CN106967016B - Compound with acetylcholinesterase inhibition effect in hypericum perforatum secondary metabolite, separation preparation and application - Google Patents

Compound with acetylcholinesterase inhibition effect in hypericum perforatum secondary metabolite, separation preparation and application Download PDF

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CN106967016B
CN106967016B CN201710277708.5A CN201710277708A CN106967016B CN 106967016 B CN106967016 B CN 106967016B CN 201710277708 A CN201710277708 A CN 201710277708A CN 106967016 B CN106967016 B CN 106967016B
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张勇慧
薛永波
郭翼
张娜
张锦文
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Huazhong University of Science and Technology
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Abstract

The invention belongs to the technical field of medicines, provides compounds with acetylcholinesterase inhibition effect separated and prepared from hypericum perforatum secondary metabolites, simultaneously provides a separation preparation method and application of the compounds, and discloses structures, separation purification, preparation methods and structure identification of new phloroglucinol compounds 1-15 of hypericum perforatum secondary metabolites and evaluation of acetylcholinesterase inhibition activity of the compounds 1-15. The invention provides an alternative compound for developing a novel acetylcholinesterase inhibitor and an anti-Alzheimer drug. Has very important significance for the comprehensive development and utilization of the gambogic plants.

Description

Compound with acetylcholinesterase inhibition effect in hypericum perforatum secondary metabolite, separation preparation and application
Technical Field
The invention belongs to the technical field of medicines, and relates to a separation preparation method and application of compounds 1-15. In particular to a separation and purification process, structure confirmation, acetylcholinesterase inhibition and the like.
Background
Alzheimer's Disease (AD), senile dementia, is a degenerative brain disease characterized by dementia, and seriously affects cognitive function, memory function, social life, personal ability, emotional personality, etc. of a patient. With the rapid increase of the population of the old people in the world, the number of people with AD also increases year by year, and the disease becomes one of the diseases seriously threatening the life of the old people in the modern society. Although various drugs have been developed to address the pathogenesis and symptoms of AD, the most successful drugs clinically used to treat AD are Acetylcholinesterase inhibitors (achei).
Hypericum perforatum (Hypericum perforatum): also known as hypericum perforatum, known in europe as "st. john 'swort", commonly known as st. john's grass, is a perennial herb of the genus hypericum of the family garciniaceae. Hypericum perforatum has a history of medicinal use of more than twenty-four hundred years in folk. The traditional Chinese medicine holds that the traditional Chinese medicine is mild in nature, pungent and bitter in taste, and has the effects of clearing away heart-fire, improving eyesight, relaxing channels, promoting blood circulation, stopping bleeding, promoting granulation, detoxifying, diminishing inflammation and promoting diuresis. At present, preparations prepared from hypericum perforatum extracts are widely marketed in Europe and America and are mainly used for treating depression, hepatitis A and B, AIDS and the like. In recent years, with the continuous increase of patients with alzheimer's disease, AD has become one of the major diseases endangering human health following heart disease and cancer. However, the disease treatment medicine is few, the curative effect is poor, the current research and development of a single-target anti-AD new medicine is frequently frustrated, and a new prevention and treatment strategy is urgently needed. Natural products, particularly those of particular three-dimensional structure, are an important source of drug development. In recent years, more and more drug developers have been working on finding compounds from medicinal plants that have novel structures and good inhibitory activity against acetylcholinesterase. Therefore, the screening of new natural products with acetylcholinesterase inhibition activity from hypericum perforatum is of great significance.
Disclosure of Invention
The invention aims to provide a compound with acetylcholinesterase inhibitory activity, and a separation and purification method and application thereof.
The structural formula of the phloroglucinol compound is shown as a formula (1); wherein the English nomenclature is as shown in Table (1).
Figure BDA0001278756030000021
Figure BDA0001278756030000031
Figure BDA0001278756030000041
Table (1) names in chinese and english for compounds 1 to 15 in formula (1):
name of Chinese Name of English
Compound 1 Saint John grass element A Hyperforatin A
Compound 2 32-epimeric Saint John's grass element A 32-epi-hyperforatin A
Compound 3 Saint John grass element B Hyperforatin B
Compound 4 Saint John grass C Hyperforatin C
Compound 5 Saint John grass element D Hyperforatin D
Compound 6 15-epimeric Saint John's grass D 15-epi-hyperforatin D
Compound 7 Saint John grass element E Hyperforatin E
Compound 8 32-epimeric Saint John's grass element E 32-epi-hyperforatin E
Compound 9 Saint John grass element F Hyperforatin F
Compound 10 Saint John grass element G Hyperforatin G
Compound 11 Saint John grass element H Hyperforatin H
Compound 12 Saint John grass element I Hyperforatin I
Compound 13 15-epimeric Saint John's grass element I 15-epi-hyperforatin I
Compound 14 Saint John grass element J Hyperforatin J
Compound 15 Saint John grass element K Hyperforatin K
The inventor obtains 15 new compounds by separating and purifying ethanol extract of Hypericum perforatum (Hypericum perforatum) which is a medicinal plant. The phloroglucinol compound is determined to be phloroglucinol compound by comprehensively using a plurality of spectrum analysis methods and other means, and the specific structure is shown as a formula (1). The compounds 1-15 are found to have inhibitory effect on acetylcholinesterase by evaluating the acetylcholinesterase inhibitory activity of the compounds 1-15, wherein the compounds 3, 5, 6, 8 and 9 have good inhibitory effect on acetylcholinesterase.
Still another object of the present invention is to provide the use of the compound represented by formula (1) for the preparation of acetylcholinesterase-inhibiting drugs.
Drawings
FIG. 1: compound 2 crystal structure;
FIG. 2: the crystal structure of compound 6;
FIG. 3: compound 7 crystal structure.
Detailed Description
Example 1: preparation and structural characterization of Compounds 1-15.
(I) preparation of Compounds 1-15 represented by formula (1)
1. Plant information
The stem and leaf of the plant is picked from Shennong Jie area of Hubei province of the people's republic of China in 2014 8 months, and is identified as Hypericum perforatum (Hypericum perforatum) by professor Zhang Chang Long Bo of China university of science and technology. The plant specimen is stored in a specimen room of a natural medicine chemistry and resource evaluation key laboratory of college of Tongji medical college of Huazhong university of science and technology, and the specimen number is HP 20140826.
2. Extraction and separation
Pulverizing dry stem and leaf (105kg) of herba Hyperici perforati, extracting with 95% ethanol for 3 times, soaking at room temperature for 4-5 days, and concentrating under reduced pressure to obtain total extract 8.3 kg. Suspending the total extract in water, and extracting with dichloromethane to obtain dichloromethane part 3.8 kg. The dichloromethane part was subjected to silica gel column chromatography (100-200 mesh), petroleum ether: acetone was gradient eluted (100: 0-0: 100) and similar fractions were pooled by TLC to give 7 fractions (I-VII). Decolorizing component III with MCI column, removing pigment, and performing reversed phase C18Column chromatography (methanol-water, 50% -100%) yielded 8 components: components III 1 to III 8.
Wherein the component III 5 is subjected to silica gel column chromatography again, and the ratio of petroleum ether: acetone gradient elution (30: 0-0: 1) finally yielded 11 fractions: III 5a to III 5 k. Wherein III 5d was purified by gel column chromatography and reverse phase High Performance Liquid Chromatography (HPLC) to give compound 10, and chiral HPLC to give compounds 5 and 6. At the same time, we isolated compounds 7 and 8 from the other component III 5f using the same method as described above. Thereafter, we carried out further reverse phase column chromatography (methanol-water, 50% -85%) on 5g of fraction iii and obtained 5 fractions: III 5g 1-III 5g 5. Subsequently, we isolated compounds 1 and 2 from III 5g3 and compounds 12 and 13 from III 5g4 by semi-preparative HPLC.
And the component III 6 is prepared by silica gel column chromatography, petroleum ether: gradient elution with ethyl acetate (30: 0-0: 1) yielded 8 fractions: III 6 a-III 6 h. Wherein fraction III 6d gave compounds 3, 4, 14 and 15 using the same column chromatography as described above for 5 g. While compounds 9 and 11 were isolated by reverse phase column chromatography (methanol-water, 60% -90%) and semi-preparative HPLC of the other fraction III 6 c.
(II) structural identification of Compounds 1-15 represented by formula (1)
And comprehensively analyzing the data of the compounds 1-15 such as high resolution mass spectrum, ultraviolet spectrum, infrared spectrum, optical rotation, nuclear magnetic resonance, circular dichroism, X-ray single crystal diffraction and the like, thereby determining the structures of the compounds 1-15.
Compound 1, Colorless oil; [ alpha ]]26 D+80(c 1.6,CH3OH)；UV(CH3OH)λmax(logε)＝203(4.10)and 281(4.04)nm；ECD(CH3OH)λmax(Δε)205(-7.45),276(+30.04),305(-13.11)nm；IR(KBr)vmax3440,2973,2929,1722,1643,1616,1446,1383,1236cm–1；HRESIMS:m/z569.3860[M+H]+(calcd for C35H53O6569.3842.) Nuclear Magnetic Resonance (NMR) data of Compound 1 are shown in tables (2) and (4).
Compound 2, Colorless crystals, mp 163-165 ℃, [ alpha ] alpha]19 D+81(c 1.2,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.20)and 281(4.06)nm；ECD(CH3OH)λmax(Δε)203(-7.31),277(+28.95),305(-12.23)nm；IR(KBr)vmax3445,2976,2925,1725,1662,1620,1454,1383,1236cm–1；HRESIMS:m/z 569.3851[M+H]+(calcd for C35H53O6569.3842.) Nuclear Magnetic Resonance (NMR) data of Compound 2 are shown in tables (2) and (4), and the crystal structure is shown in FIG. 1.
Compound 3, Colorless oil; [ alpha ]]29 D+85(c 2.5,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.23)and 273(3.97)nm；ECD(CH3OH)λmax(Δε)207(-8.84),269(+29.05),299(-7.95)nm；IR(KBr)vmax3437,2974,2929,1724,1642,1616,1446,1384,1226cm–1；HRESIMS:m/z569.3846[M+H]+(calcd for C35H53O6569.3842.) Nuclear Magnetic Resonance (NMR) data of Compound 3 are shown in tables (2) and (4).
Compound 4, Colorless oil [ α ]]30 D+16(c 2.4,CH3OH)；UV(CH3OH)λmax(logε)＝203(4.54)and 272(4.29)nm；ECD(CH3OH)λmax(Δε)205(-9.69),269(+24.88),299(-11.44)nm；IR(KBr)vmax3434,2974,2929,1725,1648,1616,1445,1384,1234cm–1；HRESIMS:m/z569.3838[M+H]+(calcd for C35H53O6569.3842.) Nuclear Magnetic Resonance (NMR) data of Compound 4 are shown in tables (2) and (4).
Compound 5, Colorless oil [ α ]]26 D+12(c 0.5,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.41)and 280(4.21)nm；ECD(CH3OH)λmax(Δε)207(-6.24),275(+17.08),304(-10.51)nm；IR(KBr)vmax3437,2975,2930,1722,1656,1621,1445,1383,1243cm–1；HRESIMS:m/z605.3828[M+Na]+(calcd for C36H54O6Na,605.3818) Nuclear Magnetic Resonance (NMR) data for compound 5 are shown in tables (2) and (4).
Compound 6, Colorless crystals, mp 108-110 ℃, [ alpha ] alpha]26 D+54(c 0.6,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.31)and 280(4.29)nm；ECD(CH3OH)λmax(Δε)205(-11.40),276(+34.12),305(-14.21)nm；IR(KBr)vmax3442,2975,2929,1724,1655,1620,1446,1382,1238cm–1；HRESIMS:m/z 583.3992[M+H]+(calcd for C36H55O6583.3999.) Nuclear Magnetic Resonance (NMR) data of Compound 6 are shown in tables (2) and (5), and the crystal structure is shown in FIG. 2.
Compound 7, Colorless crystals, mp 108-109 ℃, [ alpha ] alpha]26 D+66(c 0.3,CH3OH)；UV(CH3OH)λmax(logε)＝203(4.42)and 273(4.29)nm；ECD(CH3OH)λmax(Δε)227(+12.73),248(-4.16),273(+13.80),302(-4.92)nm；IR(KBr)vmax3437,2970,2926,1731,1626,1449,1377,1237,1212cm–1；HRESIMS:m/z 569.3857[M+H]+(calcd for C35H53O6,569.3842). Nuclear Magnetic Resonance (NMR) data of compound 7 are shown in tables (2) and (5), and the crystal structure is shown in fig. 3.
Compound 8, Colorless oil [ α ]]26 D+71(c 0.8,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.27)and 273(4.20)nm；ECD(CH3OH)λmax(Δε)227(+13.92),248(-4.30),273(+14.36),302(-4.76)nm；IR(KBr)vmax3438,2973,2927,1730,1627,1451,1365,1237,1212cm–1；HRESIMS:m/z 569.3836[M+H]+(calcd for C35H53O6569.3842.) Nuclear Magnetic Resonance (NMR) data of Compound 8 are shown in tables (2) and (5)
Compound 9, Colorless oil [ α ]]22 D+52(c 0.4,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.20)and 273(4.01)nm；ECD(CH3OH)λmax(Δε)225(+7.40),247(-1.90),271(+9.70),301(-2.86)nm；IR(KBr)vmax3449,2971,2925,1730,1622,1451,1366,1237,1209cm–1；HRESIMS:m/z 525.3547[M+H]+(calcd for C33H49O5525.3580.) Nuclear Magnetic Resonance (NMR) data of Compound 9 are shown in tables (3) and (5)
Compound 10, Colorless oil [ α ]]29 D+48(c 0.6,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.05)and273(3.93)nm；ECD(CH3OH)λmax(Δε)227(+6.47),248(-2.63),273(+7.23),302(-2.60)nm；IR(KBr)vmax3441,2972,2927,1731,1624,1452,1366,1237,1213cm–1；HRESIMS:m/z 569.3866[M+H]+(calcd for C35H53O6,569.3842)。
Nuclear Magnetic Resonance (NMR) data of compound 10 are shown in table (3) and table (5).
Compound 11, Colorless oil [ α ]]28 D+34(c 0.5,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.10)and 283(4.00)nm；ECD(CH3OH)λmax(Δε)242(-5.64),276(+15.73),302(-12.03)nm；IR(KBr)vmax3442,2972,2929,1729,1623,1408,1384,1236,1182cm–1；HRESIMS:m/z569.3851[M+H]+(calcd for C35H53O6569.3842.) Nuclear Magnetic Resonance (NMR) of Compound 11Data are shown in tables (3) and (6)
Compound 12, Colorless oil [ α ]]21 D+23(c 0.4,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.12)and 282(3.93)nm；ECD(CH3OH)λmax(Δε)243(-4.16),277(+13.37),302(-9.97)nm；IR(KBr)vmax3434,2972,2927,1727,1614,1447,1409,1382,1236cm–1；HRESIMS:m/z591.3660[M+Na]+(calcd for C35H52O6Na,591.3662) Nuclear Magnetic Resonance (NMR) data of Compound 12 are shown in tables (3) and (6)
Compound 13, Colorless oil [ α ]]21 D-28(c 0.3,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.20)and 282(4.03)nm；ECD(CH3OH)λmax(Δε)244(-4.79),276(+10.41),301(-10.55)nm；IR(KBr)vmax3435,2960,2925,1726,1617,1451,1408,1382,1230cm–1；HRESIMS:m/z591.3657[M+Na]+(calcd for C35H52O6Na,591.3662) Nuclear Magnetic Resonance (NMR) data of Compound 13 are shown in tables (3) and (6)
Compound 14, Colorless oil [ α ]]28 D+42(c 4.3,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.49)and 272(4.30)nm；ECD(CH3OH)λmax(Δε)242(-4.07),269(+12.90),294(-6.81)nm；IR(KBr)vmax3435,2972,2928,1730,1621,1446,1411,1383,1214cm–1；HRESIMS:m/z569.3860[M+H]+(calcd for C35H53O6569.3842.) Nuclear Magnetic Resonance (NMR) data of Compound 14 are shown in tables (3) and (6)
Compound 15, Colorless oil [ α ]]28 D-10(c 2.4,CH3OH)；UV(CH3OH)λmax(logε)＝202(4.35)and 273(3.97)nm；ECD(CH3OH)λmax(Δε)243(-3.74),270(+8.89),296(-5.05)nm；IR(KBr)vmax3435,2973,2928,1728,1620,1446,1412,1384,1215cm–1；HRESIMS:m/z 569.3832[M+H]+(calcd for C35H53O6569.3842.) Nuclear Magnetic Resonance (NMR) data of Compound 15 are shown in tables (3) and (6)
TABLE (2) of Compounds 1 to 813C NMR data (Record in CD)3OD).
Figure BDA0001278756030000091
Figure BDA0001278756030000101
TABLE (3) of Compounds 9 to 1513C NMR data (Record in CD)3OD).
Figure BDA0001278756030000102
Figure BDA0001278756030000111
TABLE (4) of Compounds 1 to 51H NMR data (Record in CD)3OD；J in Hz).
Figure BDA0001278756030000112
Figure BDA0001278756030000121
TABLE (5) of Compounds 6 to 101H NMR data (Record in CD)3OD；J in Hz).
Figure BDA0001278756030000122
Figure BDA0001278756030000131
TABLE (6) of Compounds 11 to 151H NMR data (Record in CD)3OD；J in Hz).
Figure BDA0001278756030000132
Example 2: the inhibition of acetylcholinesterase by compounds 1-15.
The inhibitory effect of compounds 1-15 on acetylcholinesterase was determined by the Ellman method, and the results are shown in Table (7).
TABLE (7) inhibition of acetylcholinesterase by Compounds 1-15
Figure BDA0001278756030000141
And (4) experimental conclusion: the compounds 1-15 have inhibitory effect on acetylcholinesterase. Among them, the compounds 3, 5, 6, 8 and 9 have obvious inhibition effect on acetylcholinesterase, and the compounds 1, 4, 11 and 15 have better acetylcholinesterase inhibition activity.

Claims (5)

1. Phloroglucinol compounds 1 to 15 with the structure shown in formula (1),
Figure FDA0002274576590000011
Figure FDA0002274576590000021
Figure FDA0002274576590000031
Figure FDA0002274576590000041
2. the method for preparing phloroglucinol compounds according to claim 1, wherein the phloroglucinol compounds 1 to 15 are obtained by separation and purification from Hypericum perforatum;
the method comprises the following steps:
s1, crushing dried stem leaves of hypericum perforatum, extracting for 3 times by using 95% ethanol in a multifunctional extraction tank, soaking for 4-5 days at room temperature each time, and concentrating under reduced pressure to obtain a total extract;
s2, suspending the total extract obtained in the step S1 in water, extracting with dichloromethane, and recovering the solvent under reduced pressure to finally obtain a total extract of a dichloromethane part;
s3, performing 100-200 mesh silica gel column chromatography on the dichloromethane part of the dichloromethane total extract obtained in S2, wherein petroleum ether: gradient elution with acetone 100: 0-0: 100, detecting and merging similar parts by TLC to obtain 7 components I-VII; decolorizing the component III by an MCI column, removing pigments, and performing column chromatography by methanol-water and 50-100% reverse phase C18 to obtain 8 components: components III 1 to III 8; wherein the component III 5 is subjected to silica gel column chromatography again, and the ratio of petroleum ether: acetone gradient elution finally yielded 11 fractions: III 5a to III 5 k; wherein III 5d is purified by gel column chromatography and reversed-phase high performance liquid chromatography to obtain a compound 10, and compounds 5 and 6 are obtained by a chiral HPLC method; at the same time, compounds 7 and 8 were isolated from the other fraction III 5f using the same method as described above; then, further methanol-water, 50% -85% reverse phase column chromatography was performed on 5g of fraction iii and 5 fractions were obtained: III 5g 1-III 5g 5; subsequently, compounds 1 and 2 were isolated from III 5g3 and compounds 12 and 13 were isolated from III 5g4 by semi-preparative HPLC; and the component III 6 is prepared by silica gel column chromatography, petroleum ether: gradient elution with ethyl acetate 30: 0-0: 1 gave 8 fractions: III 6 a-III 6 h; wherein fraction III 6d gives compounds 3, 4, 14 and 15 using the same column chromatography separation method as described above for 5 g; while compounds 9 and 11 were isolated from the other component III 6c by methanol-water, 60% -90% reverse phase column chromatography and semi-preparative HPLC.
3. Use of any one of compounds 1-15 according to claim 1 for the manufacture of a medicament for the inhibition of acetylcholinesterase.
4. Use of a compound 3, 5, 6, 8 or 9 as claimed in claim 1 for the manufacture of a medicament for the inhibition of acetylcholinesterase.
5. The use of any one of compounds 1-15 according to claim 1 for the manufacture of a medicament for the treatment of alzheimer's disease.
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