CN116715570A - Sesquiterpene and sesquiterpene dimer in daphne regale, preparation method thereof and application of sesquiterpene dimer in aspect of resisting parkinsonism - Google Patents

Sesquiterpene and sesquiterpene dimer in daphne regale, preparation method thereof and application of sesquiterpene dimer in aspect of resisting parkinsonism Download PDF

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CN116715570A
CN116715570A CN202310686153.5A CN202310686153A CN116715570A CN 116715570 A CN116715570 A CN 116715570A CN 202310686153 A CN202310686153 A CN 202310686153A CN 116715570 A CN116715570 A CN 116715570A
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sesquiterpene
delta
daphne
fractions
guaiane
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宋少江
黄肖霄
白明
姚国栋
吕天铭
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Shenyang Pharmaceutical University
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Abstract

The invention belongs to the technical field of medicines, and relates to five novel guaiane and carrot compounds extracted and separated from daphne plant Minjiang daphne (Daphnepenicillata red.) which comprise two guaiane dimers bidaphnenicillataA, bidaphnenicillataB with novel structures, two novel guaiane novel compounds daphneaineE, daphneaineF and a novel carrot sesquiterpene Minjiamaphne B. The detection result shows that it is specific to H 2 O 2 The induced SH-SY5Y nerve cells of the human have protective effect on oxidative damage, wherein the cell survival rate is respectively improved to 72.78 percent and 69.43 percent after the treatment of the compounds 4 and 5, and the positive drug Trolox is only 60.00 percent.

Description

Sesquiterpene and sesquiterpene dimer in daphne regale, preparation method thereof and application of sesquiterpene dimer in aspect of resisting parkinsonism
Technical field:
the invention belongs to the technical field of medicines, and particularly relates to a method for preparing guaiane compounds and carrot alkane sesquiterpenes from plant daphne Min and application of the compounds in the aspect of Parkinson's Disease (PD).
The background technology is as follows:
a common neurodegenerative disease of the nervous system, the most important pathological change of which is the denatured death of the nigra dopaminergic neurons of the midbrain, ultimately leading to motor and cognitive dysfunction in patients, threatening human health and also causing a great economic burden. At present, the treatment research of neurodegenerative diseases mainly surrounds the aspects of neuroprotection, anti-neuroinflammation, related receptor agonists and inhibitors in brain and the like. 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 much evidence suggests that increased apoptosis due to oxidative stress is closely related to neurodegenerative disorders.
Plants of the genus Daphne (Daphne) of the family daphnaceae (Thymelaeeaceae) are evergreen standing shrubs, mainly distributed and grown in Sichuan areas of our country. A few daphne plants have good medicinal value and are mainly used for treating arthritis, rheumatic arthralgia and other symptoms. The chemical components and the biological activity of the daphne regale as a rare species in daphne are blank all the time at home and abroad.
The inventor firstly researches the development of the daphne Min, and discovers that the daphne Min contains a plurality of sesquiterpenoids with novel structures and shows good PD resistance activity.
The invention comprises the following steps:
the invention aims to solve the defects of the prior art and provides sesquiterpenes and sesquiterpene dimers in daphne Min, a preparation method thereof and application in the aspect of PD (Parkinson's disease) resistance.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
in a first aspect, five of the present invention are guaiane-type sesquiterpenes, guaiane-type sesquiterpene dimers, isolated for the first time from daphne Min (Daphne penicillata red.) in daphne of the family daphnaceae, and the structure of the carrot-type sesquiterpenes is shown in the figure:
in a second aspect, the present invention provides a pharmaceutical composition comprising a sesquiterpene or a sesquiterpene dimer derivative according to the first aspect above, and a pharmaceutically acceptable carrier.
In a third aspect, the present invention provides a process for the preparation of a sesquiterpene or sesquiterpene dimer derivative according to the first aspect above, the process comprising the steps of:
(1) The guaiane sesquiterpene is prepared by using the whole plant of daphne regale, and the whole plant of daphne regale is extracted by reflux with 70% industrial ethanol for three times, each time for 2.5 hours.
(2) Recovering solvent, concentrating to obtain total extract, mixing the total extract with water, extracting with ethyl acetate and n-butanol sequentially, subjecting the extract to silica gel column chromatography, gradient eluting with dichloromethane-methanol system as eluent at 100:0-5:1, subjecting the obtained fractions to TLC thin layer chromatography and HPLC liquid phase analysis, and mixing to obtain FrA-B two fractions.
(3) Fraction A was further subjected to silica gel column chromatography using a dichloromethane-methanol system as eluent, and gradient elution was performed at 100:0-5:1 to give two fractions FrA 1-FrA.
(4) FrA2 is eluted by polyamide with methylene dichloride-methanol system as eluent in the ratio of 100:0-5:1 to obtain two fractions FrA-I and FrA-2-II.
(5) The FrA-II flow is eluted by HP-20 by using a 90% ethanol-water system to remove small polar pigment, and is eluted by using ODS column chromatography by using an alcohol-water system of 20:80-90:10 in a gradient way, and 6 fractions N1-N6 are further obtained by analyzing and bottling by using thin layer chromatography and HPLC.
(6) The obtained fraction N2 is subjected to silica gel column chromatography with a petroleum ether-ethyl acetate system of 50:1-0:1 and gradient elution to obtain 6 fractions of 2.1-2.6. Separation of the stream fraction 2.2 by HPLC in a methanol-water system 70:30 gives 2.2.1-2.2.6.
(7) Elution of 2.2.3 with acetonitrile-water system 53:47 using semi-preparative HPLC gave compounds 1 and 2. N1 was isolated by the same method to give compounds 3-5.
Preferably, the extraction is reflux extraction, 3-5 times, each for 2-3 hours.
In addition, preferably, in the preparation method, the plant used is a whole plant collected from the city of Wenchania (North latitude N31 DEG 29 '51.52', east longitude E103 DEG 38 '14.35') in the state of Sichuan, 7 months in 2019, identified as Daphnepenicillilata (Rehd.) by the company of Yunnan province.
The results of the system structure identification of the obtained compound are as follows:
the structure of compounds 1,2 was identified by high resolution mass spectrometry, one-dimensional NMR, two-dimensional NMR and computational ECD techniques. Bidaphnenicillilata A (1) is a white powder,UV(MeOH)λ max (log ε): 204nm (1.52), 248nm (0.87); ECD (methanol) lambda max (Δε)227(+126.69),275(-141.4)nm.；The 1 H(600MHz，CDCl 3 )and 13 C NMR data(150MHz，CDCl 3 ) HRESIMS gives an excimer ion peak m/z519.2719, combined with 13 C NMR calculation of formula C 22 H 24 O 9 Na([M+Na] + calcd for C 30 H 40 O 6 Na, 519.2723), the calculated unsaturation was 11. At the position of 1 HNMR(600MHz,CDCl 3 ) In the spectrum, four double bond proton signals delta are shown H 4.80 (1 h, brs, h-13 a), 4.72 (1 h, t, j=1.62 hz, h-13 b), 4.65 (1 h, t, j=1.52 hz, h-13 'a), 4.64 (1 h, brs, h-13' b); four methyl proton signals delta H 1.74(3H,t,J＝1.00Hz,H 3 -12),1.67(3H,t,J＝1.13Hz,H 3 -12′),1.60(3H,s,H 3 -14),1.42(3H,s,H 3 -14′)。 13 C NMR(150MHz,CDCl 3 ) A total of 30 carbon signals are given in the spectrum, and in combination with HSQC spectrum analysis, it is speculated that the compound includes two carbonyl carbon signals δ C 204.9 (C-3), 200.1 (C-3'), eight double bond carbon signals delta C 169.2 (C-5), 144.2 (C-4), 141.7 (C-1 '), 141.4 (C-5'), 150.5 (C-11), 150.0 (C-11 '), 109.8 (C-13), 109.5 (C-13'); four sp3 hybridized quaternary carbon signals delta C 61.8 (C-1), 77.0 (C-10), 76.6 (C-10 '), 59.1 (C-4'); four methine carbon signals delta C 54.1 (C-2 '), 54.5 (C-2), 44.8 (C-7'), 40.3 (C-7); four methyl carbon signals delta C 20.6 (C-12 '), 20.1 (C-12), 11.4 (C-14), 8.5 (C-14'). Eight methylene carbon signals delta C 63.4 (C-15 '), 64.2 (C-15), 38.9 (C-6), 37.2 (C-9'), 33.9 (C-9), 32.3 (C-8 '), 31.8 (C-6'), 31.1 (C-8). The combination of the above nuclear magnetic information and 11 unsaturations speculates that the structure may be polymerized from two guaiane-type sesquiterpenes.
Delta in HMBC spectra H 1.74(CH 3 -12) and delta C 40.3 (C-7), 109.8 (C-13) and 150.5 (C-11) are present in relation, delta H 4.80,4.72(H 2 -13) and delta C 20.1 (C-12), 40.3 (C-7) and 150.5 (C-11) are present in relation, indicating that the reaction is carried out by C-7, C-11, C-12, CH 3 -13 the presence of a side chain fragment. Same delta H 1.67(CH 3 -12') and delta C 44.8 (C-7 '), 109.5 (C-13 ') and 150.0 (C-11 ') are presentRelatedly, delta H 4.64,4.65(H 2 -13') and delta C 20.6 (C-12 '), 44.8 (C-7') and 150.0 (C-11 '), are present in association, which is illustrated by C-7', C-11', C-12', CH 3 -13' the presence of a side chain segment. Delta H 2.99 (H-7) and delta C 31.1 (C-8) and 38.9 (C-6) are present in relation, delta H 2.72,2.37(H 2 -6) and delta C 40.3 (C-7), 31.1 (C-8), 61.8 (C-1), 144.2 (C-4) and 169.2 (C-5) are present in relation, delta H 3.39,3.30(H 2 -15) and delta C 33.9 (C-9), 61.8 (C-1) and 77.0 (C-10) are present in association with delta H 2.99 (H-7) and delta H 1.52 (H-8) and 2.37 (H-7), delta H 1.52 (H-8) and delta H 2.15 (H-9) presence of 1 H- 1 H COSY is related whereby the seven-membered ring fragments formed by C-1, C-5, C-6, C-7, C-8, C-9 and C-10 are determined. Delta H 1.83 (H-7') and delta C 31.8 (C-6 '), 37.2 (C-9 ') and 32.3 (C-8 ') are present in relation, delta H 2.17,1.95(H 2 -6') and delta C 44.8 (C-7 '), 32.3 (C-8 '), 59.1 (C-4 '), 141.4 (C-4 ') and 141.7 (C-5 ') are related, delta H 2.08 (H-9) and delta C 32.3 (C-8 '), 61.8 (C-1'), 141.7 (C-5 ') and 76.6 (C-10'), delta H 2.93 (H-15') and delta C 37.2 (C-9 ') and 76.6 (C-10') are related. Seven-membered ring fragments formed by C-1', C-5', C-6', C-7', C-8', C-9' and C-10' were defined. Delta H 1.60(CH 3 -14) and delta C 144.2 (C-4), 169.2 (C-5) and 204.9 (C-3) presence correlates to determine the presence of an alpha, beta-unsaturated ketone fragment consisting of C-3, C-4 and C-5. Delta H 1.42(CH 3 -14') and delta C 54.5 (C-2), 59.1 (C-4 '), 200.1 (C-3 ') and 141.4 (C-5 ') are present in relation, delta H 2.88 (H-2) and delta C 61.8 (C-1), 59.1 (C-4 '), 77.0 (C-10), 169.2 (C-5), 204.9 (C-3) and 141.4 (C-5') are present in relation, delta H 4.13 (H-2') and delta C 54.5 (C-2), 59.1 (C-4 '), 77.0 (C-10), 76.6 (C-10 '), 200.1 (C-3) and 141.7 (C-1 ') are present, thereby determining the presence of two five-membered ring fragments consisting of C-1, C-2, C-3, C-4, C-5 and C-1', C-2', C-3', C-4', C-5', respectively, and also determining the presence of two five-membered ring fragments between them by C-4' -C-2 and C-2', respectively 'C-1 forms a carbon-carbon bond bridged together, thereby defining a sesquiterpene dimer backbone with a five-ring character of 7/5/5/5/7 for the whole molecule.
The stereochemistry of the compounds was then determined using NOESY spectra, delta H 2.17 (H-6' a) and delta H 1.42(CH 3 -14 ') and 4.13 (H-2') are NOESY-related, delta H 1.95 (H-6' b) and 1.67 (CH) 3 -12') and delta H 3.59 (H-15 ') the presence of NOE SY correlates to define C-15' as beta orientation, H-7 'and 14' -CH 3 Is alpha oriented. Delta H 2.88 (H-2) and delta H 3.30(H-15),δ H 4.13 (H-2') and delta H 2.99 (H-7) the presence of NOESY correlates to determine that H-2 and C-15 are beta oriented, H-2' and 7-CH 3 Is alpha oriented. The absolute configuration of the compound was confirmed by calculation of the ECD compared to the measured ECD. Firstly, performing conformational search on MMFF94 molecular dynamics force field by using Spartan software, selecting conformation with Boltzmann distribution more than 1% to optimize at the level of B3LYP/6-31G (d) base group, then performing ECD calculation at the level of B3LYP/6-311++ G (2 d, p) base group, and generating ECD spectrogram by fitting SpecDis software. The absolute configuration of compound 1 was determined as 1r,2s,7r,10r,2's,4's,7's,10's by comparing the calculated ECD spectrum with the measured ECD spectrum.
Through scibinder search, the compound is a novel compound which is not reported in the literature, and the compound 1 is a first reported sesquiterpene dimer compound with [5.5.3.2.2.1] eicosane skeleton of 7/5/5/5/7 five-ring system, and is named as bidaphnenicilliactaA.
Bidaphnenicillata B (2) white powdery compound,UV(MeOH)λ max (logε):204nm(1.52),248nm(0.87)；ECD(MeOH)λ max (Δε)227(+126.69),275(-141.4)nm.The 1 H(600MHz,CDCl 3 )and 13 C NMR data(150MHz,CDCl 3 ) HRESIMS (m/z): 519.2719, in combination with 13 C NMR calculation of formula C 30 H 40 O 6 ([M+Na] + calcd for C 30 H 40 O 6 Na, 519.2723), the unsaturation is 11. 1 HNMR(600MHz,DMSO-d 6 ) In the spectrum, five double bond proton signals delta are shown H 6.38 (1 h, s, h-2), 4.72 (1 h, brs, h-13 a), 4.67 (1 h, t, j=1.76 hz, h-13 b), 4.62 (1 h, t, j=1.82 hz, h-13 'a), 4.64 (1 h, brs, h-13' b); four methyl proton signals delta H 1.69(3H,s,H 3 -12),1.66(3H,s,H 3 -12′),0.82(3H,s,H 3 -14),1.00(3H,s,H 3 -14′)。 13 C NMR(150MHz,DMSO-d 6 ) A total of 30 carbon signals are given in the spectrum, and in combination with HSQC spectrum analysis, it is speculated that the compound includes two carbonyl carbon signals δ C 207.7 (C-3), 200.1 (C-3'), eight double bond carbon signals delta C 184.7 (C-1), 134.8 (C-2), 142.5 (C-1 '), 139.4 (C-5'), 150.4 (C-11), 150.8 (C-11 '), 109.1 (C-13), 108.7 (C-13'); three methine carbon signals delta C 56.0 (C-2 '), 46.2 (C-7'), 42.9 (C-7); five quaternary carbon signals delta C 54.9 (C-4), 54.1 (C-5), 75.6 (C-10), 58.8 (C-4 '), 76.5 (C-10'); four methyl carbon signals delta C 20.4 (C-12 '), 20.8 (C-12), 13.8 (C-14), 7.9 (C-14'); eight methylene carbon signals delta C 64.9 (C-15 '), 67.7 (C-15), 35.2 (C-6), 36.4 (C-9'), 32.9 (C-9), 29.7 (C-8 '), 32.5 (C-6'), 28.6 (C-8). The results of comparative analysis of nuclear magnetic data of compounds 1 and 2 show that the compounds have similar guaiane sesquiterpene dimerization frameworks, and the main difference is represented by the fact that compound 2 has an extra double bond proton signal, but lacks the methine signal at H-2 position in 1. Delta in HMBC spectra H 1.69(CH 3 -12) and delta C 42.9 (C-7), 109.1 (C-13) and 150.4 (C-11) are present in relation, delta H 4.67,4.72(H 2 -13) and delta C 20.8 (C-12), 42.9 (C-7) and 150.4 (C-11), indicating that the reaction is carried out by C-7, C-11, C-12,13-CH 3 The presence of side chain fragments is formed. Same delta H 1.66(12′-CH 3 ) And delta C 46.2 (C-7 '), 108.7 (C-13 ') and 150.8 (C-11 ') are related, delta H 4.64,4.62(H 2 -13') and delta C 20.4 (C-12 '), 46.2 (C-7') and 150.8 (C-11 '), are present in association, which is illustrated by C-7', C-11', C-12', CH 3 -13' the presence of a side chain segment. Delta H 1.57,1.37(H 2 -6) andδ C 42.9 (C-7), 28.6 (C-8), 54.1 (C-5) and 184.7 (C-1) are present in relation, delta H 3.52,3.45(H 2 -15) and delta C 32.9 (C-9), 184.7 (C-1) and 75.6 (C-10) are present in association with delta H 2.13 (H-9) and delta H 1.50(H-8),δ H 2.55 (H-7) and delta H 1.50 (H-9) and 1.37 (H-6), are present 1 H- 1 H COSY is related whereby the seven-membered ring fragments formed by C-1, C-5, C-6, C-7, C-8, C-9 and C-10 are determined. Delta H 2.08,1.99(H 2 -6') and delta C 46.2 (C-7 '), 29.7 (C-8'), 139.4 (C-5 ') and 142.5 (C-1') are related, delta H 3.28,3.34(H 2 -15') and delta C 36.4 (C-9 '), 139.4 (C-5 ') and 76.5 (C-10 ') are present in relation, delta H 1.28(H 2 -9') and delta C 46.2 (C-7 '), 29.7 (C-8 '), 64.9 (C-15 ') and 76.5 (C-10 ') are present in relation, whereby the seven-membered ring fragments formed by C-1', C-5', C-6', C-7', C-8', C-9' and C-10' are determined. Delta H 0.82(CH 3 -14) and delta C 207.7 (C-3), 54.9 (C-4), 54.1 (C-5) and 58.8 (C-4') are present in relation, delta H 1.0(CH 3 -14') and delta C 54.9 (C-4), 58.8 (C-4 '), 200.1 (C-3 ') and 139.4 (C-5 ') are present in relation, delta H 6.38 (H-2) and delta C 184.7 (C-1), 75.6 (C-10), 54.1 (C-5), 207.7 (C-3) and 54.9 (C-4) are present in relation, delta H 3.82 (H-2') and delta C 54.1 (C-5), 35.2 (C-6), 58.8 (C-4 '), 76.5 (C-10'), 142.5 (C-5 '), 200.1 (C-3') and 139.4 (C-1 ') are correlated, thereby determining the presence of two five-membered ring fragments consisting of C-1, C-2, C-3, C-4, C-5 and C-1', C-2', C-3', C-4', C-5', respectively, and also determining the bridging together of the two five-membered ring fragments by C-4'-C-4 and C-2' -C-5 carbon-carbon bonds, thereby determining the sesquiterpene dimer skeleton having 7/5/5/5/7 five-membered ring characteristics for the whole molecule. Analysis based on NOESY spectra data determines the relative configuration of Compound 2, 14' -CH 3 And 12' -CH 3 In relation to the presence of NOESY for H-6', H-15', H-6' and H-7 and H-2',14' -CH was determined 3 Beta orientation with C-15 'and H-7, and alpha orientation with H-7'. H-6 and 14-CH 3 ，13-CH 3 And H-15 is related to the presence of NOESYThereby determining 14-CH 3 C-15 and 12-CH 3 Is alpha oriented. The absolute configuration of compound 2 was determined by comparing the calculated and measured ECD spectra and was designated 4S,5R,7S,10S,2'R,4' R,7'R,10' R, and named bidaphnenicillata B. The nuclear magnetic data of compounds 1-2 are shown in Table 1.
Table 1 1-2 (a: CDCl) 3 B: DMSO) 1 H (600 MHz) and 13 c (150 MHz) NMR data
daphneaine E (3) as a pale yellow oily compound,UV(MeOH)λ max (logε):239nm(3.86)；ECD(MeOH)λ max (Δε)230(+28.3),304(-34.1)nm.The 1 H(600MHz,CDCl 3 )and 13 C NMR data(150MHz,CDCl 3 ) HRESIMS (m/z): 275.1621, in combination with 13 C NMR calculation of formula C 15 H 24 O 3 ([M+Na] + calcd for C 15 H 24 O 3 Na, 275.1623), the degree of unsaturation was 4. 1 H NMR(600MHz,CDCl 3 ) The spectrum shows proton signal delta on 1 olefin carbon H 6.14 (1 h, ddq, j=4.81, 2.73,1.29 hz), proton signal δ on 1 oxymethylene carbon H 3.58 (1 h, d, j=10.63 Hz), 3.58 (1 h, d, j=10.63 Hz), and 3 methyl hydrogen signals δ H 1.85 (3H, m), 1.30 (3H, s), 0.95 (3H, s), wherein δ H 1.85 methyl groups are attached to the double bond carbon. 13 C NMR(150MHz,CDCl 3 ) A total of 15 carbon signals are shown in the spectrum, combined with HSQC spectrum analysis, and it is assumed that 1 carbonyl carbon signal (delta) is included in the compound C 205.3 2 olefin carbon signals (delta) C 138.1 135.8), 2 sp3 hybridized quaternary carbon signals (delta) C 74.6,43.5), 2 methine carbon signals (delta) C 49.3,42.5), 5 methylene carbon signals (delta) C 69.3,46.9,43.9,42.4,26.8) and 3 methyl carbon signals (. Delta.) C 25.2,22.2,20.3)。
Delta in HMBC spectra H 1.85(H 3 -11) and delta C 205.3 (C-7), 135.8 (C-8) and 138.1 (C-9) are present in relation, delta H 6.14 (H-9) and delta C 205.3 (C-7), 135.8 (C-8) and 22.2 (C-11) are present in relation to each other, indicating the presence of an alpha, beta-unsaturated ketone fragment consisting of C-7, C-8 and C-9, and methyl CH 3 -11 is attached at the C-8 position. Delta H 6.14 (H-9) and delta C 46.9 (C-10) and 43.5 (C-1) are present in relation, delta H 2.45 (H-10 alpha) and delta C 138.1 (C-9), 135.8 (C-8), 43.5 (C-1), 42.5 (C-5), 42.4 (C-2) and 20.3 (C-12) are present in relation, delta H 0.95(H 3 -12) and 46.9 (C-10), 43.5 (C-1), the presence of which is relevant, indicating that C-10 is linked to C-9 and C-1, C-1 is linked to C-2, C-5, C-10 and 12-CH 3 Are connected. Delta H 2.51 (H-5) and delta C 49.3 (C-4), 46.9 (C-10), 43.9 (C-6), 43.5 (C-1) and 20.3 (C-12) are present in relation, delta H 3.06 (H-6α) and δ C 205.3 (C-7), 135.8 (C-8), 49.3 (C-4), 46.9 (C-10), 43.5 (C-1), 42.5 (C-5) and 20.3 (C-12) are present, thereby determining the presence of a seven-membered ring fragment consisting of C-1, C-5, C-6, C-7, C-8, C-9, C-10, with methyl groups attached to the C-1 and C-8 positions, respectively. For a pair of 1 H- 1 Analysis of the H COSY spectrum revealed delta H 3.06 (H-6α) and δ H 2.96 (H-6 beta) and delta H 2.51(H-5),δ H 2.51 (H-5) and delta H 2.37(H-4),δ H 2.37 (H-4) and delta H 1.69(H-3),δ H 1.69 (H-3) and delta H 1.61 (H-2. Alpha.) and delta H 1.38 (H-2. Beta.) the presence of five-membered rings consisting of C-1, C-2, C-3, C-4, C-5 are correlated and combined with the seven-membered rings above by C-1 and C-5. According to delta H 2.37 (H-4) and delta C 74.6 (C-13), 69.3 (C-14), 25.2 (C-15) and delta H 3.58 (H-14α) and δ C 74.6 (C-13), 49.3 (C-4) and 25.2 (C-15) in the presence of HMBC correlation, determination of C-13 and C-4, C-14 and CH 3 -15 is linked, binding pair C-13 (delta) C 74.6 And C-14 (delta) C 69.3 Chemical shift analysis, it is presumed that hydroxyl groups are attached to C-13 and C-14, respectively. Whereby the planar structure of the compound is determined.
NOESY spectra of Compound 3Analysis, 12-CH 3 NOE associated with H-14, indicating 12-CH 3 All have beta configuration, and H-4 has alpha configuration. H 3 -12 and H-6 beta (delta) H 2.96 H-5 and H-6α (δ) H 3.06 Related, indicating that H-5 is also in the alpha configuration. Thus, 12-CH 3 The relative configuration of H-4 and H-5 is defined as R, S. The relative configuration of side chain C-13 was determined by calculating its chemical shift at the level of B3LYP/6-311++ G (2 d, p) using the Density Functional Theory (DFT), and the final overall molecular relative configuration was determined to be 1R, 4S, 5S, 13R. The absolute configuration of the compound was further determined by calculation of the ECD and retrograde, and the absolute configuration of compound 3 was determined to be 1S,4R,5R,13S.
daphneanine F (4) as a pale yellow oily compound,UV(MeOH)λ max (logε):239nm(3.86)；ECD(MeOH)λ max (Δε)230(+28.3),304(-34.1)nm.The 1 H(600MHz,CDCl 3 )and 13 C NMR data(150MHz,CDCl 3 ) HRESIMS (m/z): 275.1619, in combination with 13 C NMR calculation of formula C 15 H 24 O 3 ([M+Na] + calcd for C 15 H 24 O 3 Na, 275.1623), the degree of unsaturation was 4. 1 H NMR(600MHz,DMSO-d 6 ) The spectrum shows a proton signal of 1 double bond of 6.89 (1H, dt, J=8.3, 2.7 Hz), 1 aldehyde hydrogen signal delta H 9.28 (1H, s) and 2 methyl carbon signals delta H 1.19 (3H, s) and 0.84 (3H, s). 13 CNMR(150MHz,DMSO-d 6 ) The spectra show 15 carbon signals in total, including 3 sp 2 Hybrid carbon signal (delta) C 157.2,143.4,196.0), 2 methyl carbon signals (delta) C 26.2,17.0), 4 methine carbon signals (delta) C 48.6,48.4), 6 methylene carbon signals (delta) C 68.4,41.7,28.9,25.4,20.1,39.6) and two quaternary carbon signals (delta) C 73.9,44.0)。
Delta in HMBC spectra H 9.28 (H-11) and delta C 20.1 (C-9), 143.4 (C-8) and 157.2 (C-7) are present in relation, delta H 6.89 (H-7) and delta C 20.1 (C-9), 28.9 (C-6), 48.6 (C-5), 143.4 (C-7) and 196.0 (C)-11) the presence of the C-7, C-8, C-11-forming alpha, beta-unsaturated aldehyde fragments. Delta H 1.81 (H-5) and delta C 17.0(CH 3 -12), 28.9 (C-6), 44.0 (C-1), 43.4 (C-5), 48.4 (C-4), 73.9 (C-13) and 157.2 (C-7) are present in relation, delta H 0.84(CH 3 -15) and delta C 41.7 (C-1), 44.0 (C-1), 40.1 (C-10) and 48.6 (C-5) are present in association, binding delta H 6.89 (H-7) and delta H 3.12,2.54 (H-6), 1.74,1.12 (H-10) and 2.58,1.92 (H-9) are present 1 H- 1 H COSY-related description the presence of a seven-membered ring fragment consisting of C-1, C-5, C-6, C-7, C-8, C-9, C-10, and 12-CH 3 Attached to C-1. Delta H 2.33 (H-4) and delta C 48.6 (C-5), 25.4 (C-3), 68.4 (C-14) and 73.9 (C-13) are present in relation, delta H 1.19(CH 3 -15) and delta C 48.6 (C-5), 68.4 (C-14) and 73.9 (C-13) are present in relation, delta H 1.24,1.37 (H-2) and delta C 1.63,1.57 (H-3), 1.63,1.57 (H-3) and 2.33 (H-4) presence-related description five-membered ring fragments consisting of C-1, C-2, C-3, C-4, C-5 are grouped together with the seven-membered ring fragments above by C-1 and C-5 and are composed of C-13, C-14 and 15-CH 3 The side chain of the composition is attached at C-4. Chemical shifts that bind C-13 and C-14 infer that the hydroxyl groups are attached to C-13 and C-14.
Analysis of NOESY spectra of Compound 4 revealed 12-CH 3 The presence of NOESY-related signals to H-14, H-5 and H-4, determines the 12-CH 3 In beta configuration, H-4 and H-5 are in alpha configuration. The orientation of H-4 and H-5 of Compound 4 was determined to be α,12-CH by NOESY 3 Is oriented at beta. Whereas the relative configuration of side chain C-13 was determined by calculating chemical shifts at the level of B3LYP/6-311+ + G (2 d, p) using Density Functional Theory (DFT), the final overall molecular relative configuration was determined to be 1R, 4S, 5S, 13R.
Minjiangdaphene B (5) is a colorless oily compound,UV(MeOH)λ max (logε):204nm(1.54)268nm(0.04)；ECD(MeOH)λ max (Δε)210(-7.14)nm.The 1 H(600MHz,CDCl 3 )and 13 C NMR data(150MHz,CDCl 3 ).HRESIMS(m/z):2751620, and combine with 13 C NMR calculation of formula C 15 H 24 O 3 ([M+Na] + calcd for C 15 H 24 O 3 Na, 275.1623), the degree of unsaturation was 4. 1 H NMR(600MHz,DMSO-d 6 ) There are 2 sp shown in the spectrum 2 Hybrid proton signal 4.75 (1 h, dt, j=2.8, 1.4 Hz), 4.70 (1 h, d, j=2.5 Hz), 2 methyl carbon signals δ H 1.68 (3H, s) and 0.90 (3H, s) and two hydroxyl proton signals delta H 4.87 (1 h, t, j=5.8 Hz) and 3.94 (1 h, dd, j=3.1, 1.0 Hz). 13 C NMR(150MHz,DMSO-d 6 ) The spectra show 15 carbon signals in total, including 2 sp 2 Hybrid carbon signal (delta) C 147.6,113.1), 2 methyl carbon signals (delta) C 22.8,18.1), 4 methine carbon signals (delta) C 48.9,45.3,63.9,56.7), 5 methylene carbon signals (delta) C 63.5,40.7,29.2,27.6,40.1) and two quaternary carbon signals (delta) C 63.3,43.4)。
Delta in HMBC spectra H 1.68(CH 3 -14) and delta C 48.9 (C-2), 113.1 (C-13) and 147.6 (C-12) are present in relation, delta H 4.75,4.70 (H-13) and delta C 48.9(C-2),22.8(CH 3 -14) and 147.6 (C-12) presence-related to the expression by C-2, C-13, C-12, CH 3 -14 form the presence of a terminal double bond fragment, wherein CH 3 -14 is connected to C-12. Delta H 2.26 (H-1) and delta C 18.1(CH 3 -15), 29.2 (C-10), 40.1 (C-6), 43.4 (C-5), 48.9 (C-2), 63.9 (C-9) and 147.6 (C-12) are present in relation, delta H 0.90(CH 3 -15) and delta C 45.3 (C-1), 40.7 (C-4), 40.1 (C-6) and 43.4 (C-5) are present in relation and delta H 1.41,1.30 (H-4) and delta C 27.6 (C-3), 48.9 (C-2), 43.4 (C-5), 45.3 (C-1) and 18.1 (CH) 3 -15) illustrates the presence of five-membered ring fragments consisting of C-1, C-2, C-3, C-4, C-5, and CH 3 -15 is attached to C-5. Delta H 2.93 (H-7) and delta C 40.1 (C-6), 63.3 (C-8), 63.9 (C-9) and 63.5 (C-11) are present in relation, delta H 3.95 (HO-9) and delta C 29.2 (C-10), 63.3 (C-8) and 63.9 (C-9) are present in relation, delta H 3.43,3.37 (H-11) delta C 56.7 (C-7), 63.3 (C-8) and 63.9 (C-9) presence-related description seven-membered ring tablet consisting of C-1, C-5, C-6, C-7, C-8, C-9, C-10The segments are assembled and combined with the five-membered ring segments above through C-1 and C-5. The chemical shift in combination with H-8 and H-9 speculates that a ternary oxygen ring is formed between C-8 and C-9. And meanwhile, the plane structure of the compound 5 is determined by further judging in combination with mass spectrum data.
Analysis of NOESY spectrum of Compound 5 revealed 15-CH 3 And H-7,H-1 and 9-HO, H-9 and H 2 -11 the presence of NOESY-related signals, 14-CH 3 And 15-CH 3 Determination of 15-CH in the presence of NOESY-related signals 3 H-7 and H 2 -11 is beta configuration, H-1, ho-9 and H-2 are alpha configuration, and the relative configuration of compound 5 is determined to be 1R,2R,5S,7R,8S,9S. The absolute configuration of the compound was determined by comparing the calculated ECD with the measured ECD and the absolute configuration of the molecule was finally determined to be 1R,2R,5S,7R,8S,9S. The nuclear magnetic data assignment for compounds 3-5 is shown in Table 2.
Table 2 3-5 (a: CDCl) 3 B: DMSO) 1 H (600 MHz) and 13 c (150 MHz) NMR data
In a fourth aspect, the present invention provides the use of a sesquiterpene or a sesquiterpene dimer derivative according to the first aspect or a pharmaceutical composition according to the second aspect for the manufacture of a medicament for treating parkinson's disease.
The neuroprotective activity of the hydrogen peroxide induced SH-SY5Y nerve cell injury of five novel compounds separated from daphne Min is researched, and in-vitro test results show that the compounds 4 and 5 show relatively better activity of resisting the hydrogen peroxide induced SH-SY5Y nerve cell injury at 50 mu M. The survival rates are 72.78% and 69.43% (Trolox 60.00% positive drug) respectively. Therefore, the novel guaiane sesquiterpene has the prospect of further developing medicaments for preventing and treating nerve injury.
Compared with the prior art, the invention has the following beneficial effects: the invention has the advantages that the sesquiterpene or sesquiterpene dimer compound is an optical pure compound with a determined three-dimensional configuration, and has better neuroprotective activity and further development value.
Description of the drawings:
UV spectrum of compound 1 of fig. 1;
hresis spectrum of compound 1 of fig. 2;
UV spectrum of compound 2 of fig. 3;
hresis spectrum of compound 2 of fig. 4;
UV spectrum of compound 3 of fig. 5;
hresis spectrum of compound 3 of fig. 6;
UV spectrum of compound 4 of fig. 7;
hresis spectrum of compound 4 of fig. 8;
the UV spectrum of compound 5 of fig. 9;
figure 10 hresis spectrum of compound 5.
The specific embodiment is as follows:
the examples set forth below are presented to aid one skilled in the art in a better understanding of the present invention and are not intended to limit the invention in any way.
Example 1: preparation of Compounds 1-5
50kg of dry whole plant of daphne regale (Daphnepenicillilta Rehd.) is taken, and extracted with 70% industrial ethanol under reflux for 3 times each for 2.5h, and the solvent is recovered to obtain about 3.5kg of total extract. After the total extract was suspended with water, the extract was sequentially extracted with ethyl acetate and n-butanol, and about 500g of an ethyl acetate layer extract and about 1900g of an n-butanol layer extract were finally obtained. The ethyl acetate layer extract and the n-butanol layer extract were eluted with a dichloromethane-methanol system at 100:0-5:1, performing rapid gradient elution by reduced pressure silica gel column chromatography, and combining the obtained fractions into FrA-B fractions after TLC thin layer chromatography and HPLC liquid phase analysis. Fraction A was further subjected to silica gel column chromatography using a dichloromethane-methanol system as eluent at a ratio of 100:0-5:1 to provide two fractions FrA of about 50g and FrA of about 200g. FrA2 is eluted with a methylene chloride-methanol system as eluent in a ratio of 100:0-5:1 by polyamide to obtain two fractions FrA-I of about 60g and Fr A2-II of about 120g. The FrA-II fraction was eluted with HP-20 using a 90% ethanol-water system to remove small polar pigments, and was eluted with an ODS column chromatography gradient of 20:80-90:10 using an ethanol-water system, and 6 fractions N1 about 20g, N2 about 20g, N3 about 13g, N4 about 10g, N5 about 14g, N6 about 15g were further obtained by thin layer chromatography and HPLC analysis of the vial combination. The obtained fraction N2 is subjected to silica gel column chromatography with a petroleum ether-ethyl acetate system of 50:1-0:1 and gradient elution, and 6 fractions of 2.1-2.6 are obtained. Preparing a column pair with C18 by HPLC; the fraction 2.2 was separated in reverse phase with methanol-water system 70:30 to give 2.2.1-2.2.6, and the 2.2.3 fraction was further eluted with acetonitrile-water system 53:47 by HPLC using C18 semi-preparative column to give compounds 1 (5 mg) and 2 (1 mg). Separating the N1 fractions in a similar manner to obtain 5 fractions 1.1-1.5, subjecting the 1.4 fractions to reverse phase separation in a methanol-water system 75:25 by using a C18 preparative column to obtain 1.4.1-1.4.6, and further subjecting the 1.4.2 fractions to elution in an acetonitrile-water system 62:38 by using a C18 semi-preparative column by using HPLC to obtain compound 3 (3 mg); eluting 1.4.3 with acetonitrile-water system 60:40 to give compound 4 (2 mg); elution of 1.4.4 with acetonitrile-water system 59:41 afforded compound 5 (5 mg).
Example 2: compounds 1-5 are directed to H in vitro 2 O 2 Activity investigation of induced human SH-SY5Y nerve cell injury protection
Investigation of Compound pair H Using MTT assay 2 O 2 Activity of induced injury protection of human SH-SY5Y nerve cells. No H was added to the blank 2 O 2 And compounds, but vaccinated with human SH-SY5Y neural cells (ATCC, rockville, MD, USA); adding H into the negative control group 2 O 2 And cells. The administration method comprises adding compounds 1-5 (12.5,25,50 μM) at different concentrations into blank culture medium, pretreating for 1 hr, and adding 200 μ M H 2 O 2 At 5% CO 2 The incubation was continued for 4h in an incubator at 37℃to establish an oxidative damage model. 20 μLMTT (5 mg/mL) was added to each well for 4h and the crystals formed were dissolved in 150 μL DMSO. The absorbance at 492nm was measured with a microplate reader and the survival rate was calculated according to the following formula:
cell viability (%) = [ a 490(sample) –A 490(control) ]/[A 490(control) –A 490(blank) ]×100％。
And the neuroprotective activity of compounds 1-5 was evaluated therewith. After treatment with compounds 1-5, the cell viability was 54.95%, 44.32%, 53.68%, 72.78%, 69.43% (positive drug Trolox 60.00%), respectively, wherein compound 4 and compound 5 showed relatively better neuroprotective activity, with the potential to be further developed as anti-PD drugs.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims (10)

1. A guaiane sesquiterpene or sesquiterpene dimer derivative in daphne regale characterized in that: the derivative has the structure shown as follows:
2. the sesquiterpene or sesquiterpene dimer derivative according to claim 1, characterized in that said daphne Min is daphne Min [ Daphne penicillata Rehd ] which is a plant of the genus daphne of the family daphnaceae.
3. A pharmaceutical composition characterized by: the pharmaceutical composition comprising the sesquiterpene or sesquiterpene dimer derivative according to claim 1 or claim 2 and a pharmaceutically acceptable carrier.
4. A process for the preparation of guaiane sesquiterpene or sesquiterpene dimer derivatives in daphne Min according to claim 1, characterized in that: the preparation method comprises the following steps:
taking a dry whole plant of daphne regale, heating and reflux-extracting with 70% industrial ethanol, mixing the extracting solutions, concentrating to obtain an extract, extracting the extract with ethyl acetate, subjecting the obtained component to silica gel column chromatography, and performing rapid gradient elution with a dichloromethane-methanol system at a ratio of 100:0-5:1 by using a reduced pressure silica gel column chromatography to obtain two fractions FrA-B;
fraction A is further subjected to silica gel column chromatography, and gradient elution is carried out by using a dichloromethane-methanol system as an eluent in a ratio of 100:0-5:1 to obtain two fractions FrA1-FrA2
FrA2 is eluted by polyamide with methylene dichloride-methanol system as eluent in the proportion of 100:0-5:1 to obtain two fractions FrA-I and A2-II;
eluting FrA-II fraction with HP-20 by using 90% ethanol-water system to remove small polar pigment, and gradient eluting with ODS column chromatography by using 20:80-90:10 ethanol-water system to obtain 6 subfractions N1-N6;
the obtained fraction N2 is subjected to gradient elution by a petroleum ether-ethyl acetate system 50:1-0:1 through a silica gel column chromatography to obtain 6 fractions 2.1-2.6, the fractions 2.2 are separated by a methanol-water system 70:30 through HPLC to obtain 2.2.1-2.2.6, 2.2.3 fractions are separated to obtain compounds 1 and 2, N1 is also separated by the silica gel column chromatography to obtain 5 fractions 1.1-1.5, 1.4 is separated by the methanol-water system 75:25 through HPLC to obtain 1.4.1-1.4.6, and 1.4.2, 1.4.3 and 1.4.4 are separated by a C18 column acetonitrile-water system 59:41-62:38 to obtain compounds 3-5.
5. The process for producing a sesquiterpene or a sesquiterpene dimer derivative according to claim 4, wherein: the daphne regale is daphne regale [ Daphne penicillata Rehd ] which is a daphne plant of daphnaceae.
6. The process for producing a sesquiterpene or a sesquiterpene dimer derivative according to claim 4, wherein: reflux-extracting dried whole plant of Minjiang daphne with 70% industrial ethanol for 3 times, each for 2-3 hr.
7. The process for producing a sesquiterpene or a sesquiterpene dimer derivative according to claim 4, wherein: the acetonitrile-water mobile phases of 75:25-50:50 are separated by 1.4.2, 1.4.3, 1.4.4, 2.2.3.
8. Use of guaiane sesquiterpene and sesquiterpene dimer derivatives or pharmaceutically acceptable salts thereof in daphne Min according to claim 1 or claim 2 for the preparation of an antiparkinsonian drug.
9. Use of a guaiane sesquiterpene or a sesquiterpene dimer derivative or a pharmaceutically acceptable salt thereof in daphne Min according to claim 1 or claim 2 or a pharmaceutical composition according to claim 3 for the preparation of a medicament for the prevention or treatment of parkinson's disease.
10. The use according to claim 9, characterized in that: the derivative or the pharmaceutical composition is suitable for H 2 O 2 The induced SH-SY5Y cell oxidative damage has neuroprotective activity.
CN202310686153.5A 2023-06-09 2023-06-09 Sesquiterpene and sesquiterpene dimer in daphne regale, preparation method thereof and application of sesquiterpene dimer in aspect of resisting parkinsonism Pending CN116715570A (en)

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