Isopentenyl sulfone amide compounds and preparation method and application thereof
阅读说明：本技术 一类异戊烯基砜酰胺类化合物及其制备方法和用途 (Isopentenyl sulfone amide compounds and preparation method and application thereof ) 是由 杨光忠 陈玉 年贺凤 于 2020-07-03 设计创作，主要内容包括：本发明属于天然药物医药技术领域,具体提供了一类异戊烯基砜酰胺类化合物及其制备方法和用途。本发明从五叶山小橘叶中分离纯化得到了五种化合物,结构通式为<Image he="360" wi="700" file="DDA0002568957580000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>实验表明这五种化合物对癌细胞SGC7901、HCT-116、HepG-2均有一定程度的抑制作用,并且对炎症因子NO具有显著的抑制作用；本发明为开发新的抗肿瘤药物和抗炎药物提供了备选化合物,对山小橘属植物的综合开发利用具有非常重要的意义。(The invention belongs to the technical field of natural medicine and medicine, and particularly provides isopentenyl sulfone amide compounds and a preparation method and application thereof. The invention separates and purifies five compounds from the leaves of aegle marmelos with the general formula of structure Experiments show that the five compounds have certain inhibition effects on cancer cells SGC7901, HCT-116 and HepG-2 and have obvious inhibition effects on inflammatory factors NO; the invention is to develop a newThe antitumor drug and the anti-inflammatory drug provide alternative compounds, and have very important significance for the comprehensive development and utilization of the plant of the aegle.)
1. The isopentenyl sulfone amide compound is characterized by being obtained by separating and purifying isopentenyl sulfone amide compound from leaves of aegle marmelos, and the structural general formula of the isopentenyl sulfone amide compound is shown as formula (I):
wherein, compound 1:R2＝H；
compound 2:R2＝H；
compound 3:
compound 4:R2＝H；
compound 5:R2＝OCH3。
2. a process for the preparation of the prenyl sulfone amides as claimed in claim 1, comprising the steps of:
s1, weighing dried leaves of the aegle marmelos, crushing, extracting by using ethanol, and then concentrating under reduced pressure to obtain ethanol extract;
s2, adding methanol into the ethanol extract for dissolving, then adding petroleum ether for extraction, and recovering the solvent under reduced pressure to obtain a methanol extract;
s3, performing polyamide column chromatography and gradient elution on the methanol extract to obtain a component Fr. II, performing silica gel column chromatography and gradient elution on the obtained component Fr. II, and detecting and combining similar components by TLC to obtain a component Fr.IIE; inverting C of the obtained component Fr.IIE18Performing column chromatography, performing gradient elution, and detecting by TLC to obtain components Fr.IIE2, Fr.IIE3, and Fr.IIE4; performing silica gel column chromatography on the obtained component Fr.IIE2, performing gradient elution, and detecting and combining similar components by TLC to obtain components Fr.IIE2d and Fr.IIE2e;
performing high performance liquid chromatography purification on the obtained component Fr.IIE2d, and isocratic eluting to obtain a compound 2;
purifying the obtained component Fr. IIE2E by reversed phase high performance liquid chromatography, and isocratic eluting to obtain a compound 1;
purifying the obtained component Fr. IIE3 by high performance liquid chromatography, and isocratic eluting to obtain a compound 3 and a compound 4;
subjecting the obtained fraction Fr. IIE4 to silica gel column chromatography, gradient elution, detecting by TLC and combining similar fractions to obtain a fraction Fr.IIE4d, and subjecting the obtained fraction Fr.IIE4d to high performance liquid chromatography purification and isocratic elution to obtain a compound 5.
3. The method for producing prenyl sulfone amide compounds according to claim 2, wherein in step S3, the conditions for gradient elution of methanol extract are: gradient elution is carried out by purified water and ethanol according to the volume ratio of the purified water to the ethanol of 1:0, 7:3, 1:1, 3:7 and 1: 19.
4. The method for producing an isopentenyl sulfone amide compound as claimed in claim 2, wherein in step S3, the conditions for gradient elution of component fr.ii are as follows: gradient elution is carried out by using dichloromethane and methanol according to the volume ratio of 100:1, 20:1, 9:1, 8:2 and 0: 1.
5. The method for producing an isopentenyl sulfone amide compound as claimed in claim 2, wherein in step S3, the conditions for gradient elution of component fr.iie are as follows: performing gradient elution by using methanol and water according to the volume ratio of 1:0, 7:3, 1:1, 3:7 and 0: 1.
6. The method for producing prenyl sulfone amide compounds according to claim 2, wherein in step S3, the conditions for gradient elution of component Fr.IIE2 are as follows: performing gradient elution by using petroleum ether and ethyl acetate according to the volume ratio of 9:1, 6:4, 2:8 and 0: 1.
7. The method for producing an isopentenyl sulfone amide compound as claimed in claim 2, wherein in the step S3, the conditions for isocratic elution of the component fr.iie2d are as follows: performing isocratic elution by using acetonitrile and formic acid aqueous solution according to the volume ratio of the acetonitrile to the formic acid aqueous solution of 60: 40; isocratic elution conditions for component fr.iie2e were: and performing isocratic elution by using acetonitrile and water according to the volume ratio of the acetonitrile to the water of 45: 55.
8. The method for producing an isopentenyl sulfone amide compound as claimed in claim 2, wherein in the step S3, the conditions for isocratic elution of the component fr.iie3 are as follows: and performing isocratic elution by using acetonitrile and water according to the volume ratio of the acetonitrile to the water of 62: 38.
9. The method for producing prenyl sulfone amide compounds according to claim 2, wherein in step S3, the conditions for gradient elution of component Fr.IIE4 are as follows: carrying out gradient elution by using petroleum ether and ethyl acetate according to the volume ratio of 9:1, 7:3, 4:6 and 0: 1; the conditions for isocratic elution of component fr.iied 4d were: and performing isocratic elution by using acetonitrile and formic acid aqueous solution according to the volume ratio of the acetonitrile to the formic acid aqueous solution of 70: 30.
10. The use of the prenyl sulfone amide compounds of claim 1 or prenyl sulfone amide compounds prepared by the process of claim 2 for the preparation of anti-gastric cancer drugs, anti-liver cancer drugs, anti-colon cancer drugs or anti-inflammatory drugs.
Technical Field
The invention relates to the technical field of natural medicine and medicine, in particular to isopentenyl sulfone amide compounds extracted from aegle marmelos leaves and a preparation method and application thereof.
Background
The fructus Fortunellae margaritae (Glycosmis pentaphyla) is a plant of genus Fortunella (Glycosmis) of Rutaceae, is a traditional Dai medicine in China, and has the effects of tonifying earth, invigorating stomach, strengthening body, dispelling wind, promoting blood circulation, relieving pain, etc. In India traditional medicine, the aegle marmelos can treat cough, rheumatism, anemia, arthritis, cellulitis and other diseases. In the garzburg area of bangladesh, aegle marmelos is used to prevent various cancers. Research on phytochemistry of aegle marmelos shows that the main chemical components of the aegle marmelos are mainly alkaloid compounds, and the reported structural types comprise acridone, carbazole, quinolone, quinazoline, furan-pyridine, carbazole indole and the like; and the research on non-alkaloid components is less, and the currently reported flavone, flavanone, phenolic aldehyde glycoside, isoflavone glycoside, hydroquinone bisglucoside and the like.
Disclosure of Invention
In view of the above, the invention provides isopentenyl sulfone amide compounds separated and purified from leaves of aegle marmelos, and a preparation method and application thereof.
The invention provides an isopentenyl sulfone amide compound, which is obtained by separating and purifying from leaves of aegle marmelos, and the structural general formula of the isopentenyl sulfone amide compound is shown as a formula (I):
wherein, compound 1:R2＝H；
compound 2:
compound 3:R2＝H；
compound 4:
compound 5:
the invention also provides a preparation method of the isopentenyl sulfone amide compound, which comprises the following steps:
s1, weighing dried leaves of the aegle marmelos, crushing, extracting by using ethanol, and then concentrating under reduced pressure to obtain ethanol extract;
s2, adding methanol into the ethanol extract for dissolving, then adding petroleum ether for extraction, and recovering the solvent under reduced pressure to obtain a methanol extract;
s3, performing polyamide column chromatography and gradient elution on the methanol extract to obtain components Fr.I, Fr. II, Fr. III, Fr. IV and Fr.V, performing silica gel column chromatography on the obtained component Fr. II, performing gradient elution, and detecting and combining similar components by TLC to obtain components Fr.IIA, Fr.IIB, Fr.IIC, Fr.IID, Fr.IIE, Fr.IIF, Fr.IIG, Fr.IIH, Fr.III, Fr.IIJ, Fr.IIK, Fr.IIL and Fr.IIM; reverse phase C with fraction Fr. IIE obtained from methanol and water18Performing column chromatography, performing gradient elution, and detecting by TLC to obtain components Fr.IIE1, Fr.IIE2, Fr.IIE3, Fr.IIE4, Fr.IIE5, Fr.IIE6, and Fr.IIE7; subjecting the obtained fraction Fr.IIE2 to silica gel column chromatography, gradient elution, and detecting by TLC to combine similar fractions to obtain fractions Fr.IIE2a, Fr.IIE2b, Fr.IIE2c, Fr.IIE2d, Fr.IIE2e, Fr.IIE2f, and Fr.IIE2g;
purifying the obtained component Fr. IIE2d by high performance liquid chromatography, and isocratic eluting to obtain a
purifying the obtained component Fr. IIE2E by reversed phase high performance liquid chromatography, and isocratic eluting to obtain a
purifying the obtained component Fr. IIE3 by high performance liquid chromatography, and isocratic eluting to obtain a
the obtained fraction Fr. IIE4 was subjected to silica gel column chromatography, gradient elution, and TLC detection to combine similar fractions to obtain fractions Fr.IIE4a, Fr.IIE4b, Fr.IIE4c, Fr.IIE4d, Fr.IIE4e, Fr.IIE4f, Fr.IIE4g, and Fr.IIE4h, and the obtained fraction Fr. IIE4d was subjected to high performance liquid chromatography purification and isocratic elution to obtain
Further, in step S3, the conditions for gradient elution of the methanol extract are: gradient elution is carried out by purified water and ethanol according to the volume ratio of the purified water to the ethanol of 1:0, 7:3, 1:1, 3:7 and 1: 19.
Further, in step S3, the conditions for gradient elution of component fr.ii are: gradient elution is carried out by using dichloromethane and methanol according to the volume ratio of 100:1, 20:1, 9:1, 8:2 and 0: 1.
Further, in step S3, the conditions for gradient elution of component fr.iie are: performing gradient elution by using methanol and water according to the volume ratio of 1:0, 7:3, 1:1, 3:7 and 0: 1.
Further, in step S3, the conditions for gradient elution of component fr.iie2 are: performing gradient elution by using petroleum ether and ethyl acetate according to the volume ratio of 9:1, 6:4, 2:8 and 0: 1.
Further, in step S3, the conditions for isocratic elution of component fr.iie2d are: performing isocratic elution by using acetonitrile and a formic acid aqueous solution (in the formic acid aqueous solution, the volume content of formic acid is 1 per thousand, and the balance is water) according to the volume ratio of the acetonitrile to the formic acid aqueous solution of 60:40 at the flow rate of 3 mL/min.
Further, in step S3, the conditions for isocratic elution of component fr.iie2e are: the elution was performed isocratically using acetonitrile and water at a flow rate of 3mL/min in a volume ratio of 45: 55.
Further, in step S3, the conditions for isocratic elution of component fr.iie3 are: the elution was performed isocratically using acetonitrile and water at a flow rate of 3mL/min in a volume ratio of 62: 38.
Further, in step S3, the conditions for gradient elution for component fr.iie4 are: gradient elution is carried out by utilizing petroleum ether and ethyl acetate according to the volume ratio of 9:1, 7:3, 4:6 and 0: 1.
Further, in step S3, the conditions for isocratic elution of component fr.iied 4d are: performing isocratic elution by using acetonitrile and a formic acid aqueous solution (in the formic acid aqueous solution, the volume content of formic acid is 1 per mill, and the balance is water) according to the volume ratio of the acetonitrile to the formic acid aqueous solution of the formic acid, wherein the flow rate of the acetonitrile to the formic acid aqueous solution is 3 mL/min.
The isopentenyl sulfone amide compound can be applied to preparation of anti-gastric cancer drugs, anti-liver cancer drugs or anti-colon cancer drugs.
The isopentenyl sulfone amide compound can be applied to preparation of anti-inflammatory drugs.
The technical scheme provided by the invention has the beneficial effects that: the methanol extract of medicinal plant aegle marmelos is separated and purified to obtain 5 new compounds, and the 5 new compounds are determined to be isopentenyl sulfone amide compounds by comprehensively applying a plurality of spectrum analysis methods; the antiproliferative activity evaluation of the obtained compounds 1-5 shows that the compounds 1-5 have a certain inhibition effect on three cancer cells (SGC7901, HCT-116 and HepG-2), wherein the
Drawings
FIG. 1 is a flow chart of the extraction and separation process for the preparation of prenyl sulfone amides in example 1 of the present invention;
FIG. 2 shows
FIG. 3 shows
FIG. 4 is a DEPT (Distorsionless Enhancement by polarization Transfer technique) (θ ═ 90 ℃) spectrum of
fig. 5 is a DEPT (θ ═ 135 °) spectrum of
FIG. 6 is a HSQC (Heteronuclear single quantum correlation) spectrum of
FIG. 7 is a diagram showing an HMBC (1H detected heteronuclear multiple bond correlation, heteronuclear multiple carbon correlation of 1H) spectrum of
FIG. 8 shows
FIG. 9 is a ROESY (Rotating Frame overhauser effect Spectroscopy, NOE spectrum of Rotating coordinate system) spectrum of
FIG. 10 shows a UV spectrum of
FIG. 11 is a High resolution electrospray Ionization Mass spectrometry (HR-ESI-MS) spectrum of
FIG. 12 shows
FIG. 13 shows
fig. 14 is a DEPT (θ ═ 90 °) spectrum of
fig. 15 is a DEPT (θ ═ 135 °) spectrum of
FIG. 16 is an HSQC spectrum of
FIG. 17 is a HMBC spectrum of
FIG. 18
FIG. 19 is a ROESY spectrum of
FIG. 20 shows a UV spectrum of
FIG. 21 is a HR-ESI-MS spectrum of
FIG. 22 shows
FIG. 23 shows
fig. 24 is a DEPT (θ ═ 90 °) spectrum of
fig. 25 is a DEPT (θ ═ 135 °) spectrum of
FIG. 26 is an HSQC spectrum of
FIG. 27 is an HMBC spectrum of
FIG. 28 is a photograph of
FIG. 29 is a ROESY spectrum of
FIG. 30 shows a UV spectrum of
FIG. 31 is a HR-ESI-MS spectrum of
FIG. 32 shows
FIG. 33 is a photograph of
fig. 34 is a DEPT (θ ═ 90 °) spectrum of
fig. 35 is a DEPT (θ ═ 135 °) spectrum of
FIG. 36 is an HSQC spectrum of
FIG. 37 is an HMBC spectrum of
FIG. 38 shows
FIG. 39 is a ROESY spectrum of
FIG. 40 is a UV spectrum of
FIG. 41 is a HR-ESI-MS spectrum of
FIG. 42 is a photograph of
FIG. 43 is a photograph of
fig. 44 is a DEPT (θ ═ 90 °) spectrum of
fig. 45 is a DEPT (θ ═ 135 °) spectrum of
FIG. 46 is an HSQC spectrum of
FIG. 47 is a HMBC spectrum of
FIG. 48 shows
FIG. 49 is a ROESY spectrum of
FIG. 50 is a UV spectrum of
FIG. 51 is a HR-ESI-MS spectrum of
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be further described with reference to the accompanying drawings and examples.
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