CN106916161A - A kind of isoamylene radical chromocor and its purposes in treatment diseases associated with inflammation medicine is prepared - Google Patents
A kind of isoamylene radical chromocor and its purposes in treatment diseases associated with inflammation medicine is prepared Download PDFInfo
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- CN106916161A CN106916161A CN201710042126.9A CN201710042126A CN106916161A CN 106916161 A CN106916161 A CN 106916161A CN 201710042126 A CN201710042126 A CN 201710042126A CN 106916161 A CN106916161 A CN 106916161A
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- artoheteroid
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- C—CHEMISTRY; METALLURGY
- 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
Abstract
The present invention relates to a kind of isoamylene radical chromocor, and application of the compound in treatment diseases associated with inflammation medicine is prepared.Described isoamylene radical chromocor is from Moraceae jackfruit platymiscium jackfruitArtocarpus heterophyllusIn an isolated noval chemical compound, artoheteroid C are named as, with following structures：.The compound has strong inhibitory activity to Polymorphonuclear Leukocyte respiratory burst, its IC50It is 7.5 μM, can further prepares treatment diseases associated with inflammation medicine, for the various oxidative damage 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 medicine.
Background technology
Neutrophil leucocyte（PMNs）It is that human body resists the first line of defence that external pathogen is invaded.When PMNs identifies acceptor
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
Produce substantial amounts of superoxide anion (O2 •-)。O2 •-There occurs that one is under the catalysis of superoxide dismutase and myeloperoxidase
Row free chain reaction, generates 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 referred to 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 cause to damage while invasion bacterium is killed, also to normal surrounding tissue, cause obstruction microcirculation, in injured blood vessel
Chrotoplast and extravascular tissue cell, release and promotion release inflammatory mediator, as " saboteur ".Such as Patients With Rheumatoid Arthritis
In, by wrongful activation, a large amount of ROS of generation cause the corrosion of articular cartilage tissue to neutrophil leucocyte.And for example septicopyemia
Or in surgical injury, wound, burn, ischemical reperfusion injury, the PMNs of excessive activation can cause tissue damage, when serious
Cause runaway inflammatory reaction, including compensatory anti-inflammatory response syndrome (cARS), SIRS (SIRS) etc..
Thus, it is found that the material for suppressing PMNs respiratory bursts has weight for the various oxidative damages caused by treatment PMNs respiratory bursts
Want meaning.
JackfruitArtocarpus heterophyllusAlso known as " tree POLO ", " wooden POLO ", " cows belly is really " etc., it is mulberry
Section's jackfruit platymiscium, has cultivation extensively in south China each province of China and Taiwan.Jackfruit has various pharmaceutical usages among the people,
Anaemia, asthma and skin disease are such as treated, is alleviated and is twitched and ulcer, calmness, anti-syphilis, expelling parasite.Modern chemistry and pharmacological research
Show, the root of jackfruit is rich in substantial amounts of isopentene group phenolic constituent, press down with antitumor, anti-oxidant, antibacterial, tyrosinase
System, phosphatide enzyme level, cathepsin K suppress isoreactivity.In the early stage 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, be named as
artoheteroid C。
The content of the invention
It is clinically to breathe quick-fried with PMNs it is an object of the invention to provide the material active with PMNs respiratory bursts are suppressed
The treatment for sending out related inflammation provides medicine.Invention is specifically related to a kind of isoamylene radical chromocor extracted in jackfruit root, with such as
Lower shown chemical constitution：
。
The compound is the noval chemical compound for having no document report, is named as artoheteroid C.
The further object of the present invention is to provide above-claimed cpd and is preparing anti-inflammatory（With PMNs respiratory burst related inflammations）
New application in medicine.
Compound of the present invention is prepared by following methods：
Jackfruit root herb（17 Kg）, with the extraction of 95% ethanol seepage, extract solution is concentrated under reduced pressure to obtain the Kg of medicinal extract 1.5.Medicinal extract is with water
It is suspended, successively with petroleum ether, chloroform, ethyl acetate and extracting n-butyl alcohol, and is concentrated to dryness respectively.Take chloroform extraction position medicinal extract
532 g, carry out macroporous resin column chromatography（Post specification：15*55cm, 5.3 Kg）, alcohol-water gradient elution is used, obtain 10 flow points
frs. H1-H10.Gel Sephadex LH-20 posts on stream part H5 (10.0 g), methyl alcohol elutes to obtain 10 stream parts：frs.
H5L1-H5L10.Reverse ODS posts, methanol-water (2 on stream part H5L5 (1.5 g):8→10:0, v/v) elute, obtain 4 flow points
H5L5O1-H5L5O4.Sephadex LH-20 gel columns, chloroform-methanol (1 in flow point H5L5O4 (483.0 mg) continuation:
1, v/v) elute, obtain 7 flow point frs. H5L5O4L1-H5L5O4L7.H5L5O4L1 (36.0 mg) therein is by preparing
Type HPLC (CH3CN-H2O, 11:9, v/v) separate and obtain compound a rtoheteroid C (4.6 of the present invention
mg, tR 35 min)。
Show by active testing, compound a rtoheteroid C of the present invention are to Buddhist ripple acetate
(PMA) the Polymorphonuclear Leukocyte outburst for stimulating has significant inhibitory action, its half-inhibition concentration (IC50) it is 7.5
M。
Compound of the present invention can be further prepared into treating the medicine of PMNs respiratory bursts caused inflammation out of control.
Brief description of the drawings
The chemical structural formula of Fig. 1 Artoheteroid C.
Fig. 2 be compound a rtoheteroid C of the present invention proton nmr spectra (1H NMR)。
Fig. 3 be compound a rtoheteroid C of the present invention carbon-13 nmr spectra (13H NMR)。
Fig. 4 is that the main HMBC (H → C) of compound a rtoheteroid C of the present invention is related.
Fig. 5 is actual measurement ECD and its computer simulation the ECD spectrum of compound a rtoheteroid C of the present invention.
Specific embodiment
The specific embodiment being given by the following, can further be well understood to the present invention.
The preparation of isoamylene radical chromocor artoheteroid C in the jackfruit of embodiment 1
Jackfruit root herb（17 Kg）, with the extraction of 95% ethanol seepage, extract solution is concentrated under reduced pressure to obtain the Kg of medicinal extract 1.5.Medicinal extract is with water
It is suspended, successively with petroleum ether, chloroform, ethyl acetate and extracting n-butyl alcohol, and is concentrated to dryness respectively.Take chloroform extraction position medicinal extract
532 g, carry out macroporous resin column chromatography（Post specification：15*55cm, 5.3 Kg）, alcohol-water gradient elution is used, obtain 10 flow points
frs. H1-H10.Gel Sephadex LH-20 posts on stream part H5 (10.0 g), methyl alcohol elutes to obtain 10 stream parts：frs.
H5L1-H5L10.Reverse ODS posts, methanol-water (2 on stream part H5L5 (1.5 g):8→10:0, v/v) elute, obtain 4 flow points
H5L5O1-H5L5O4.Sephadex LH-20 gel columns, chloroform-methanol (1 in flow point H5L5O4 (483.0 mg) continuation:
1, v/v) elute, obtain 7 flow point frs. H5L5O4L1-H5L5O4L7.H5L5O4L1 (36.0 mg) therein is by preparing
Type HPLC (CH3CN-H2O, 11:9, v/v) separate and obtain compound a rtoheteroid C (4.6 of the present invention
mg, tR 35 min)。
The Structural Identification of isoamylene radical chromocor artoheteroid C in the jackfruit of embodiment 2
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) it is aobvious
Show that the compound has the typical absorption characteristic of isoamylene radical chromocor class compound.Artoheteroid C's1H H NMR spectroscopies
（600 MHz, dimethyl sulfoxide-d 6 ）Show following proton signal：One hydroxyl of hydrogen bond associationδ H12.33
(1H, s, OH-5)；A pair of aromatics of meta 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
ABX type spin coupling systemsδ 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).The hydrogen of Artoheteroid C
Spectrum is much like with known compound artonin L, primary difference is that artonin L have two methoxyl groups and
Artoheteroid C only one of which methoxyl groups.Artoheteroid C's13C NMR and DEPT spectrum occur in that 21 carbon letters
Number, from a lavonoid backbone（15 carbon）, an isopentene group（5 carbon）With a methoxyl group.By HSQC and HMBC bis-
Nuclear magnetic resonance experiment, our all H and C signal to artoheteroid C have carried out full ownership (table 1) proton signalsδ H3.77 (MeO-4 ') and carbon signalδThe HMBC explanation methoxy substitutions of c 147.7 occur in C-4 ' positions.Isopentene group takes
In generation, occurs at C-3, and forms dihydrofuran ring with the C-5 ' dioxide givings of B rings.This can be by the related (figures of following HMBC
4) 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).By than
12 of actual measurement ECD and computer simulation compared with artoheteroid CRWith 12STwo kinds of ECD of configuration, have found artoheteroid
C and 12RConfiguration fitting it is fine（Fig. 5）, therefore the absolute configuration of determination C-12 isR.Then, the structure quilt of artoheteroid C
It is defined as shown in Fig. 1.
The hydrogen spectrum and carbon modal data of the compound a rtoheteroid C of the present invention of table 1a
aThe NMRs of Bruker Avance 600;Chemical displacement value (ppm) passes through (CD3)2SO corrections ( H
2.50; C 39.52).
The artoheteroid C of embodiment 3 are tested to the Cytotoxic evaluation of rat PMN s
The pertinent literature of reference standard trypanblue exclusion method determines cytotoxicities of the artoheteroid C to PMNs.Under 37 °C, 1
The PMNs cell suspensions of mL（1×106）（2% FCS-HBSS）With 10 μ L DMSO or artoheteroid C（Final concentration scope
From 1 to 1000 μM）It is incubated 30 minutes together.The trypan blue dye liquor of 112 μ L 0.4%, high-power microscope are added in every part of sample
Under, calculate cytotoxic effect of the sample to PMNs by counting 100 situations of cells absorption trypan blue.Result shows,
Artoheteroid C are 180More than M just starts toxicity of the performance to PMNs.
Measure of the artoheteroid C of embodiment 4 to rat PMN s respiratory burst inhibiting rates
SD rats are taken, male and female are not limited, eye socket takes blood, 1% liquaemin anti-freezing, glucan T-500 sedimented red cells, lymphocyte point
Chaotropic is separated, hypotonic removing residual red blood cells, and rat PMN purity and activity are detected (with trypan blue exclusion>95%), then use
Cell diluent adjustment cell concentration is 2 × 106Individual ml-1.4 DEG C of preservations, use in 12 h, and PMNs vigor is constant.
PMNs is by exogenous stimulant-Fo Bo acetates (phorbol)（PMA）There is respiratory burst after activation, produce a large amount of
Active oxygen radical, free radical by luminous agent luminol capture produce chemiluminescence (Chemiluminesence, CL),
Respiratory burst and the phagocytic function positive correlation of the cell quantity and PMNs of PMN-CL intensity and PMNs.Take 1 ml PMNs cells dilute
Liquid is released in glow cup, 200 μ l luminol working solutions are added thereto to, is placed in and 10 min is incubated in superweak luminescence measuring instrument
(parameter setting：Luminous 37 DEG C of pond temperature, the V of voltage 1000, detection time 1800 most long s), records spontaneous photoreduction process and (counts
Time interval 5 is s).It is subsequently adding 10 μ l sample solutions（It is blank with 10 μ l DMSO）Continue to determine 5 min, plus
Enter 8g·ml-1The μ l of PMA stimulants 10, continue to determine 15 min, record measurement result.PMN-CL intensity is with luminous note
Number peak height is represented.PMN-CL inhibiting rates are calculated by formula (1).
PMN-CL inhibiting rates (%)=×100%
With PMN-CL inhibiting rates as ordinate, sample concentration is abscissa, sets up amount effect relation curve, can be asked by amount effect curve
Calculate concentration (the i.e. IC of sample when luminous inhibiting rate is 50%50Value).With vitamin C (Vc) as positive control.As a result table
Bright, the rat PMN s outbursts that artoheteroid C stimulate PMA are with strong inhibition effect, IC50 It is 7.5M, its activity
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 as described in claim 1 and its physiologically acceptable salt or hydrate, preparing, treatment is inflammatory
Application in disease medicament.
3. application of the compound as described in claim 1 in treatment diseases associated with inflammation medicine is prepared, it is characterised in that inflammation
Property disease refer to rheumatoid arthritis, Compensatory Anti-Inflammatory reaction syndrome, systemic toxin.
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| CN110183312A (en) * | 2019-07-25 | 2019-08-30 | 江西中医药大学 | A kind of isopentene group talan and its purposes in preparation treatment diseases associated with inflammation drug |
| CN110183311A (en) * | 2019-07-25 | 2019-08-30 | 江西中医药大学 | A kind of isopentene group stilbene and its purposes in preparation treatment diseases associated with inflammation drug |
| CN110183415A (en) * | 2019-07-25 | 2019-08-30 | 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 |
| CN110183413A (en) * | 2019-07-25 | 2019-08-30 | 江西中医药大学 | Diphenylethylene compounds in two color jackfruits and its purposes in preparation treatment diseases associated with inflammation drug |
| CN110183414A (en) * | 2019-07-25 | 2019-08-30 | 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 |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110183312A (en) * | 2019-07-25 | 2019-08-30 | 江西中医药大学 | A kind of isopentene group talan and its purposes in preparation treatment diseases associated with inflammation drug |
| CN110183311A (en) * | 2019-07-25 | 2019-08-30 | 江西中医药大学 | A kind of isopentene group stilbene and its purposes in preparation treatment diseases associated with inflammation drug |
| CN110183415A (en) * | 2019-07-25 | 2019-08-30 | 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 |
| CN110183413A (en) * | 2019-07-25 | 2019-08-30 | 江西中医药大学 | Diphenylethylene compounds in two color jackfruits and its purposes in preparation treatment diseases associated with inflammation drug |
| CN110183414A (en) * | 2019-07-25 | 2019-08-30 | 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 |
| 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 |
| 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 |
| 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 |
| 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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Effective date of registration: 20201118 Address after: A1-202-203, building a, Kexing Science Park, 15 Keyuan Road, Science Park community, Yuehai street, Nanshan District, Shenzhen, Guangdong Province Patentee after: Shenzhen Beimei Pharmaceutical Co.,Ltd. Address before: 330000 Jiangxi city of Nanchang province Wanli District Hing Wan Road No. 818 Patentee before: JIANGXI University OF TRADITIONAL CHINESE MEDICINE |
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