CN113024525B - Indole and quinazolone alkaloid and medical application thereof - Google Patents
Indole and quinazolone alkaloid and medical application thereof Download PDFInfo
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07—ORGANIC CHEMISTRY
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- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Abstract
The invention belongs to the technical field of medicines, relates to indole and quinazolinone alkaloids and medical application thereof, and particularly relates to optically pure indole and quinazolinone alkaloids extracted from blue leaves (folium isatidis) of cabbage leaves of plants and application of the compounds in preparation of neuroprotective drugs. The indole and quinazolone alkaloid or the salt thereof has the following structure. The invention also relates to a pharmaceutical composition of the quinazolinone alkaloid or the salt thereof and application of the quinazolinone alkaloid or the salt thereof in preparing neuroprotective drugs.
Description
The technical field is as follows:
the invention belongs to the technical field of medicines, relates to indole and quinazolinone alkaloids and medical application thereof, and particularly relates to optically pure indole and quinazolinone alkaloids extracted from blue leaves (folium isatidis) of cabbage leaves of plants and application of the compounds in preparation of neuroprotective drugs.
Background art:
stem of blue (Isatis indigotica Fortune): is plant of genus Isatis of family Brassicaceae (Cruciferae). Native China has cultivation all over the country. The root (isatis root) and the leaf (dyers woad leaf) can be used as medicines, and have the effects of clearing away heat and toxic materials, cooling blood, removing ecchymoses, relieving sore throat and relieving pain. Is mainly used for treating the initial stage of nutrient-blood warm diseases and the exogenous wind-heat syndrome caused by warm-heat virus in clinic. In addition, the research on the health-care functions of the plants such as anti-aging, beauty treatment and the like in recent years provides better development prospects for the development and research of health-care foods and new medicines of the plants.
Oxidative Stress (OS): it refers to a pathological condition in which excessive production of active oxygen in the body leads to imbalance of oxidation and antioxidant systems, resulting in oxidative damage of cells or tissues. Reactive Oxygen Species (ROS) cause oxidative damage to DNA, proteins, lipids, etc., destroy the structural and functional integrity of cells, cause apoptosis or necrosis, and are associated with various diseases.
The models for researching oxidative stress at home and abroad are mainly divided into an animal model and an in-vitro cell culture model, wherein the in-vitro cell culture model which is most widely applied is H2O2Model of oxidative damage. H2O2As one of the active oxygen substances, the active oxygen substance not only can easily permeate cell membranes to react with iron ions in cells to generate high-activity free radicals, but also is easy to obtain and stable in property, and has become an important tool for researching the oxidative damage of various cells at home and abroad.
Aging (senility) and oxidative stress: aging is a complex life process involving all aspects of life. Such as gene regulation disorder, apoptosis, free radical damage, substance metabolism imbalance, reduction of antioxidant enzyme activity, immune dysfunction, neuroendocrine disorder, tissue cell degeneration, reduction of physiological function, etc. Among them, the theory of free radical aging considers that free radical damage plays an important role in aging, and is a main 'micro-damage' factor causing body aging. Also, it is an effective way to delay aging and reduce cell damage by counteracting or reducing the imbalance of oxidation and antioxidant systems caused by excessive ROS production in vivo
The invention content is as follows:
the invention provides four kinds of indole and quinazolone alkaloids or salts thereof, which have the following structures:
the indole and quinazolone alkaloids are separated from leaf of cabbage (Isatis indigotica fortunei) of Brassicaceae cabbage (Isatis indigotica fortine).
The technical scheme for preparing the indole and quinazolinone alkaloid comprises the following steps:
(1) extracting dry cabbage blue leaves with 70-80% industrial ethanol, concentrating the extractive solution to obtain extract, and extracting the extract with dichloromethane.
(2) Subjecting the extract obtained from the dichloromethane extraction solution to silica gel column chromatography, and performing column chromatography with a dichloromethane-methanol system 100:1-3:1 gradient elution was performed and a total of 4 fractions A, B, C, D were collected.
(3) Eluting fraction C with 30% -90% (30%, 60%, 90%) ethanol-water by polyamide column chromatography to obtain three components C1、C2、C3。
(4) Followed by the addition of component C1Eluting with alcohol-water system with HP-20 column chromatography gradient 0:100-90:10 to obtain 3 fractions C1.1、C1.2、C1.3。
(5) C is to be1.3Further eluting with alcohol-water system 10:90-90:10 by ODS column chromatography to obtain 2 fractions C1.3.1、C1.3.2。
(6) Component C obtained1.3.1Gradient elution was performed by silica gel column chromatography with petroleum ether-ethyl acetate system 50:1-1:1, and the resulting fractions were purified by methanol-water 35: 65-40: 60 preparation and semi-preparation HPLC acetonitrile-water 18:82 gave compounds 1,2,3 and 4.
(7) The four compounds were resolved using chiral column chromatography using Daicel Chiralpak IG in acetonitrile/water system 50:50-60:40 to give compounds 1a and 1b, and Daicel Chiralpak IC column in n-hexane/isopropanol system 3:1-2:1 to give compounds 2a and 2 b. Compounds 3a and 3b were obtained using Chiralpak AD-H with a n-hexane to isopropanol system 8:1-6: 1.4 a and 4b were obtained using Daicel chiralpak IG with n-hexane: isopropanol system 1:1-1: 2.
The extraction in the step (1) is reflux extraction for 2-3 times, and each time lasts for 3-4 hours.
The leaf of cabbage leaf of the step (1) is leaf of Brassicaceae (Cruciferae), Isatis indigotica genus plant, cabbage blue (Isatis indigotica fortine).
The compound obtained is identified by the system structure as follows:
the planar structures of the compounds 1,2,3 and 4 were identified by ultraviolet spectroscopy, high resolution mass spectrometry, and one-dimensional and two-dimensional NMR techniques. And determining the absolute configuration of the split optically pure compound 1a/1b-2a/2b-3a/3b-4a/4b by utilizing actually measured ECD, calculated ECD comparison and calculated nuclear magnetic technology.
Resolving the compound 1 by a Daicel Chiralpak IG chiral chromatographic column to obtain 1a
And
the ratio is about 3:2, with the CD spectra being mirrored. Their absolute configuration is determined by comparing calculated and measured ECDs. The experimental CD curve of 1a is matched to the calculated ECD curve preset to a 3R configuration, while the experimental CD curve of 1b is matched to the calculated ECD curve of a 3S configuration. Thus defining 1a and 1bThe absolute configurations are 3R and 3S, respectively, and are named as isatindeindoline E1And isatindiindoline E2。
The relative configuration of compound 2 is determined by NOESY spectra in which the presence of a hydroxy hydrogen at the C-6 'position and a methoxy hydrogen at the C-1' position are correlated, indicating that these two groups are on the same side, thereby determining that the hydroxy group at the C-6 'position and the methoxy group at C-1' of the relative configuration of the compound are in the beta orientation.
Resolving the compound 2 by a Daicel Chiralpak IC chiral chromatographic column to obtain the compound
And
at a ratio of about 1:1, their CD spectra are approximately mirror images. Their absolute configuration is determined by comparing calculated and measured ECDs. The experimental CD curves of 2a and 2b were fitted to the calculated ECD curves preset to 1'R,6' R and 1'S,6' S configurations, respectively. Thus, it was determined that the absolute configurations of 2a and 2b were 1'R,6' R and 1'S,6' S, respectively, and named as isatindoleacetonitriline A1And isatindoleacetonitriline A2。
Resolving the compound 3 by a Chiralpak AD-H chiral chromatographic column to obtain the compound
And
in a ratio of about 1:1, their CD spectra are mirrored. Their absolute configuration is determined by comparing calculated and measured ECDs. The experimental CD curves of 3a and 3b were fitted to the calculated ECD curves preset for 3aS and 3aR configurations, respectively. Thus, the absolute configurations of 3a and 3b were determined to be 3aS and 3aR, respectively. And is named deoxyvsicinone A1And deoxyvsicinone A2。。
Resolving compound 4 by Daicel chiralpak IG chiral chromatographic column to obtain
And
in a ratio of about 3:2, their CD spectra are approximately mirror images. Their absolute configuration is by comparisonECD is calculated and measured. The experimental CD curve of 4a is matched to the calculated ECD curve preset for the 4R configuration, while the experimental CD curve of 4b is matched to the calculated ECD curve of the 4S configuration. Thus, it was confirmed that the absolute configurations of 4a and 4b were 4R and 4S, respectively, and they were named Cycloanthralkylproline A1And Cycloanthrylproline A2。
The nuclear magnetic data for compounds 1a/1b, 2a/2b, 3a/3b, 4a/4b are shown in the following table:
TABLE 11 a/1b, 2a/2b, 3a/3b, 4a/4b in DMSO-d6In1H (400MHz) and13c (100MHz) NMR data
Four novel alkaloid compound pairs H2O2The induced nerve protection effect of human SH-SY5Y nerve cell injury is investigated, and in vitro cell test results show that the indole and quinazolinone alkaloid has the nerve cell protection effect, and particularly the compounds 1a and 4b have the H protection effect2O2The induced oxidative damage of human SH-SY5Y cells has obvious protective effect.
Description of the drawings:
figure 1 UV spectrum of compound 1;
FIG. 2 HRESIMS spectra of Compound 1;
FIG. 3 HMBC spectra (600MHz, CDCl) of Compound 13)；
FIG. 4 HSQC spectra (600MHz, CDCl) of Compound 13)；
FIG. 5 chiral resolution chromatogram of Compound 1;
FIG. 6 CD spectra of Compound 1 a;
FIG. 7 CD spectrum of Compound 1 b;
FIG. 8 UV spectrum of Compound 2;
FIG. 9 HRESIMS spectrum of Compound 2;
FIG. 10 HMBC spectra (600MHz, CDCl) of Compound 23)；
FIG. 11 HSQC spectra (600MHz, CDCl) of Compound 23)；
Figure 12 chiral resolution chromatogram of compound 2;
figure 13 CD spectrum of compound 2 a;
figure 14 CD spectrum of compound 2 b;
FIG. 15 UV spectrum of Compound 3;
FIG. 16 HRESIMS spectrum of Compound 3;
FIG. 17 HMBC spectra (600MHz, CDCl) of Compound 33)；
FIG. 18 HSQC spectra (600MHz, CDCl) of Compound 33)；
Figure 19 chiral resolution chromatogram of compound 3;
FIG. 20 CD spectrum of compound 3 a;
figure 21 CD spectrum of compound 3 b;
FIG. 22 UV spectrum of Compound 4;
FIG. 23 HRESIMS spectrum of Compound 4;
FIG. 24 HMBC spectra (600MHz, CDCl) of Compound 43)；
FIG. 25 HSQC spectra (600MHz, CDCl) of Compound 43)；
FIG. 26 chiral resolution chromatogram of Compound 4;
figure 27 CD spectrum of compound 4 a;
FIG. 28 CD profile of Compound 4 b;
figure 29 calculated ECD spectra for compounds 1,2,3, 4;
the specific implementation mode is as follows:
the examples set out below are intended to assist the person skilled in the art in a better understanding of the invention, but do not limit it in any way.
Example 1: preparation of Compounds 1a/1b-4a/4 b.
A method for preparing indole and quinazolone alkaloids compounds from leaf of cabbage comprises reflux-extracting dry leaf of cabbage with 80% industrial ethanol twice (4 hr each time), mixing extractive solutions, concentrating to obtain 4280g extract, extracting the extract with dichloromethane, and extracting supernatant with n-butanol. The dichloromethane layer obtained therein was combined to obtain 864g of crude fraction, which was subjected to silica gel column chromatography and gradient elution with dichloromethane-methanol system 100:1-3:1 to collect a total of 4 fractions A, B, C, D.
Fraction C (864g) was eluted with polyamide in 30% ethanol-water, 60% ethanol-water and 90% ethanol-water to give three fractions C1、C2、C3。
Followed by the addition of component C1(88.9g) gradient elution with alcohol-water system 0:100-90:10 using HP-20 column chromatography gave 3 fractions C1.1、C1.2、C1.3。
C is to be1.3(15.5g) further gradient elution was performed by ODS column chromatography using an alcohol-water system 10:90-90:10 to give 2 fractions C1.3.1、C1.3.2。
Component C obtained1.3.1(6.0g) gradient elution by silica gel column chromatography with Petroleum ether-Ethyl acetate System 50:1-1:1 and preparative and semi-preparative HPLC (acetonitrile-water 18:82) of the resulting fractions gave Compound 1(4.1mg, tR＝42min)、2(5.8mg,tR＝50min)、3(4.4mg,tR＝54min)、4(18.1mg,tR＝56min)。
The four compounds were then resolved using chiral column chromatography using Daicel Chiralpak IG in acetonitrile: water 53:47 to give compound 1a (2.8mg, t;)R14.8min) and 1b (1.9mg, t)R19.5min) and purified using a Daicel Chiralpak IC column with n-hexane: isopropanol 3:1 to give compound 2a (1.8mg, t:), and purified using a column chromatography columnR41min) and 2b (1.5mg, t)R45 min). Compound 3a (11.0mg, t) was obtained using Chiralpak AD-H as n-hexane: isopropanol 8:1R20.8min) and 3b (8.0mg, t)R25.0 min). Using Daicel chiralpak IG, 4a (2.2mg, t) was obtained as n-hexane: isopropanol 1:1R60.9min) and 4b (1.4mg, t)R＝89.7min)。
Example 2: compounds 1a/1b-2a/2b on H in vitro2O2And (3) the research of the protective effect of the induced human SH-SY5Y nerve cell damage.
Investigation of Compound Pair H Using MTT assay2O2Protection against induced SH-SY5Y cell damage. The cells were placed in a 96-well plate, left to stand for 12H in 100. mu.L of culture medium, SH-SY5Y nerve cells were pretreated for 1H with different concentrations of compound 1a/1b-4a/4b (12.5,25, 50. mu.M), and H2O2Cells were treated (1mM) for 36 h. The culture broth was then replaced with phosphate buffer solution containing 0.5mg/mL MTT and left at 37 ℃ for 4 h. The supernatant was removed and DMSO (150 mL/well) was added as H2O2(1mM) cells treated alone were used as a control, and different concentrations of treated cells were detected using an ultraviolet spectrophotometer at 490nm (Thermo Scientific Multiskan MK3, Shanghai, China). The degree of survival of the cells was expressed as percent survival and analyzed using GraphPad Prism 6 software. The results show that the compounds 1a/1b-4a/4b show remarkable protective effect under different concentrations. 1a/1b, 3a and 4a/4b have the strongest effect under the concentration of 50 mu M, and compared with 67.9 +/-4.23 percent of positive drugs, the cell survival rate reaches 77.2 +/-2.88 percent, 69.9 +/-1.42 percent, 63.1 +/-1.03 percent and 61.1 +/-3.15 percent. 2b and 3b have the strongest effect under the concentration of 12.5 mu M, and compared with 64.1 +/-4.89% of the positive drug, the cell survival rate reaches 65.8 +/-3.29% and 64.4 +/-2.03%. 2a and 4b have the strongest effect under the concentration of 25 mu M, and compared with 65.2 +/-1.98 percent of the positive drug, the cell survival rate reaches 63.7 +/-3.54 percent and 72.1 +/-0.98 percent.
TABLE 2 percentage of cell survival after dosing
Percent cell survival in model group compared to control group###P<0.001; percent cell survival in experimental versus model groups<0.01,***P<0.01。
Claims (7)
1. Indole and quinazolinone alkaloids shown in the following structures or salts thereof:
2. a process for preparing the indole and quinazolinone alkaloid or salt thereof according to claim 1,
(1) extracting dry cabbage blue leaves with ethanol, concentrating the extract to obtain an extract, and extracting the extract with dichloromethane;
(2) concentrating the dichloromethane extract to obtain an extract, and performing silica gel column chromatography on the extract at a ratio of 100:1-3: gradient elution is carried out on 1 dichloromethane/trichloromethane-methanol, and 4 fractions A, B, C, D are collected in total;
(3) subjecting the fraction C to polyamide column chromatography, and gradient eluting with 30% -90% ethanol-water system to obtain three components C1、C2、C3；
(4) Component C1Eluting with HP-20 column chromatography in ethanol-water system at a gradient of 0:100-90:10 to obtain 3 fractions C1.1、C1.2、C1.3；
(5) C is to be1.3Further performing ODS column chromatography with ethanol-water system gradient of 10:90-90:10 to obtain 2 fractions C1.3.1、C1.3.2；
(6) Component C obtained1.3.1Gradient eluting with petroleum ether-ethyl acetate system 50:1-1:1 by silica gel column chromatography, and subjecting the obtained components to preparative and semi-preparative HPLC to obtain compounds 1,2,3 and 4;
resolving compounds 1, 4 with Daicel Chiralpak IG to give compounds 1a and 1b when acetonitrile: water =50:50-60: 40; when n-hexane to isopropanol =1:1-1:2, 4a and 4b are obtained; resolving compound 2 with Daicel Chiralpak IC to obtain compounds 2a and 2b when n-hexane: isopropanol =3:1-2: 1; and (3) resolving the compound 3 by using Chiralpak AD-H to obtain the compounds 3a and 3b when n-hexane: isopropanol =8:1-6: 1.
3. The method according to claim 2, wherein the ethanol in the step (1) is 70 to 80% industrial ethanol; the extraction is reflux extraction for 2-3 times, each for 3-4 hr.
4. The process according to claim 2, said leaf of cabbage leaf of Brassicaceae cabbage genus plant Bmcorn (cabbage) leaf of BrassicaceaeIsatis indigotica Fortune) And (4) leaves.
5. A pharmaceutical composition comprising the indole and quinazolinone alkaloid of claim 1 or a salt thereof and a pharmaceutically acceptable carrier or excipient.
6. The use of the indole and quinazolinone alkaloid of claim 1 or a salt thereof or the pharmaceutical composition of claim 5 in the preparation of neuroprotective drugs.
7. The use of the indole and quinazolinone alkaloid or salt thereof according to claim 1 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for protecting SH-SY5Y nerve cell damage.
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Non-Patent Citations (4)
| Title |
|---|
| Alkaloids with neuroprotective effects from the leaves of Isatis indigotica collected in the Anhui Province, China;Si-Fan Liu等;《Phytochemistry》;20180228;第149卷;第132-139页 * |
| Antiviral enantiomers of a bisindole alkaloid with a new carbon skeleton from the roots of Isatis indigotica;Yu-Feng Liu等;《Chinese Chemical Letters》;20150605;第26卷;第931-936页 * |
| Bioactive spiropyrrolizidine oxindole alkaloid enantiomers from Isatis indigotica Fortune;Si-Fan Liu等;《Org. Biomol. Chem.》;20181127;第16卷;第9430-9439页 * |
| New Alkaloids from Isatis indigotica;Xiaoyun Wu等;《Tetrahedron》;19971231;第53卷(第39期);第13323-13328页 * |
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