CN114890978B - Phenolic compound, and preparation method and application thereof - Google Patents
Phenolic compound, and preparation method and application thereof Download PDFInfo
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
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Abstract
The invention relates to a phenolic compound and a preparation method and application thereof, in particular to a phenolic compound in hawthorn fruits and a preparation method and application thereof, belonging to the technical field of medicines. Phenolic compounds and pharmaceutically acceptable salts and isomers thereof, wherein the phenolic compounds have chemical structural formulas shown in the following formula I, formula II or formula III,
Description
Technical Field
The invention relates to a phenolic compound and a preparation method and application thereof, in particular to a phenolic compound in hawthorn fruits and a preparation method and application thereof, belonging to the technical field of medicines.
Background
Parkinson's Disease (PD), a common neurodegenerative disease, is clinically manifested as bradykinesia (bradykinesia and completion), stiffness (increased muscular tension), tremors, and abnormal postural reflex, wherein an idiopathic case is Parkinson's Disease (PD), an idiopathic lesion of adult onset. The degenerative death of the midbrain substantia nigra dopaminergic neurons results in a significant decrease in striatal dopaminergic neuron content and the pathogenesis is the primary pathological change. PD is common among the elderly, and in young parkinson's disease with an average age of about 60 years and less than 40 years. The prevalence of PD in people over 65 years old in China is about 1.7%. Most parkinson's disease patients are sporadic cases, with less than 10% of patients having a family history. The exact etiology leading to this pathological change is currently unknown, and genetic factors, environmental factors, age-related aging, oxidative stress, etc. may be involved in the degenerative death process of dopaminergic neurons, but there is sufficient evidence that increased apoptosis due to oxidative stress is closely related to dopaminergic neuronal degenerative changes. Hydrogen peroxide (H) 2 O 2 ) Model of induced SH-SY5Y cell parkinson's disease: h 2 O 2 The method has the advantages that the method has damage to the dopamine nerve cells, toxic hydroxyl groups are generated under the catalysis of ferrous ions, and the damaged cells can enable the dopaminergic nerve cells to be placed in an oxidative stress state. The literature has previously reported that hawthorns (crataegus pinnatifida bge.) have a variety of chemical components, some of which are found to have better neuroprotective activity.
Disclosure of Invention
The phenolic compound is prepared by extracting fruits of hawthorn (Crataegus pinnatifida bge.) and has good neuroprotective activity. The phenolic compound is extracted and separated from fructus crataegi of the genus Crataegus of the family Inonotus. The compounds and the activity thereof related to the invention have not been reported in patents or documents so far.
Phenolic compounds and pharmaceutically acceptable salts and isomers thereof, wherein the phenolic compounds have chemical structural formulas shown in the following formula I, formula II or formula III,
the phenolic compound and pharmaceutically acceptable salts and isomers thereof are extracts obtained by extracting hawthorn fruits.
It is another object of the present invention to provide a process for producing the above-mentioned phenolic compound.
The preparation method of the phenolic compound comprises the following process steps:
s1, extracting and concentrating haw fruits by using ethanol to obtain extract, extracting the obtained extract by using ethyl acetate and n-butanol in sequence, performing isocratic gradient elution on an ethyl acetate part and an n-butanol part by using a silica gel column chromatography by using a dichloromethane-methanol system of 100:1-5:1, and collecting 4 fractions I-IV in total;
s2, performing gradient elution on the fraction I through HP20 column chromatography by using an ethanol-water system to obtain 2 fractions A1 and A2;
s3, separating the fractions A1 and A2 through ODS column, performing gradient elution by using an ethanol-water system, and combining and collecting to obtain 5 fractions Fr.1, fr.2, fr.3, fr.4 and Fr.5;
s4, fr.3, fr.4 is separated by silica gel column, and is subjected to gradient elution by methylene chloride-methanol system, wherein the eluted fraction is subjected to preparative HPLC, and CH is used as the eluent 3 OH-H 2 Eluting with O, and subjecting to semi-preparative HPLC chromatography with CH 3 CN-H 2 O is eluted, separated and purified to obtain 1, a compound 2 and a compound 3.
Preferably, in the step S1, the dried haw fruit is extracted with 70% industrial ethanol under reflux for 3 times, each for 4 hours, and the extracts are combined and concentrated to obtain the extract.
Preferably, in the step S1, the ratio of dichloromethane-methanol is 100:1, 50:1, 30:1, 20:1, 10:1,5:1, respectively.
Preferably, in the step S2, the ethanol-water system is 30%,60%,90% ethanol-water system; in the step S3, the ethanol-water system is 40%,50%,60%,70%,80% ethanol-water system.
It is a further object of the present invention to provide pharmaceutical compositions comprising the above phenolic compounds and the use of the above phenolic compounds.
A pharmaceutical composition comprises the phenolic compound, pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier, wherein the phenolic compound has a chemical structural formula shown in the following formula I, formula II or formula III,
the invention relates to application of phenolic compounds and pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in preparing medicines for preventing or treating parkinsonism.
Further, the phenolic compound and pharmaceutically acceptable salt thereof or the pharmaceutical composition of the invention are used for preparing drugs for preventing or treating H 2 O 2 Use of an induced neuroprotective active agent against oxidative damage to SH-SY5Y cells in humans.
The beneficial effects of the invention are as follows: the invention extracts three new phenolic compounds isolated from dried mature fruits of the plant hawthorns (Crataegus pinnatifida bge.) of the genus hawthorns of the family micro-family inopsis: (+) -Crataegusol L, (-) -Crataegusol L, crataegusoid H. The compound is obtained by adopting chromatographic methods such as silica gel, HP20 column chromatography, ODS column chromatography, HPLC and the like. Meanwhile, the invention also discloses the anti-Parkinson's syndrome (PD) neuroprotective activity of the compound (+) -Crataegusol L, (-) -Crataegusol L and Crataegusoid H in preparation of medicaments and medical application thereof. The preparation method is simple, good in reproducibility and high in purity. The obtained compound has good PD resisting activity.
Drawings
Fig. 1: compound 1/2 (+) -hresis;
fig. 2: compounds 1/2 1 H NMR spectra (400 MHz, CDCl) 3 )；
Fig. 3: compounds 1/2 13 C NMR spectra (100 MHz, CDCl) 3 )；
Fig. 4: compound 1/2HMBC spectra (600 MHz, CDCl) 3 )；
Fig. 5: compound 1/2NOESY spectrum (600 MHz, CDCl) 3 )；
Fig. 6: compound 1/2ECD scheme (MeOH);
fig. 7: (+) -hresis of compound 3;
fig. 8: compound 3 1 H NMR spectra (400 MHz, CDCl) 3 )；
Fig. 9: compound 3 13 C NMR spectra (100 MHz, CDCl) 3 )；
Fig. 10: HMBC spectra of Compound 3 (600 MHz, CDCl) 3 )。
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way.
The test methods described in the following examples, unless otherwise specified, are all conventional; the reagents and materials, unless otherwise specified, are commercially available.
Example 1
The preparation method of the phenolic compound comprises the following process steps:
s1, reflux-extracting dried hawthorn fruits (50 kg) with 70% industrial ethanol for 3 times, 4 hours each time, combining the extracting solutions and concentrating to obtain extractum. The obtained extract is extracted by ethyl acetate and n-butanol successively. The ethyl acetate fraction (600 g) and the n-butanol fraction (1000 g) were subjected to silica gel column chromatography, and subjected to isocratic gradient elution with a methylene chloride-methanol system, and 4 fractions I to IV were collected in total, wherein the gradient of the methylene chloride-methanol system is as follows: 100:1, 50:1, 30:1, 20:1, 10:1,5:1.
S2, performing gradient elution on the fraction I (132 g) through HP20 column chromatography by using an ethanol-water system to obtain 2 fractions A1 and A2, wherein the gradient of the ethanol-water system is as follows: 30%,60%,90% ethanol-water system
S3, separating fractions A1 (40 g) and A2 (80 g) by ODS column respectively, performing gradient elution by an ethanol-water system, and combining and collecting to obtain 5 fractions (Fr.1, fr.2, fr.3, fr.4, fr.5), wherein the gradient of the ethanol-water system is 40%,50%,60%,70% and 80%.
S4, fr.3 (15 g), fr.4 (10 g) was separated by a silica gel column and eluted with a gradient through a dichloromethane-methanol 50:1, 30:1, 20:1, 10:1 system, wherein the eluted fraction was subjected to preparative HPLC on CH 3 OH-H 2 O (75:25) and then subjected to semi-preparative HPLC chromatography on CH 3 CN-H 2 O (48:52) elution, separation and purification to obtain 1 (2.7 mg, t) R 35.9 min), compound 2 (2.8 mg, t R 36.5 min), compound 3 (9.1 mg, t R 29.6 min)。
The 3 phenolic compounds extracted and separated from the hawthorn of the genus Crataegus of the family Crataegus have the following structures:
the obtained compound is subjected to systematic structural identification, and the result is as follows:
compound 1, yellow oil; [ alpha ]]20D+30.8 (c 0.10, meOH); gives molecular ion peaks [ M+Na ] according to their HRESIMS] + m/z369.1248(calcd for C 19 H 22 O 6 Na, 369.1309), molecular formula C 19 H 22 O 6 An unsaturation of 9; UV (MeOH) lambda max (logε):280nm(3.55),230nm(3.18)；ECD(MeOH)λ max (Δε)241(+67.15),285(+35.07)nm.
Compound 2, yellow oil; [ alpha ]]20D-31.6 (c 0.10, meOH); gives molecular ion peaks [ M+Na ] according to their HRESIMS] + m/z369.1248(calcd for C 19 H 22 O 6 Na, 369.1309), molecular formula C 19 H 22 O 6 An unsaturation of 9; UV (MeOH) lambda max (logε):280nm(3.08),230nm(2.77)；ECD(MeOH)λ max (Δε)241(-64.10),285(-40.56)nm.
Compound 1 and compound 2 1 H NMR(400MHz,CDCl 3 ) In the spectrum, delta H 6.85 (1 h, d, j=8.1 Hz), 6.76 (1 h, d, j=1.8 Hz), 6.70 (1 h, dd, j=8.1, 1.8 Hz), 6.85 (1 h, d, j=8.1 Hz), 6.76 (1 h, d, j=1.8 Hz), 6.70 (1 h, dd, j=8.1, 1.8 Hz) are proton signals coupled by two sets of benzene rings ABX. Delta H 4.64 (2H, s) are suggested as two oxygen methines. In addition, two methoxy proton signals δ3.85 (6 h, s) are also shown in the hydrogen spectrum. 13 CNMR(100MHz,CDCl 3 ) Nineteen carbon signals are given in the spectrum, including twelve aromatic carbon signals, two methoxy carbon signals, two oxygen methines, one quaternary carbon and two methyl carbon signals.
In the HMBC spectra, H-1 is correlated with the presence of C-1'/C-2'/C-6 '/C-1', H-1/H-2/H-2 '"/H-3" is associated with the presence of C-1' ", the presence of H-9/C-9 'has been correlated to indicate that the 2, 2-dimethylldioxolane fragment is linked to the two benzene rings via C-1' and C-1", respectively. By 3-OCH 3 ,3′-OCH 3 The presence of BC in relation to C-3, C-3 'respectively determines that two methoxy groups are attached to C-3 and C-3', respectively.
Since the presence of H-1 and H-2' in the NOESY spectrum correlates, the relative configuration of the compounds, H-1, H-2, is determined to be trans. Since the optical rotation value was close to 0 and there was no significant Cotton effect in the ECD spectrum, it was speculated that the compound could be a racemic mixture. A further separation of the pair of enantiomers, compound 1 and Compound 2, in a ratio of about 1:1, was achieved by chiral chromatography column DaicelChiralpak IC, which exhibited mirrored Cotton effect and opposite optical rotation values. Absolute configuration by comparing the calculated ECD spectra with the measured ECD spectra of compound 1 and compound 2, compound 1 was better matched with the calculated 1s,2s configuration, thereby determining that the absolute configuration of compound 1 was 1s,2s, and the absolute configuration of 2 was 1r,2r.
In summary, the steric structures of compounds 1 and 2 were determined, and both were novel compounds not reported in the literature, named (1 s,2 s) -crataegusol L and (1 r,2 r) -crataegusol L, respectively, by scibinder search.
Compound 1 and compound 2 1 H spectrum 13 C spectral data
Compound 3, yellow oil; gives molecular ion peaks [ M+Na ] according to their HRESIMS] + m/z263.0524(calcd for C 11 H 12 O 6 Na, 263.0526), molecular formula C 11 H 12 O 6 The unsaturation degree is 6; UV (MeOH) lambda max (logε):264nm(3.12),216nm(3.42)。
1 H NMR(400MHz,CDCl 3 ) In the spectra, δ7.58 (1 h, d, j=1.9 Hz), 7.71 (1 h, dd, j=8.3, 1.9 Hz), 6.95 (1 h, d, j=8.3 Hz) are suggested as proton signals for a set of ABX coupling systems on the benzene ring; delta 4.83 (2H, s) is a oxymethylene proton signal; and two methoxy signals δ3.95 (3 h, s), 3.79 (3 h, s). 13 CNMR(400MHz,CDCl 3 ) The spectra give a total of eleven carbon signals, including eight olefinic carbon signals and three aliphatic carbon signals.
In the HMBC spectra, the presence of H-2' in association with C-1'/C-3' indicates linking of the phenylpropanoid side chain. OCH (optical OCH) 3 -3 is C-3 related, OCH 3 A correlation of 3' with C-3' indicates that methoxy groups are attached at the C-3 and 3' positions. The planar structure of the compound was determined by HMBC correlation.
In summary, the structure of compound 3 was determined, and this compound was a novel compound not reported in the literature, named crataegusoid H, by scibinder search.
Compound 3 1 H spectrum 13 C spectral data
Investigation of Compound pair H Using MTT assay 2 O 2 Induced SH-SY5Y neural cellsActivity of the injury protection effect. Cells were placed in 96-well plates, left to stand for 12H with 100. Mu.L of culture medium, and SH-SY5Y neural cells were pretreated with the same concentration of compounds 1-3 (50. Mu.M) for 1H, followed by addition of H at a final concentration of 200. Mu.M 2 O 2 The reaction time is 4 hours. The broth was then replaced with phosphate buffer containing 0.5mg/mL MTT and left at 37℃for 4h. The supernatant was removed and DMSO (150 mL/well) was added to H 2 O 2 (200. Mu.M) cells treated individually were used as control groups and the treated cells were examined at 490nm using an ultraviolet spectrophotometer (Thermo Scientific Multiskan MK, shanghai, china). The viability of the cells was expressed as percent viability and analyzed using GraphPad Prism6 software and the results are shown in the following table.
Data values ± SD, n=3.p <0.001, p <0.01, and p <0.05 of hydrogen peroxide model.
Compounds 1 and 3 showed significant or comparable neuroprotective activity in vitro as the positive drug. Therefore, the phenolic compound has the prospect of further developing medicaments for preventing and treating parkinsonism.
The invention has the advantages that the compounds are all optical pure compounds with determined three-dimensional configuration, and meanwhile, the compounds have strong PD resistance activity and have further development value.
Claims (7)
1. Phenolic compounds and pharmaceutically acceptable salts thereof, the phenolic compounds have a chemical structural formula shown in the following formula I or formula II,
。
2. the phenolic compound according to claim 1 and pharmaceutically acceptable salts thereof, wherein: the phenolic compound is an extract obtained by extracting hawthorn fruits.
3. The process for preparing phenolic compounds according to claim 1, comprising the following process steps:
s1, extracting and concentrating haw fruits by using ethanol to obtain an extract, extracting the obtained extract by using ethyl acetate and n-butanol in sequence, performing silica gel column chromatography on an ethyl acetate part and an n-butanol part, and performing isocratic gradient elution by using dichloromethane-methanol to collect 4 fractions I-IV, wherein the ratio of the dichloromethane-methanol is 100:1, 50:1, 30:1, 20:1, 10:1 and 5:1 respectively;
s2, performing gradient elution on the fraction I through HP20 column chromatography by using an ethanol-water system to obtain 2 fractions A1 and A2, wherein the ethanol-water system is a 30%,60% and 90% ethanol-water system;
s3, separating the fractions A1 and A2 through ODS columns, performing gradient elution through an ethanol-water system, and combining and collecting 5 fractions Fr., fr.2, fr.3, fr.4 and Fr.5, wherein the ethanol-water system is 40%,50%,60%,70% and 80%;
s4, fr., fr.4 by separating with silica gel column, gradient eluting with dichloromethane-methanol system, wherein the eluted fraction is subjected to preparative HPLC, and subjected to purification with CH 3 OH-H 2 Eluting with O, and subjecting to semi-preparative HPLC chromatography with CH 3 CN -H 2 Eluting with O, separating and purifying to obtain a compound 1 and a compound 2.
4. A method according to claim 3, characterized in that: in the step S1, the dried hawthorn fruits are taken and extracted by reflux with 70% industrial ethanol for 3 times, each time for 4 hours, and the extract is combined and concentrated to obtain extractum.
5. A pharmaceutical composition comprising the phenolic compound of claim 1 or 2, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
6. Use of a phenolic compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, for the preparation of a medicament for the prevention or treatment of parkinson's disease.
7. The use according to claim 6, characterized in that: preparation of a medicament for preventing or treating H 2 O 2 Use of an induced neuroprotective active agent against oxidative damage to SH-SY5Y cells in humans.
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