatography separation and pigment removal by a small-hole adsorption resin MCI column, wherein the volume ratio of methanol to water is 30: 70-100: after 0 gradient elution, combining Fr.9.3.2-Fr.9.3.4, performing ODS reversed phase column chromatography, and performing gradient elution with a methanol-water volume ratio of 30: 70-100: 0 to obtain 4 sub-components Fr.9.3.2.1-Fr.9.3.2.4, performing semi-preparative high performance liquid chromatography on the component Fr.9.3.2.2, wherein the methanol-water volume ratio is 83: and 17, isocratic elution is carried out, and the compound trigochromene A is obtained.
4. The method for producing a chromane dimer compound, trigochromene a, according to claim 2, characterized in that: the ethanol water solution in the step a is 95% ethanol water solution in volume fraction.
5. The method for producing a chromane dimer compound, trigochromene a, according to claim 2, characterized in that: in the step a, refluxing and extracting by using an ethanol water solution for 3 times, wherein each time is 3 hours.
6. Use of the chromane dimer compound of claim 1, or an analog, tautomer, regioisomer, stereoisomer, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of a neoplastic disease.
7. Use of the chromane dimer compound of claim 1, or an analog, tautomer, regioisomer, stereoisomer, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, for the preparation of a health product for the prevention of neoplastic disease.
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