CN106916161B - A kind of isoamylene radical chromocor and its purposes in preparing treatment diseases associated with inflammation drug - Google Patents
A kind of isoamylene radical chromocor and its purposes in preparing treatment diseases associated with inflammation drug Download PDFInfo
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- CN106916161B CN106916161B CN201710042126.9A CN201710042126A CN106916161B CN 106916161 B CN106916161 B CN 106916161B CN 201710042126 A CN201710042126 A CN 201710042126A CN 106916161 B CN106916161 B CN 106916161B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/06—Peri-condensed systems
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Abstract
The present invention relates to a kind of isoamylene radical chromocors and the compound to prepare the application in treating diseases associated with inflammation drug.The isoamylene radical chromocor is from Moraceae jackfruit platymiscium jackfruitArtocarpus heterophyllusIn an isolated noval chemical compound, be named as artoheteroid C, there are following structures：.The compound has strong inhibitory activity, IC to Polymorphonuclear Leukocyte respiratory burst50It is 7.5M can further prepare treatment diseases associated with inflammation drug, for the various oxidative damages caused by clinical treatment neutrophil leucocyte excessive activation, such as rheumatoid arthritis, Compensatory Anti-Inflammatory reaction syndrome, systemic toxin.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of isoamylene radical chromocor class compound in jackfruit is controlled in preparation
Treat the application in diseases associated with inflammation drug.
Background technology
Neutrophil leucocyte（PMNs）It is the first line of defence that human body resists external pathogen invasion.When PMNs identifies receptor
After the complex that the small peptide of secretion or bacterium are formed with Serum Antibody, through the receptor-mediated activation for causing cell on film, rapidly
Generate a large amount of superoxide anion (O2 •-)。O2 •-A system has occurred under the catalysis of superoxide dismutase and myeloperoxidase
Row free chain reaction produces various active oxygens（ROS）, including hydroxy radical（HO·）, hydrogen peroxide（H2O2）And it is secondary
Chloric acid（HOCl）.These ROS can efficiently eliminate the pathogenic microorganism of invasion, and this phenomenon is known as respiratory burst.Normal
Under physiological condition, the respiratory burst of PMNs is formd the maximally efficient pathogen of body and is resisted mechanism by accuracy controlling.However,
ROS can also be caused to damage while killing invasion bacterium to normal surrounding tissue, cause obstruction microcirculation, damage intravascular
Chrotoplast and extravascular tissue cell, release and promotion release inflammatory mediator, become " saboteur ".Such as Patients With Rheumatoid Arthritis
In, for neutrophil leucocyte by wrongful activation, a large amount of ROS of generation cause the corrosion of articular cartilage tissue.For another example septicopyemia
Or in surgical injury, wound, burn, ischemical reperfusion injury, the PMNs of excessive activation can cause tissue damage, when serious
Lead to runaway inflammatory reaction, including compensatory anti-inflammatory response syndrome (cARS), systemic inflammatory response syndrome (SIRS) etc..
Thus, it is found that inhibiting the substance of PMNs respiratory bursts that there is weight for the various oxidative damages caused by treatment PMNs respiratory bursts
Want meaning.
JackfruitArtocarpus heterophyllusAlso known as " tree polo ", " the wooden polo ", " cows belly fruit " etc., it is mulberry
Section's jackfruit platymiscium has extensive cultivation in China south China each province and Taiwan.Jackfruit civil there are many pharmaceutical usage,
It such as treats anaemia, asthma and skin disease, alleviate twitch and ulcer, calmness, anti-syphilis, expelling parasite.Modern chemistry and pharmacological research
Show that the root of jackfruit is rich in a large amount of isopentene group phenolic constituent, there is antitumor, anti-oxidant, antibacterial, tyrosinase to press down
System, phosphatidase inhibit, cathepsin K inhibits isoreactivity.In early period in screening active ingredients of this seminar, jackfruit root
95% ethanol extract is demonstrated by stronger inhibitory activity to rat PMN s respiratory bursts.Therefore, the present invention is to the activity extract
In-depth study is carried out, an active isoamylene radical chromocor is therefrom obtained, is a noval chemical compound, is named as
artoheteroid C。
Invention content
The object of the present invention is to provide with the active substance of PMNs respiratory bursts is inhibited, breathed with PMNs for clinically quick-fried
The treatment for sending out related inflammation provides drug.Invention has such as more particularly to a kind of isoamylene radical chromocor extracted in jackfruit root
Chemical constitution shown in lower：
。
The compound is to have no the noval chemical compound of document report, is named as artoheteroid C.
The further object of the present invention be to provide above compound prepare it is anti-inflammatory（With PMNs respiratory burst related inflammations）
New application in drug.
Compound of the present invention is prepared by following methods：
Jackfruit root herb（17 Kg）, leaked and extracted with 95% ethyl alcohol, 1.5 Kg of medicinal extract is concentrated under reduced pressure to obtain in extracting solution.Medicinal extract
It is suspended with water, uses petroleum ether, chloroform, ethyl acetate and extracting n-butyl alcohol successively, and be concentrated to dryness respectively.Chloroform is taken to extract position
532 g of medicinal extract carries out macroporous resin column chromatography（Column specification：15*55cm, 5.3 Kg）, with alcohol-water gradient elution, obtain 10
Flow point frs. H1-H10.Gel Sephadex LH-20 columns on fraction H5 (10.0 g), methanol elute to obtain 10 fractions：frs.
H5L1-H5L10.Reversed ODS columns, methanol-water (2 on fraction H5L5 (1.5 g):8→10:0, v/v) it elutes, obtains 4 flow points
H5L5O1-H5L5O4.Flow point H5L5O4 (483.0 mg) continues upper Sephadex LH-20 gel columns, chloroform-methanol (1:
1, v/v) it elutes, obtains 7 flow point frs. H5L5O4L1-H5L5O4L7.H5L5O4L1 (36.0 mg) therein is by preparing
Type HPLC (CH3CN-H2O, 11:9, v/v) separation obtains compound a rtoheteroid C (4.6 of the present invention
mg, tR 35 min)。
Show compound a rtoheteroid C of the present invention to Buddhist wave acetate (PMA) by active testing
The Polymorphonuclear Leukocyte outburst of stimulation has significant inhibiting effect, half-inhibition concentration (IC50) it is 7.5M。
Compound of the present invention can be further prepared into the drug for the treatment of PMNs respiratory bursts caused inflammation out of control.
Description of the drawings
The chemical structural formula of Fig. 1 Artoheteroid C.
Fig. 2 be compound a rtoheteroid C of the present invention nuclear magnetic resonance spectroscopy (1H NMR)。
Fig. 3 be compound a rtoheteroid C of the present invention carbon-13 nmr spectra (13H NMR)。
The main HMBC (H → C) that Fig. 4 is compound a rtoheteroid C of the present invention is related.
The actual measurement ECD and its computer simulation ECD spectrums that Fig. 5 is compound a rtoheteroid C of the present invention.
Specific implementation mode
The present invention can be further well understood in the specific embodiment being given by the following.
The preparation of isoamylene radical chromocor artoheteroid C in 1 jackfruit of embodiment
Jackfruit root herb（17 Kg）, leaked and extracted with 95% ethyl alcohol, 1.5 Kg of medicinal extract is concentrated under reduced pressure to obtain in extracting solution.Medicinal extract
It is suspended with water, uses petroleum ether, chloroform, ethyl acetate and extracting n-butyl alcohol successively, and be concentrated to dryness respectively.Chloroform is taken to extract position
532 g of medicinal extract carries out macroporous resin column chromatography（Column specification：15*55cm, 5.3 Kg）, with alcohol-water gradient elution, obtain 10
Flow point frs. H1-H10.Gel Sephadex LH-20 columns on fraction H5 (10.0 g), methanol elute to obtain 10 fractions：frs.
H5L1-H5L10.Reversed ODS columns, methanol-water (2 on fraction H5L5 (1.5 g):8→10:0, v/v) it elutes, obtains 4 flow points
H5L5O1-H5L5O4.Flow point H5L5O4 (483.0 mg) continues upper Sephadex LH-20 gel columns, chloroform-methanol (1:
1, v/v) it elutes, obtains 7 flow point frs. H5L5O4L1-H5L5O4L7.H5L5O4L1 (36.0 mg) therein is by preparing
Type HPLC (CH3CN-H2O, 11:9, v/v) separation obtains compound a rtoheteroid C (4.6 of the present invention
mg, tR 35 min)。
The Structural Identification of isoamylene radical chromocor artoheteroid C in 2 jackfruit of embodiment
Artoheteroid C, a kind of Yellow amorphous powder, HR-ESI-MS provide quasi-molecular ion peakm/z
381.0979 （[M-H]-, C21H17O7, calculated value: 381.0980）, determine that its molecular formula is C21H18O7.Infrared spectrum (ν max
3430, 2974, 1651, 1612, 1504, 1467, 1356 cm-1) and ultraviolet spectra (λ max 263, 316, 378
Nm) show that the compound has the typical absorption characteristic of isoamylene radical chromocor class compound.Artoheteroid C's1H
H NMR spectroscopy（600 MHz, dimethyl sulfoxide-d 6 ）Show following proton signal：The hydroxyl of one hydrogen bond associationδ H12.33 (1H, s, OH-5)；The aromatic of a pair of of meta position couplingδ H6.33 (1H, d, J = 1.8 Hz, H-8) and
6.13 (1H, d, J = 1.8 Hz, H-6)；One isolated aromaticδ H6.38 (H-3′)；One methoxyl groupδ H
3.77 (3H, s, MeO-4′)；Two methylδ H1.57 (3H, s, H3-14) and 1.23 (3H, s, H3- 15) and one
A ABX types spin coupling systemδ H2.60 (lH, t, J = 15.1 Hz, Ha-11), 3.10 (lH, dd, J =
15.1, 7.0, Hz, Hb-11), and 3.34 (lH, dd, J = 15.1, 7.0 Hz, H-12)。Artoheteroid
C hydrogen spectrum it is much like with known compound artonin L, primary difference is that artonin L there are two methoxyl group and
Only there are one methoxyl groups by artoheteroid C.Artoheteroid C's13C NMR and DEPT, which are composed, has showed 21 carbon letters
Number, come from a lavonoid backbone（15 carbon）, an isopentene group（5 carbon）With a methoxyl group.By HSQC and HMBC bis-
Nuclear magnetic resonance experiment, we have carried out full ownership (table 1) proton signals to all H and C signal of artoheteroid Cδ H3.77 (MeO-4 ') and carbon signalδThe HMBC of c 147.7 illustrates that methoxy substitution is happened at the positions C-4 '.Isopentene group takes
In generation, is happened at C-3, and forms dihydrofuran ring with the C-5 ' dioxide givings of B rings.This can pass through the related (figures of following HMBC
4) it is confirmed： Ha-11/Hb- 11 and C-2 (δc 159.9), C-3 (δc 111.7), C-4 (δc 179.6), C-6′
(δc 131.8), C-12 (δc 45.9), C-13 (δc 92.6)；H-12 and C-1 ' (δc 104.3), C-5′ (δc
136.7), C-6′, C-11 (δc 19.4), C-13, C-14 (δc 27.8), and C-15 (δc 22.4).Pass through ratio
Survey ECD and computer simulation 12 compared with artoheteroid CRWith 12SThe ECD of two kinds of configurations has found artoheteroid
C and 12RConfiguration fitting it is fine（Fig. 5）, therefore determine that the absolute configuration of C-12 isR.Then, the structure quilt of artoheteroid C
It is determined as shown in Fig. 1.
The hydrogen spectrum and carbon modal data of 1 compound a rtoheteroid C of the present invention of tablea
a600 Nuclear Magnetic Resonance of Bruker Avance;Chemical displacement value (ppm) passes through (CD3)2SO corrections ( H 2.50; C 39.52).
3 artoheteroid C of embodiment test the Cytotoxic evaluation of rat PMN s
The pertinent literature of reference standard trypanblue exclusion method measures cytotoxicities of the artoheteroid C to PMNs.37°C
Under, the PMNs cell suspensions of 1 mL（1×106）（2% FCS-HBSS）With 10 μ L DMSO or artoheteroid C（Final concentration
Range is from 1 to 1000 μM）It is incubated with 30 minutes.The trypan blue dye liquor of 112 μ L 0.4% is added in every part of sample, height is shown
Under micro mirror, cytotoxic effect of the sample to PMNs is calculated by counting the case where 100 cells absorb trypan blue.As a result table
Bright, artoheteroid C are 180M or more just starts to show the toxicity to PMNs.
Measurement of the 4 artoheteroid C of embodiment to rat PMN s respiratory burst inhibiting rates
SD rats are taken, male and female are unlimited, and eye socket takes blood, 1% heparin sodium anti-freezing, glucan T-500 sedimented red cells, and lymph is thin
Born of the same parents' separating liquid detaches, hypotonic removing residual red blood cells, and rat PMN purity and activity are detected (with trypan blue exclusion>95%),
It is again 2 × 10 with cell diluent adjustment cell concentration6A ml-1.4 DEG C of preservations, use in 12 h, and PMNs vigor is permanent
It is fixed.PMNs is by exogenous stimulant-Fo Bo acetates (phorbol)（PMA）Respiratory burst occurs after activation, generates
A large amount of active oxygen radical, free radical by luminous agent luminol capture generate chemiluminescence (Chemiluminesence,
CL), the respiratory burst of the cell quantity and PMNs of PMN-CL intensity and PMNs and phagocytic function positive correlation.Take 1 ml PMNs thin
Born of the same parents' dilution is added 200 μ l luminol working solutions, is placed in superweak luminescence measuring instrument and is incubated 10 thereto in glow cup
Min (parameter settings：Shine 37 DEG C of pond temperature, 1000 V of voltage, and longest detection time 1800 s), records spontaneous photoreduction process
(5 s of counting time period).Then 10 μ l sample solutions are added（Using 10 μ l DMSO as blank control）Continue measurement 5
Min is added 8g·ml-110 μ l of PMA stimulants continue to measure 15 min, record measurement result.PMN-CL intensity is to send out
Light numeration peak height indicates.PMN-CL inhibiting rates are calculated by formula (1).
PMN-CL inhibiting rates (%)=×100%
Using PMN-CL inhibiting rates as ordinate, sample concentration is abscissa, establishes amount effect relation curve, passes through amount effect curve
Concentration (the i.e. IC for calculating sample when the inhibiting rate that shines is 50% can be sought50Value).With vitamin C (Vc) it is used as positive control.Knot
Fruit shows that artoheteroid C have strong inhibition effect, IC to the rat PMN s outbursts that PMA is stimulated50 It is 7.5M,
Activity is better than positive control Vc（IC50 =24.3 M）.
Claims (3)
1. a kind of new isoamylene radical chromocor class compound a rtoheteroid C, it is characterised in that the compound has following institute
The chemical constitution shown：
。
2. compound a rtoheteroid C as described in claim 1 and its physiologically acceptable salt are preparing treatment inflammation
Application in disease property disease medicament.
3. compound a rtoheteroid C as described in claim 2 are preparing the application in treating diseases associated with inflammation drug,
It is characterized in that diseases associated with inflammation refers to that rheumatoid arthritis, Compensatory Anti-Inflammatory reaction syndrome, systemic inflammatory reaction are comprehensive
Close disease.
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110183413B (en) * | 2019-07-25 | 2019-10-29 | 江西中医药大学 | Diphenylethylene compounds in two color jackfruits and its purposes in preparation treatment diseases associated with inflammation drug |
| CN110183311B (en) * | 2019-07-25 | 2019-10-29 | 江西中医药大学 | A kind of isopentene group stilbene and its purposes in preparation treatment diseases associated with inflammation drug |
| CN110183312B (en) * | 2019-07-25 | 2019-11-15 | 江西中医药大学 | A kind of isopentene group talan and its purposes in preparation treatment diseases associated with inflammation drug |
| CN110183414B (en) * | 2019-07-25 | 2019-10-25 | 江西中医药大学 | One of two color jackfruits isopentene group talan and its purposes in preparation treatment diseases associated with inflammation drug |
| CN110183415B (en) * | 2019-07-25 | 2019-10-29 | 江西中医药大学 | One of two color jackfruits diphenyl ethylene derivatives and its purposes in preparation treatment diseases associated with inflammation drug |
| CN114432291A (en) * | 2020-11-02 | 2022-05-06 | 苏州凯祥生物科技有限公司 | Application of isopentene flavonoid compound in preparation of medicine |
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| Inhibitory effects of phenolic compounds from Artocarpus styracifolius on respiratory burst of rat neutrophils;REN Gang等;《Pharm Biol》;20140220;全文 * |
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