CN109988219A - A kind of sequiterpene cyclohexenone compounds and its preparation method and application - Google Patents
A kind of sequiterpene cyclohexenone compounds and its preparation method and application Download PDFInfo
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- CN109988219A CN109988219A CN201910323259.2A CN201910323259A CN109988219A CN 109988219 A CN109988219 A CN 109988219A CN 201910323259 A CN201910323259 A CN 201910323259A CN 109988219 A CN109988219 A CN 109988219A
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Abstract
The invention belongs to terpenoid technical fields more particularly to a kind of sequiterpene cyclohexenone compounds and its preparation method and application.Sequiterpene cyclohexenone compounds provided by the invention have novel skeleton structure, enrich the diversity of sequiterpene cyclohexenone compounds；And the sequiterpene cyclohexenone compounds have anti-inflammatory and anti-tumor activity；Sequiterpene cyclohexenone compounds are prepared by microbial fermentation in the present invention, the preparation method period is short, condition of culture is mild, by-product is few, stereoselectivity is strong, at low cost, it is easily industrialized, not only conform with the demand of modern environmental protection and low-carbon economy, additionally it is possible to which the volume production for sequiterpene cyclohexenone compounds provides new way；Sequiterpene cyclohexenone compounds provided by the invention can be applied to prepare anti-inflammatory and anti-tumor drug, provide new selection for exploitation anti-inflammatory drug.
Description
Technical field
The present invention relates to terpenoid technical field more particularly to a kind of sequiterpene cyclohexenone compounds and its systems
Preparation Method and application.
Background technique
Terpenoid (terpenes)-molecular formula is the hydro carbons and its containing oxygen derivative of the multiple of isoprene unit,
It is that there is a major class natural products, including monoterpene, sequiterpene, diterpene, sequiterpene cyclonene, triterpene of great diversity etc.
Deng.Many terpenoids have been currently being developed to the important medicine for the treatment of cancer, bacterium infection, malaria and other various human diseases
Object.Therefore, the synthesis of terpenoid just seems very important.But since biosynthetic pathway does not illustrate completely yet, terpene
The factors such as structure and not pervasive unified synthetic strategy of the compound with non-modularization, the source way of terpenoid
Diameter still relies on the extraction of natural products.
Sequiterpene cyclohexenone compounds are the secondary metabolite of only a few microorganism, according to the literature, such change
Closing object has the multiple biological activities such as anti-inflammatory, anti-cell is malicious, antitumor and antibacterial.Therefore, sesquiterpene cyclohexene is developed
Ketone compounds are of great significance to the status for solving current abuse of antibiotics.
Summary of the invention
The purpose of the present invention is to provide a kind of sequiterpene cyclohexenone compounds, such compound structure is novel, tool
There is anti-inflammatory and anti-tumor activity.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The present invention provides a kind of sequiterpene cyclohexenone compounds, have structure shown in Formulas I or Formula II:
Wherein, R is-OH or CH3COO-。
The present invention provides the preparation method of sequiterpene cyclohexenone compounds described in above-mentioned technical proposal, including it is following
Step:
Penicillium expansum is inoculated in fermentation medium and is fermented, be expanded mould fermentation material；
The penicillium expansum fermentation material is mixed with alcohol, carries out ultrasonic extraction, the peaceful crude extract of the mould that is expanded；
The peaceful crude extract of the penicillium expansum is purified, sequiterpene cyclohexenone compounds are obtained.
Preferably, the raw material of the fermentation medium includes potato or rice.
Preferably, the temperature of the fermentation is 20~30 DEG C, and the time is 25~35d, and the mode of the fermentation is solid hair
Ferment.
Preferably, the ratio between the quality of the penicillium expansum fermentation material and the volume of alcohol are (30~50) g:(50~100) mL.
Preferably, the alcohol is methanol, ethyl alcohol, propyl alcohol or isopropanol.
Preferably, the time of the ultrasonic extraction is 20~40min, and power is 250~350W.
Preferably, the step of purifying includes first being eluted using silica gel column chromatography, then by gained eluent into
Row chromatogram purification obtains sequiterpene cyclohexenone compounds.
Preferably, eluant, eluent used in the elution is chloroform-methanol and petroleum ether-acetone, the flow velocity of the eluant, eluent
For 2~5mL/min.
The present invention provides sequiterpene cyclohexenone compounds described in above-mentioned technical proposal prepare it is anti-inflammatory and antitumor
Application in drug.
The present invention provides a kind of sequiterpene cyclohexenone compounds, such compound is with novel skeleton structure
Terpenoid enriches the diversity of sequiterpene cyclohexenone compounds；
Sequiterpene cyclohexenone compounds provided by the invention have anti-inflammatory and anti-tumor activity, can according to embodiment
Know, which shows apparent inhibitory activity to the generation of NO, and shows apparent suppression to 5 kinds of tumour cells
System activity；
Sequiterpene cyclohexenone compounds are prepared by microbial fermentation in the present invention, and the preparation method period is short, trains
Feeding mild condition, by-product is few, stereoselectivity is strong, at low cost, it is easy to accomplish industrialization not only conforms with modern environmental protection and low-carbon
Economic demand, additionally it is possible to which the volume production for sequiterpene cyclohexenone compounds provides new way；
Sequiterpene cyclohexenone compounds provided by the invention can be applied to prepare anti-inflammatory and anti-tumor drug, to open
Hair anti-inflammatory drug provides new selection.
Detailed description of the invention
Fig. 1 is the peaceful first of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 11H-NMR spectrum；
Fig. 2 is the peaceful first of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 113C-NMR and
DEPT spectrum；
Fig. 3 is the peaceful first of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 11H-1H COSY
Spectrum；
Fig. 4 is the HMBC spectrum of the peaceful first of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1；
Fig. 5 is the hsqc spectrum of the peaceful first of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1；
Fig. 6 is the NOESY spectrum of the peaceful first of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1；
Fig. 7 is the HR-ESI-MS of the peaceful first of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1
Spectrum；
Fig. 8 is the X-ray monocrystalline of the peaceful first of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1
Structure；
Fig. 9 is the peaceful second of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 11H-NMR spectrum；
Figure 10 is the peaceful second of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 113C-NMR and
DEPT spectrum；
Figure 11 is the peaceful second of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 11H-1H
COSY spectrum；
Figure 12 is the HMBC spectrum of the peaceful second of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1；
Figure 13 is the hsqc spectrum of the peaceful second of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1；
Figure 14 is the NOESY spectrum of the peaceful second of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1；
Figure 15 is the HR-ESI- of the peaceful second of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1
MS spectrum；
Figure 16 is the ECD of sequiterpene cyclohexenone compounds penicillium expansum peaceful first and second prepared by the embodiment of the present invention 1
Experimental patterns；
Figure 17 is sequiterpene cyclohexenone compounds penicillium expansum peaceful third prepared by the embodiment of the present invention 11H-NMR
Spectrum；
Figure 18 is sequiterpene cyclohexenone compounds penicillium expansum peaceful third prepared by the embodiment of the present invention 113C-NMR and
DEPT spectrum；
Figure 19 is sequiterpene cyclohexenone compounds penicillium expansum peaceful third prepared by the embodiment of the present invention 11H-1H
COSY spectrum；
Figure 20 is the HMBC spectrum of sequiterpene cyclohexenone compounds penicillium expansum peaceful third prepared by the embodiment of the present invention 1；
Figure 21 is the hsqc spectrum of sequiterpene cyclohexenone compounds penicillium expansum peaceful third prepared by the embodiment of the present invention 1；
Figure 22 is the NOESY spectrum of sequiterpene cyclohexenone compounds penicillium expansum peaceful third prepared by the embodiment of the present invention 1；
Figure 23 is the HR-ESI- of sequiterpene cyclohexenone compounds penicillium expansum peaceful third prepared by the embodiment of the present invention 1
MS spectrum；
Figure 24 is the ECD of sequiterpene cyclohexenone compounds penicillium expansum peaceful third prepared by the embodiment of the present invention 1 and fourth
Experimental patterns；
Figure 25 is the peaceful fourth of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 11H-NMR
Spectrum；
Figure 26 is the peaceful fourth of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 113C-NMR and
DEPT spectrum；
Figure 27 is the peaceful fourth of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 11H-1H
COSY spectrum；
Figure 28 is the HMBC spectrum of the peaceful fourth of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1；
Figure 29 is the hsqc spectrum of the peaceful fourth of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1；
Figure 30 is the NOESY spectrum of the peaceful fourth of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1；
Figure 31 is the HR-ESI- of the peaceful fourth of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1
MS spectrum；
Figure 32 is the X-ray list of the peaceful fourth of sequiterpene cyclohexenone compounds penicillium expansum prepared by the embodiment of the present invention 1
Crystal structure.
Specific embodiment
The present invention provides a kind of sequiterpene cyclohexenone compounds, have structure shown in Formulas I or Formula II:
Wherein, R is-OH or CH3COO-。
In the present invention, R is CH in the compound of the structure shown in the Formulas I3When COO-, the sequiterpene cyclohexenone analog
It closes object and is denoted as the peaceful first of penicillium expansum；
When R is-OH in the compound of the structure shown in the Formulas I, it is green that the sequiterpene cyclohexenone compounds are denoted as extension
Mould peaceful second；
R is CH in the compound of the structure shown in the Formulas I3When COO-, the sequiterpene cyclohexenone compounds are denoted as expansion
Penicillium patulum peaceful third；
When R is-OH in the compound of the structure shown in the Formulas I, it is green that the sequiterpene cyclohexenone compounds are denoted as extension
Mould peaceful fourth.
The present invention provides the preparation method of sequiterpene cyclohexenone compounds described in above-mentioned technical proposal, including it is following
Step:
Penicillium expansum is inoculated in fermentation medium and is fermented, be expanded mould fermentation material；
The penicillium expansum fermentation material is mixed with alcohol, carries out ultrasonic extraction, the peaceful crude extract of the mould that is expanded；
The peaceful crude extract of the penicillium expansum is purified, sequiterpene cyclohexenone compounds are obtained.
Penicillium expansum is inoculated in fermentation medium by the present invention to ferment, and be expanded mould fermentation material.In this hair
In bright, the penicillium expansum is preferably derived from yellow grass crow, and more preferably isolated from the root of yellow grass crow, the penicillium expansum is
The endogenetic fungus of yellow grass crow.After the present invention preferably first activates the penicillium expansum, then ferment；The step of the activation
It is rapid that preferably the penicillium expansum is inoculated on PDA slant medium, after 25~30 DEG C of 5~7d of constant temperature incubation, lived
The penicillium expansum of change is placed it in 5 DEG C of refrigerators and is stored for future use.
In the present invention, the raw material of the fermentation medium preferably includes potato or rice, more preferably potato.This
Invention is not particularly limited the fermentation medium, can make penicillium expansum growth and breeding.In the embodiment of the present invention
In, raw potatoes are specifically divided into the bulk (or in water by rice in steep) that diameter is 1~3cm and are placed in tissue cultures
Bottle in (45~50g/ bottle), then will the tissue culture flasks cover after at 120~150 DEG C progress high-temperature sterilization 30~
50min, it is cooling, obtain fermentation medium.
In the present invention, the inoculum concentration of the inoculation is preferably 1~3%.The present invention is to the condition of the inoculation without spy
Different requirement selects mode well known to those skilled in the art to be inoculated with.In an embodiment of the present invention, specifically will
The penicillium expansum of activation is inoculated in fermentation medium, and constant temperature incubation is carried out after capping, and be expanded mould fermentation material.
In the present invention, the mode of the fermentation is preferably solid fermentation, and the temperature of the fermentation is preferably 20~30 DEG C,
More preferably 26~28 DEG C；Time is preferably 25~35d, more preferably 28~30d.The present invention can using solid fermentating mode
Shorten fermentation time.
It being expanded after mould fermentation material, the present invention mixes the penicillium expansum fermentation material with alcohol, ultrasonic extraction is carried out,
The peaceful crude extract of the mould that is expanded.In the present invention, the alcohol is preferably methanol, ethyl alcohol, propyl alcohol or isopropanol；The present invention is with alcohol
The peaceful first, second of penicillium expansum, third, fourth are extracted from penicillium expansum fermentation material for solvent.In the present invention, the extension is green
The ratio between quality and the volume of alcohol of mould fermentation material are preferably (30~50) g:(50~100) mL, more preferably (40~45) g:(70
~80) mL, most preferably 45g:80mL.The present invention does not have special restriction to the mixed mode, selects art technology
Mode known to personnel mixes.
In the present invention, the time of the ultrasonic extraction is preferably 20~40min, more preferably 30min, and power is preferably
250W~350W, more preferably 300W.The present invention preferably carries out the ultrasonic extraction at room temperature.The ultrasound is completed to mention
After taking, gained extracting solution is preferably filtered by the present invention, and then the solvent in removal gained filtrate, the mould that is expanded are rather thick
Extract.The solvent in filtrate is removed present invention preferably employs the mode of vacuum distillation；In an embodiment of the present invention, specifically will
Filtrate decompression is concentrated into no alcohol taste, and the pressure of the reduced pressure is preferably 10~15kPa, more preferably 12kPa；The decompression
The temperature of concentration is preferably 45~55 DEG C, and more preferably 50 DEG C.
After the peaceful crude extract of the mould that is expanded, the present invention purifies the peaceful crude extract of the penicillium expansum, obtains sesquialter
Terpene cyclohexenone compounds.
In the present invention, the step of purifying preferably includes first to be eluted using silica gel column chromatography, then by gained
Eluent carries out chromatogram purification, obtains sequiterpene cyclohexenone compounds.The preferred present invention is first to wash with chloroform-methanol
De- agent is eluted, and is then eluted using petroleum ether-acetone as eluant, eluent.In chloroform-methanol of the present invention, chloroform
Volume ratio with methanol is preferably 100:0~20:1.It in an embodiment of the present invention, specifically first will with chloroform-methanol
Gained mixture is mixed with silica gel, removes solvent, dress column, is then that solvent is washed with chloroform by the peaceful crude extract dissolution of penicillium expansum
It is de- to obtain chloroform elution fraction；Silicagel column is carried out to chloroform elution fraction using petroleum ether-acetone of volume ratio 30:1 as eluant, eluent
Chromatographic elution obtains the eluent containing penicillium expansum peaceful first and second, and petroleum ether-acetone using volume ratio 15:1 is eluant, eluent to chlorine
Imitative elution fraction carries out silica gel column chromatography elution, obtains the eluent containing penicillium expansum peaceful third and fourth.In the present invention, for molten
The chloroform-methanol of the despreading peaceful crude extract of Penicillium patulum is preferably the eluant, eluent of arbitrary volume ratio, and the present invention utilizes arbitrary volume
The chloroform-methanol of ratio will be adsorbed on silica gel after the peaceful crude extract dissolution of penicillium expansum.In the present invention, the silica gel and expansion
The mass ratio of the peaceful crude extract dry weight of Penicillium patulum is preferably 0.8~1.5:1；The partial size of the silica gel is preferably 300~400 mesh.?
In the present invention, the method for the removal solvent is preferably distillation under vacuum；The temperature of the vacuum distillation is preferably 48~55 DEG C,
More preferably 50 DEG C.In the present invention, when carrying out the elution, the flow velocity of eluant, eluent is preferably 2~5mL/min, more preferably
3mL/min。
Present invention preferably employs gel column chromatographies to carry out chromatogram purification to gained eluent, specifically will be described green containing extension
The eluent of mould peaceful first and second and the eluent containing penicillium expansum peaceful third and fourth are purified through sephadex column, are obtained
The peaceful first, second of penicillium expansum, Bing Heding.In the present invention, the solvent for carrying out the purifying is preferably methanol, the flow velocity of the methanol
Preferably 0.4~0.6mL/min, more preferably 0.5mL/min.Complete it is described after purification, the present invention preferably by products therefrom into
Row drying, the peaceful first, second of the mould that is expanded, Bing Heding.The present invention does not have special restriction to the mode of the drying, selects this
Mode known to the technical staff of field is dried.
The present invention provides sequiterpene cyclohexenone compounds described in above-mentioned technical proposal prepare it is anti-inflammatory and antitumor
Application in drug.Sequiterpene cyclohexenone compounds provided by the invention have significant anti-inflammatory and anti-tumor activity, energy
It is enough to be applied to prepare anti-inflammatory and anti-tumor drug.When preparing anti-inflammatory and anti-tumor drug, in described anti-inflammatory and anti-tumor drug
Preferably include the peaceful first, second of penicillium expansum, third or fourth that mass percent is 1~99%, more preferably 55~90%；It is described anti-inflammatory
With preferably can also include pharmaceutic adjuvant in anti-tumor drug, the present invention not have special restriction to the pharmaceutic adjuvant, select
The pharmaceutical aids of this field routine.The present invention does not have special limit to described anti-inflammatory and anti-tumor drug preparation method
It is fixed, the dosage forms such as tablet, granule or injection are made using preparation method well known in the art.
Below with reference to embodiment to sequiterpene cyclohexenone compounds provided by the invention and its preparation method and application
It is described in detail, but they cannot be interpreted as limiting the scope of the present invention.
Embodiment 1
Penicillium expansum is inoculated on PDA slant medium, after 28 DEG C of constant temperature incubation 5d, the penicillium expansum activated,
It is placed in 5 DEG C of refrigerators and stores for future use；
Clean potato is taken, is divided into the potato block that diameter is 1cm and is placed in tissue culture flasks (45g/ bottles), tissue is trained
It supports and carries out high-temperature sterilization 30min after bottle covers at 120 DEG C, it is cooling, obtain fermentation medium；
The penicillium expansum of the activation is inoculated into the fermentation medium according to 1% inoculum concentration, 28 after capping
Constant temperature incubation 30d at DEG C, be expanded mould fermentation material；
Penicillium expansum fermentation material described in 50g is mixed with 80mL methanol, gained mixed solution is ultrasonic under the conditions of 40kHz
30min, filtering, takes filtrate to be concentrated under reduced pressure into no alcohol taste, obtains the peaceful crude extract of 27.0g penicillium expansum；
With 30mL chloroform-methanol (volume ratio 2:1) dissolve the peaceful crude extract of 27.0g penicillium expansum, then with 27.0g silicon
Glue (300~400 mesh) mixing is concentrated under reduced pressure removal solvent, fills column；It then is that solvent affords chloroform elution portion with chloroform
Point；Silica gel column chromatography elution is carried out to chloroform elution fraction using petroleum ether-acetone of volume ratio 30:1 as eluant, eluent, is obtained containing expansion
The eluent of Penicillium patulum peaceful first and second carries out silicon to chloroform elution fraction using petroleum ether-acetone of volume ratio 15:1 as eluant, eluent
Plastic column chromatography elution, obtain the eluent containing penicillium expansum peaceful third and fourth, using methanol as solvent, to the peaceful first of the penicillium expansum,
Second, third and the eluent of fourth carry out dextran gel column chromatography purifying, dry, obtain sequiterpene cyclohexenone compounds-expansion
The peaceful first, second of Penicillium patulum, Bing Heding.
The peaceful first, second of the penicillium expansum that Example 1 is prepared, third, fourth pass through 1D/2D NMR (one-dimensional nuclear magnetic resonance wave
Spectrum and 2D nuclear magnetic resonance spectroscopy) and HR-ESI-MS (high-resolution electrospray ionization mass spectrometry) progress Structural Identification.
The peaceful first, second of available compound penicillium expansum, third, the H and connected C of fourth are composed by hsqc spectrum combination carbon
Chemical shift δ ownership, such as table 1.
1 penicillium expansum of table peaceful first, second, third, fourth13C (150MHz) and1H (600MHz) NMR data, CDCl3For solvent.
According to table 1, the HR-ESI-MS m/z:[M+H of compound 1]+Quasi-molecular ion peak be 401.2323 (C24H33O5
[M+H]+Calculated value: 401.2334) show that its molecular formula is C24H32O5, contain 9 degrees of unsaturation.Wherein 2 double bond C-8=C-
9 and C-4 '=C-5 ', a ketone carbonyl (- C=O) and an ester carbonyl group (- COO-) occupy 4 degrees of unsaturation altogether, remaining 5 are not
Saturation degree shows that compound 1 has five ring skeletons.The infrared spectroscopy of compound 1 is in 3444,1734 and 1712cm-1The absorption peak at place
Show to contain hydroxyl and carbonyl in compound 1.By to compound 11H、13C, change known to the analysis of DEPT and HSQC H NMR spectroscopy
It closes and contains 4 methyl [δ in object 1H0.88(H3-13),0.83(H3-14),0.94(H3-15),2.06(H3-9′)；δC33.2(C-
13), 21.7 (C-14), 19.4 (C-15), 20.9 (C-9 ')], 8 methylene [δHIt is shown in Table 2；δC36.1(C-1),18.9(C-2),
41.7(C-3),18.7(C-6),31.5(C-7),27.1(C-11),44.6(C-12),60.4(C-7′,oxygenated)]、3
A methine [δH1.24(H-5),6.57(H-2′),3.38(H-5′)；δC51.2(C-5),147.5(C-2′,olefinic),
62.2 (C-5 ', oxygenated)] and 9 quaternary carbon [δC33.3(C-4),121.9(C-8,olefinic),136.4(C-9,
olefinic),37.7(C-10),69.8(C-1′,oxygenated),129.0(C-3′,olefinic),193.5(C-4′,α,
β-unsaturated ketone),63.3(C-6′,oxygenated),170.5(C-8′,ketone)]。
The planar structure of compound 1 is compared by nuclear magnetic data and 2DNMR experiment determines.H2-1(δH1.15m,
1.64m)/H2-2(δH1.42-1.48m,1.57m)/H2-3(δH1.37m, 1.93m) and H-5/H2-6(δH1.70m,1.42m)/
H2- 7 (1.87-1.93m, 2H's)1H-1H COSY correlation combination H2- 1/C-2, C-3, C-10 and C-5；H2- 2/C-3, C-4 and C-
10；H2- 3/C-4 and C-5；H-5/C-4, C-10, C-6 and C-7；H2- 6/C-4, C-10, C-7 and C-8；H2-7/C-8,C-9；H3-
13/C-3, C-4, C-5 and C-14；H3- 14/C-3, C-4, C-5 and C-13 and H3The HMBC of -15/C-1, C-5, C-9 and C-10
Related (Fig. 4) confirms the presence of a bicyclic sequiterpene dilute (rings A and B).Epoxydon part (epoxy hexamethylene
Ketenes part) (ring D) presence be then according to following HMBC correlation determine: H-2 '/C-12, C-3 ', C-4 ' and C-6 '；H-
5 '/C-3 ', C-4 ' and C-6 '；H2- 7 '/C-2 ', C-3 ', C-4 ' and C-8 ' and H3-9′/C-8′.And H2-12/C-7,C-8,C-
9, C-1 ' and C-6 ' and H2The HMBC of -11/C-8, C-9, C-1 ' and C-6 ' are related, show the dilute segment of sequiterpene and apical ring oxygen
Rhzomorph part is connected by a cyclohexene ring (ring C).The chemical displacement value δ of C-1 'C69.8 show itself and a hydroxyl
Base phase connects.Therefore, the planar structure of compound 1 is confirmed as the sequiterpene epoxy hexane ketone connected by a cyclohexene ring
Polymer, New skeleton compound obtained by which is derived for one as known compound cyclisation.The relative configuration of compound 1
It is determined respectively by NOESY experiment (Fig. 6) and single crystal X-ray diffraction experiment with absolute configuration.H3-14/H3-15,H3-15/Hβ-
The NOE correlation of 11 and H β -11/H-5 ' shows H3-14,H3- 15 and H-5 ' is located at β；And H3The NOE correlation of -13/H-5 is then
Show H3- 13 and H-5 is located at α.It is true by single crystal X-ray diffraction experiment [Cu K α, Flack parameter 0.00 (6)]
The absolute configuration (Fig. 8) of compound 1 is determined.Therefore, the structure of compound 1 is confirmed completely, is named as penicillium expansum
Peaceful first.
The HR-ESI-MS m/z:[M+H of compound 2]+Quasi-molecular ion peak be 359.2215 (C22H31O4[M+H]+Meter
Calculation value: 395.2217) show that its molecular formula is C22H30O4, contain 8 degrees of unsaturation.Careful control compounds 2 and compound 1
's1H and13C H NMR spectroscopy finds that the one-dimensional spectrum of the two almost can be completely overlapped, the difference is that compound 2 compares compound
1 has lacked the signal (δ an of acetyl groupH2.06s,δC20.9,170.5) its HMBC data (Figure 12), is further analyzed, with chemical combination
Object 1 compares, and the H present in compound 1 has been lacked in compound 22- 7 '/C-8 ' and H3The HMBC correlation of -9 '/C-8 '
Show the structure fragment that acetyl group is not present in compound 2.Therefore it is presumed that the deacetylation that compound 2 is compound 1 produces
Object.Since compound 2 has lacked the structure of an acetyl group compared with compound 1, the relative configuration of compound 2 is tried using NOESY
It tests and determines (Figure 14), H3-14(δH0.83s)/H3-15(δH0.94s),H3-15/Hβ-11(δH2.88d) and H β -11/H-5 '
(δHNOE correlation 3.38s) shows H3-14,H3- 15 and H-5 ' is located at β；And H3-13(δH0.88s)/H-5(δH1.24d)
NOE correlation then show H3- 13 and H-5 is located at α.Since there are identical molecular skeleton, and opposite structure in 2 and compound 1
Type is completely the same.In order to further determine the absolute configuration of compound 2, the experiment ECD spectrogram of compound 1 and 2 is compared,
It was found that the ECD map of the two is almost overlapped (Figure 16), therefore, the absolute configuration of compound 2 is confirmed as the S of 5S, 10S, 1 ',
5 ' S, 6 ' R, compound 2 are named as the peaceful second of penicillium expansum.
The HR-ESI-MS m/z:[M+Na of compound 3]+Quasi-molecular ion peak be 423.2146 (C24H32O5Na[M+Na]+Meter
Calculation value: 423.2142) show that its molecular formula is C24H32O5, contain 9 degrees of unsaturation.Wherein 2 double bond C-8=C-9 and C-3 '
=C-2 ', a ketone carbonyl (- C=O) and an ester carbonyl group (- COO-) occupy 4 degrees of unsaturation altogether, remaining 6 degree of unsaturation
Show that compound 3 has six ring skeletons.The infrared spectroscopy of compound 3 is in 3439,1734 and 1718cm-1The showing of absorption peak at place
It closes and contains hydroxyl and carbonyl in object 3.By to it1H,13Contain 4 in compound 3 known to the analysis of C, DEPT and HSQC NMR data
A methyl [δH2.08(H3-9′),0.94(H3-15),0.87(H3-13),0.81(H3-14)；δC33.7(C-13),21.4(C-
14), 21.0 (C-9 '), 20.9 (C-15)], 8 methylene [δHIt is shown in Table 2；δC75.8(C-12,oxygenated),61.2(C-
7′,oxygenated),42.3(C-3),39.5(C-1),33.3(C-7),26.4(C-11),19.1(C-6),18.2(C-2)],
4 methine [δH6.84(H-2′),3.82(H-5′),1.84(H-9),0.97(H-5)；δC 135.5(C-2′,
), olefinic 58.4 (C-9), 57.3 (C-5 '), 56.4 (C-5)] and 8 quaternary carbon [δC 194.4(C-4′,α,β-
unsaturated ketone),170.5(C-8′),134.6(C-3′,olefinic),89.1(C-1′,oxygenated),
69.3 (C-6 '), 48.9 (C-8), 37.8 (C-10), 33.2 (C-4)], the above spectral data shows that compound 3 is chemical combination strongly
The analog of object 1.
H in compound 32-1(δH1.13m,1.58m)/H2-2(δH1.45m,1.66m)/H2-3(δH1.19m, 1.43m) and
H-5/H2-6(δH1.19m,1.75m)/H2- 7 (1.56m, 2.31m's)1H-1H COSY correlation and H2-1/C-2,C-3,C-10
And C-5；H2- 2/C-2, C-4 and C-10；H2- 3/C-4, C-5 and C-10；H-5/C-4, C-10, C-6 and C-7；H2-6/C-4,C-
10, C-7 and C-8；H2-7/C-8,C-9；H3- 11/C-3, C-4, C-5 and C-12；H3- 12/C-3, C-4, C-5 and C-11 and
H3The HMBC of -13/C-1, C-5, C-9 and C-10 related (Figure 20) show the structure fragment dilute there are bicyclic sesquiterpene.H-2'/C-
1', C-3', C-4' and C-7'；H-5'/C-3', C-4' and C-6'；H2- 7'/C-3', C-4', C-5' and C-8' and H3-9'/C-
The HMBC correlation of 8' shows to contain the structure fragment of epoxydon in compound 3.H-7/C-1'；H-2'/C-8 and H2-
11(δH1.67overlapped, 2.78t)/C-8, C-9, C-1', C-2' is related to the HMBC of C-6' show sequiterpene part and
Epoxydon part passes through a five-membered ring connection.The chemical displacement value and H of C-12 and C-1'2-12/C-7,C-8,C-9
The presence for showing four membered oxygen rings related to the HMBC of C-1'.H3-14/H3-15；H3- 15/H β -11 and H2-12(δH4.29d,4.82d)；Hβ-11/H-12(δHIt is 4.82d) related to the NOE of H-5' to show that these groups are located at β, and H3-13/H-
The NOE correlation of 5 and H-9/H-5 shows that these groups are located at α.By comparing the experiment value ECD of compound 3 and compound 4
The mono-crystalline structures (Figure 32) of map (Figure 24) binding compounds 4 also demonstrate the absolute configuration of compound 3, and structure such as Formulas I is changed
It closes object 3 and is named as penicillium expansum peaceful third.
The HR-ESI-MS m/z:[M+Na of compound 4]+Quasi-molecular ion peak be 381.2038 (C22H30O4Na[M+Na]+Meter
Calculation value: 381.2036) show that its molecular formula is C22H30O4, contain 8 degrees of unsaturation.Control compounds 4 and compound 31H
With13Compound 4 has lacked an acetyl group signal compared to compound 3 known to C H NMR spectroscopy, in addition, the H in compound 32-7′/C-
2 ', C-3 ', C-4 ', and C-8 ' and H3The missing of the HMBC of -9 '/C-8 ' related (Figure 28) also indicates that compound 4 is compound 3
Deacetylation product.Likewise, the missing of acetyl group is so that the chemical displacement value of C-3 ' moves (δ to low field in compound 4C
134.6 → 138.8), therefore, compound 4 is confirmed as the deacetylation derivative of compound 3.The relative configuration of compound 4 is logical
It crosses NOESY experiment to determine, H3-14(δH0.80s)/H3-15(δH0.94s)；H3-15/Hβ-11(δH2.77t) and H2-12(δH4.29d,4.82d)；Hβ-11/H-12(δH4.82d) and H-5 ' (δHNOE correlation 3.79s) shows that these groups are located at β,
And H3-13(δH0.87s)/H-5(δH0.94d) and H-5/H-9 (δHNOE correlation 1.84dd) then shows that these groups are located at α
Position.Therefore, the relative configuration of compound 4 is confirmed as the S* of 5S*, 8R*, 9R*, 10S*, 1 ', 5 ' S*, 6 ' R*, with compound 3
Relative configuration is consistent.The absolute configuration of compound 4 is determined by ECD experiment and single crystal X-ray diffraction, due to compound 4 and is changed
Closing object 3 has identical skeleton and identical relative configuration, by the experiment ECD spectrum (Figure 24) of the two it can be seen that the two
There is identical absolute configuration.In addition, the monoclinic crystal of compound 4 obtains in petroleum ether-acetone (4:1, v/v) system, lead to
It crosses single crystal X-ray diffraction and has obtained its structure [Figure 32, Flack parameter=-0.06 (7)], thus also demonstrate it absolutely
To being configured as the S of 5S, 8R, 9R, 10S, 1 ', 5 ' S, 6 ' R.The determination of 4 absolute configuration of compound also demonstrates 3 absolute configuration of compound
Correctness.So far, the structure of compound 4 is confirmed completely, and compound 4 is named as the peaceful fourth of penicillium expansum.
In conclusion the structural formula for the peaceful first, second of compound penicillium expansum, third, fourth that embodiment 1 is prepared can be determined
Are as follows:
Embodiment 2
The peaceful first, second of compound penicillium expansum prepared by embodiment 1, third, fourth carry out anti-inflammatory and antitumor activity screening.
1, the peaceful first, second of compound penicillium expansum, third, the anti-inflammatory activity of fourth:
Nitric oxide has extensive and important biology adjusting function, has in inflammation, tumour and cardiovascular system etc.
Important function.When immunocyte is stimulated by microbial endotoxins, inflammatory mediator etc., a large amount of induction type one can be generated and aoxidized
Nitrogen synzyme generates NO and carries out immune response.Therefore, inhibiting NO to generate is the direct indicator of compound anti-inflammatory activity.
(1) the mouse monokaryon macrophage RAW264.7 (being purchased from Chinese Academy of Sciences Shanghai cell bank) of logarithmic growth phase, with 1 μ
G/mL LPS carries out induction stimulation, while being added at the peaceful first, second of compound penicillium expansum, third, fourth that embodiment 1 is prepared
Reason, the peaceful first, second of compound penicillium expansum, third, the final concentration of fourth be followed successively by 0.195 μM, 0.391 μM, 0.781 μM, 1.563 μM,
3.125 μM and 6.250 μM of six gradients, each gradient are arranged three Duplicate Samples, cultivate under the conditions of 25 DEG C.
Setting without medicine group and L-NMMA (total no inhibitor) positive drug group according to above-mentioned same steps at
Reason, as control.
(2) after cell pellet overnight (10h) culture, the NO production quantity of each group is detected at 570nm；To the training being incubated overnight
MTS is added in nutrient solution and carries out cell survival rate detection, excludes the toxic effect of compound on intracellular.
NO generation inhibiting rate (%)=(be free of medicine group OD570nmMedicine group OD570nm)/be free of medicine group OD570nm×
100%；
IC50(half-inhibitory concentration) is calculated by Reed&Muench method, obtains the peaceful first, second of compound penicillium expansum, third, fourth
NO inhibitory activity IC50。
2, the peaceful first, second of compound penicillium expansum, third, the anti-tumor activity of fourth:
MTS method detects cell activity principle: MTS is a kind of completely new MTT analog, is a kind of dyestuff of yellow color.It is living
Succinate dehydrogenase can be metabolized reduction MTS in cell mitochondrial, generate soluble formazan compound, and the content of formazan can be with
It is measured at 490nm with microplate reader., formazan growing amount is directly proportional to viable count in general, therefore, can basis
Optical density OD value deduces the number of living cells.
(1) it is outstanding that individual cells inoculating cell: are made into the culture solution (DMEM or RMPI1640) containing 10% fetal calf serum
Liquid, with 3000~15000, every hole cell inoculation to 96 orifice plates, every 100 μ L of pore volume, attached cell shifts to an earlier date 12~24 hours and connects
Kind culture.
(2) be added testing compound solution: compound is dissolved with DMSO, compound with 40 μM, 8 μM, 1.6 μM, 0.32 μM,
0.064 μM of concentration secondary screening, every 200 μ L of hole final volume, every kind of processing are all provided with 3 multiple holes.
(3) develop the color: 37 degrees Celsius culture 48 hours after, attached cell abandon hole in culture solution, every hole add 20 μ L of MTS solution and
100 μ L of culture solution；Suspension cell abandons 100 μ L culture supernatants, and every hole adds the MTS solution of 20 μ L；If (MTS is molten for 3 blank multiple holes
The mixed liquor of 100 μ L of 20 μ L of liquid and culture solution), continue incubation 2~4 hours, measures absorbance value after the progress that reacts fully.
(4) colorimetric: selection 492nm wavelength, multi-function microplate reader (MULTISKAN FC) read each hole absorbance value, record
As a result, cell survival rate is that ordinate draws cell growth curve, using two-point method using concentration as abscissa after data processing
The IC of (Reed andMuench method) calculating compound50Value.
(5) positive reference compound: experiment is all provided with two positive compounds of cis-platinum (DDP) and taxol (Taxol) every time,
Using concentration as abscissa, cell survival rate is that ordinate draws cell growth curve, using two-point method (Reed and Muench
Method) calculate compound IC50Value.
Experimental result shows, to the peaceful first, second of compound penicillium expansum, third, the NO inhibitory activity of fourth (positive control are as follows:
L-NMMA) in screening test, the peaceful first, second of compound penicillium expansum, third, fourth the generation of nitric oxide (NO) is shown it is bright
Aobvious inhibitory activity (table 2).To the peaceful first, second of compound penicillium expansum, third, fourth to the inhibitory activity of external five kinds of tumour cells
In (positive control are as follows: cis-platinum, taxol) screening test, the peaceful first, second of penicillium expansum, third, fourth show it is good anti-swollen
Tumor activity (table 2).Therefore, the peaceful first, second of penicillium expansum, third, fourth, which have, develops anti-inflammatory and anti-tumor drug as lead compound
Researching value.
The peaceful first, second of 2 penicillium expansum of table, third, the NO inhibitory activity of fourth and antitumor activity screening (IC50)
Embodiment 3
Penicillium expansum is inoculated on PDA slant medium, after 28 DEG C of constant temperature incubation 5d, the penicillium expansum activated,
It is placed in 5 DEG C of refrigerators and stores for future use；
45g rice in steep 12h in 40mL water is taken, rice is taken out and is placed in tissue culture flasks (50g/ bottles), by tissue
Culture bottle carries out high-temperature sterilization 30min at 120 DEG C after covering, cooling, obtains fermentation medium；
The penicillium expansum of the activation is inoculated into the fermentation medium according to 1% inoculum concentration, 26 after capping
Constant temperature incubation 25d at DEG C, be expanded mould fermentation material；
Penicillium expansum fermentation material described in 45g is mixed with 120mL methanol, gained mixed solution is ultrasonic under the conditions of 40kHz
30min, filtering, takes filtrate to be concentrated under reduced pressure into no alcohol taste, obtains the peaceful first, second of 27.0g penicillium expansum, third, fourth crude extract；
The peaceful first, second of the penicillium expansum, third, fourth crude extract are dissolved with 30mL chloroform-methanol (volume ratio 2:1),
It is mixed again with 27.0g silica gel (300~400 mesh), removal solvent is concentrated under reduced pressure, fills column；Then it is solvent elution with chloroform, obtains
Chloroform elution fraction；Silica gel column chromatography is carried out to chloroform elution fraction as eluant, eluent using petroleum ether-acetone of volume ratio 30:1 to wash
It is de-, the eluent containing penicillium expansum peaceful first and second is obtained, chloroform is eluted using petroleum ether-acetone of volume ratio 15:1 as eluant, eluent
Part carries out silica gel column chromatography elution, the eluent containing penicillium expansum peaceful third and fourth is obtained, using methanol as solvent, to the extension
The peaceful first, second of mould, third and the eluent of fourth carry out dextran gel column chromatography purifying, dry, obtain sequiterpene cyclohexenone analog
The peaceful first, second of compound-penicillium expansum, Bing Heding.
As seen from the above embodiment, the present invention provides a kind of sequiterpene cyclohexenone compounds, such compound is
Terpenoid with novel skeleton structure enriches the diversity of sequiterpene cyclohexenone compounds；The present invention provides
Sequiterpene cyclohexenone compounds have anti-inflammatory and anti-tumor activity, according to embodiment it is found that life of the compound to NO
Cheng Jun shows apparent inhibitory activity, and shows apparent inhibitory activity to 5 kinds of tumour cells；The present invention passes through micro-
Sequiterpene cyclohexenone compounds are prepared in biofermentation, the preparation method period is short, condition of culture is mild, by-product is few,
Stereoselectivity is strong, at low cost, it is easy to accomplish industrialization not only conforms with the demand of modern environmental protection and low-carbon economy, additionally it is possible to be
The volume production of sequiterpene cyclohexenone compounds provides new way；Sequiterpene cyclohexenone compounds provided by the invention can
Applied to anti-inflammatory and anti-tumor drug is prepared, new selection is provided for exploitation anti-inflammatory drug.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of sequiterpene cyclohexenone compounds have structure shown in Formulas I or Formula II:
Wherein, R is-OH or CH3COO-。
2. the preparation method of sequiterpene cyclohexenone compounds described in claim 1, comprising the following steps:
Penicillium expansum is inoculated in fermentation medium and is fermented, be expanded mould fermentation material；
The penicillium expansum fermentation material is mixed with alcohol, carries out ultrasonic extraction, the peaceful crude extract of the mould that is expanded；
The peaceful crude extract of the penicillium expansum is purified, sequiterpene cyclohexenone compounds are obtained.
3. preparation method according to claim 2, which is characterized in that the raw material of the fermentation medium include potato or
Rice.
4. preparation method according to claim 2, which is characterized in that the temperature of the fermentation is 20~30 DEG C, and the time is
25~35d；The mode of the fermentation is solid fermentation.
5. preparation method according to claim 2, which is characterized in that the quality of the penicillium expansum fermentation material and the body of alcohol
The ratio between product is (30~50) g:(50~100) mL.
6. preparation method according to claim 2, which is characterized in that the alcohol is methanol, ethyl alcohol, propyl alcohol or isopropanol.
7. preparation method according to claim 2, which is characterized in that the time of the ultrasonic extraction is 20~40min, function
Rate is 250~350W.
8. preparation method according to claim 2, which is characterized in that include first using silicagel column color the step of the purifying
Spectrum is eluted, and gained eluent is then carried out chromatogram purification, obtains sequiterpene cyclohexenone compounds.
9. preparation method according to claim 7, which is characterized in that eluant, eluent used in the elution is chloroform-methanol
With petroleum ether-acetone, the flow velocity of the eluant, eluent is 2~5mL/min.
10. any one of sequiterpene cyclohexenone compounds described in claim 1 or claim 2~9 the preparation method system
Standby obtained sequiterpene cyclohexenone compounds are preparing the application in anti-inflammatory and anti-tumor drug.
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