CN110343116A - A kind of Flos Chrysanthemi Indici extract and preparation method thereof and the application in preparation treatment medicine for nasopharyngeal - Google Patents

A kind of Flos Chrysanthemi Indici extract and preparation method thereof and the application in preparation treatment medicine for nasopharyngeal Download PDF

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CN110343116A
CN110343116A CN201811572377.9A CN201811572377A CN110343116A CN 110343116 A CN110343116 A CN 110343116A CN 201811572377 A CN201811572377 A CN 201811572377A CN 110343116 A CN110343116 A CN 110343116A
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hydrogen
flos chrysanthemi
chrysanthemi indici
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顾琼
徐峻
程燕芳
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Sun Yat Sen University
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Abstract

The present invention provides a kind of Flos Chrysanthemi Indici extracts, and its new opplication in preparation prevention and treatment medicine for nasopharyngeal, and provide the preparation method of Flos Chrysanthemi Indici extract simultaneously.Flos Chrysanthemi Indici extract provided by the invention is for inhibiting the growth of nasopharyngeal carcinoma cell to have a significant effect, and nasopharyngeal carcinoma cell HONE-1 can be arrested in the G2/M phase, and it can induce apoptosis in nasopharyngeal carcinoma cells, compound provided by the invention derives from plant, securely and reliably, inhibit nasopharyngeal carcinoma effect good, can be applied to the drug of preparation treatment nasopharyngeal carcinoma.

Description

A kind of Flos Chrysanthemi Indici extract and preparation method thereof and in preparation treatment medicine for nasopharyngeal Application
Technical field
The present invention relates to Chinese herbal medicine active constituent and technical field of pharmaceuticals, more particularly, to a kind of Flos Chrysanthemi Indici extract And preparation method thereof and preparation treatment medicine for nasopharyngeal in application.
Background technique
Nasopharyngeal carcinoma (Nasopharyngeal carcinoma, NPC) is a kind of high-incidence malignant tumour in South China, China Disease accounts for about 18% in Nattonal Cancer crowd.The formation of nasopharyngeal carcinoma may with Epstein-Barr virus (Epstein-Barr Virus, EBV) infection, environmental factor are related with inherent cause.Clinical manifestation is band blood etc. in headache, Hearing, nasal obstruction and tears.Nasopharynx The treatment of cancer mainly based on radiotherapy, is often aided with chemicals combination therapy, chemotherapy common broad-spectrum anti-tumor drug, such as 5- Fluorouracil, cis-platinum and gemcitabine etc..But radiotherapy and chemotherapy can bring many side reactions, such as headache, dry to patient And fever, heart and Toxicity of Kidney etc. have seriously affected people's lives quality.Moreover, often there is part again in treatment of nasopharyngeal carcinoma Hair and nasopharyngeal carcinoma cell are easily to far-end transfer phenomenon.
Natural products is the important sources of lead compound in drug development process.It is both at home and abroad it has been reported that some natural Compound has anti-nasopharyngeal carcinoma activity, including alkaloid, triterpene, flavonoids etc..Wild chrysanthemum is the plant of composite family Chrysanthemum perennial herb The dry capitulum of object mother chrysanthemum (Chrysanthemum indicum L.), wild resource are relatively abundanter.It is distributed widely in The ground such as China northeast, North China, northwest, East China, southwest.Modern research shows that wild chrysanthemum mainly contains volatile oil, flavones, terpene With the chemical components such as organic acid, there is broad-spectrum antiseptic, antiviral, decompression isoreactivity.The present invention reports a kind of Flos Chrysanthemi Indici extract Anti- nasopharyngeal carcinoma activity.
Summary of the invention
One of the object of the invention is to provide a kind of Flos Chrysanthemi Indici extract.
Another object of the present invention is to provide the preparation methods of above-mentioned Flos Chrysanthemi Indici extract.
A further object of the present invention is to provide application of the above-mentioned Flos Chrysanthemi Indici extract in preparation treatment medicine for nasopharyngeal.
Above-mentioned technical purpose is implemented with the following technical solutions in the present invention:
Shown in a kind of Flos Chrysanthemi Indici extract, the structural formula of the Flos Chrysanthemi Indici extract such as formula (I) and formula (II):
Wherein, R1For hydrogen, hydroxyl or C1~C5 saturation or unsaturated alkyl, wherein R1In hydrogen can be by cyano, nitro, carboxylic Base, amide or ester replace, R2For hydrogen, hydroxyl or C1~C5 saturation or unsaturated alkyl, wherein R2In hydrogen can by cyano, nitro, Carboxyl, amide or ester replace, R3For hydrogen, hydroxyl or C1~C5 saturation or unsaturated alkyl.
As a kind of perferred technical scheme, R1For hydrogen, hydroxyl or C1~C5 saturated alkyl, wherein R1In hydrogen can by- CO-R ' replaces, and R ' is C1~C5 saturated alkyl or C1~C5 unsaturated alkyl；R2For hydrogen, hydroxyl or C1~C5 saturation or insatiable hunger And alkyl, wherein R2In hydrogen can be by-CO-R ' replace, R ' be C1~C5 saturated alkyl or C1~C5 unsaturated alkyl.
As a kind of perferred technical scheme, unsaturated alkyl is alkenyl.
As a kind of perferred technical scheme, R ' is-C (CH3)=CH (CH3) or-CH=C (CH3)2。
As a kind of perferred technical scheme, when the Flos Chrysanthemi Indici extract is structural formula shown in formula (I), R1For hydrogen, Hydroxyl or C1~C3 saturated alkyl, wherein R1In hydrogen can be by-CO-R ' replace, R ' be-C (CH3)=CH (CH3) or-CH=C (CH3)2；R2For hydrogen, hydroxyl or C1~C3 saturated alkyl, wherein R2In hydrogen can be by-CO-R ' replace, R ' be-C (CH3)=CH (CH3) or-CH=C (CH3)2, R3For H, C1~C3 saturated alkyl or=CH2。
As a kind of perferred technical scheme, when the Flos Chrysanthemi Indici extract is structural formula shown in formula (II), R1For hydrogen, Hydroxyl or C1~C3 saturated alkyl, wherein R1In hydrogen can be by-CO-R ' replace, R ' be-C (CH3)=CH (CH3) or-CH=C (CH3)2；R2For H, C1~C3 saturated alkyl or=CH2。
As a preference, the Flos Chrysanthemi Indici extract is one of following structural formula:
Present invention simultaneously provides the preparation methods of the Flos Chrysanthemi Indici extract, the preparation method is that: on the ground by wild chrysanthemum Part is dried, and is crushed, and is extracted four times with 95% ethanol water room temperature, 72 hours every time, is merged concentrate, be extracted with ethyl acetate, Ethyl acetate is recovered under reduced pressure and obtains ethyl acetate portion medicinal extract.Ethyl acetate portion crosses normal phase silicagel column, petrol ether/ethyl acetate Precentagewise 10:0,9:1,4:1,2:1,0:1 crosses column respectively, and fraction is again through repeatedly isolated.
The present invention protects application of the Flos Chrysanthemi Indici extract in preparation prevention and treatment medicine for nasopharyngeal simultaneously.
Further, the drug further includes acceptable carrier or auxiliary material in pharmaceutics.
It when the compounds of this invention is used as drug, can directly use, or be used in the form of pharmaceutical composition.The medicine Compositions preferably comprise the active constituent i.e. the compounds of this invention formula (I) and formula (II) that weight ratio is 0.1~99%, most preferably The compounds of this invention for being 0.5~90% containing weight ratio, remaining is nontoxic to humans and animals and lazy to be pharmaceutically acceptable Pharmaceutical acceptable carrier and/or excipient of property.
The pharmaceutical carrier or excipient is one or more solids, semisolid and liquid diluent, filler and medicine Tetramune adjuvant.Pharmaceutical composition of the invention is used in the form of per weight dose.Drug of the invention can be through injecting (intravenous, intramuscular injection) and oral two kinds of forms administration.
The amount of application of the compounds of this invention can be according to route of administration, the age of patient, weight, the type for the disease treated Change with severity etc., daily dose can be 0.01~10mg/kg weight, preferably 0.1~5mg/kg weight.It can be primary Or it is used for multiple times.
Compared with the existing technology, the present invention has the advantage that and effect:
Flos Chrysanthemi Indici extract provided by the invention can be incited somebody to action for inhibiting the growth of nasopharyngeal carcinoma cell to have a significant effect Nasopharyngeal carcinoma cell HONE-1 is arrested in the G2/M phase, and can induce apoptosis in nasopharyngeal carcinoma cells, and ingredient is safe and reliable, can be applied to prepare The drug for treating nasopharyngeal carcinoma.
Detailed description of the invention
Fig. 1 is that compound 5 influences result to nasopharyngeal carcinoma HONE-1 Apoptosis.
Fig. 2 is compound 5 to nasopharyngeal carcinoma HONE-1 cell-cycle arrest experimental result.
Fig. 3 is the separating obtained compound structure figure of the method for the present invention.
Fig. 4 is crucial in the NMR spectra of compound 11H-1The COSY of HHMBCAnd NOESY Relational graph.
Fig. 5 is the mono-crystalline structures figure of compound 1.
Fig. 6 is experiment and the calculating ECD map of compound 2,10 and 12.
Fig. 7 is crucial in NMR spectra in compound 7,10-121H-1The COSY of HHMBCAnd NOESYRelational graph.
Specific embodiment
Further illustrate the present invention below in conjunction with specific embodiments and the drawings, but embodiment the present invention is not done it is any The restriction of form.Unless stated otherwise, the present invention uses reagent, method and apparatus is the art conventional reagents, method And equipment.
Unless stated otherwise, agents useful for same and material of the present invention are commercially available.
Embodiment 1:
The method of prepare compound formula (I) and formula (II) from wild chrysanthemum (Chrysanthemum indicum):
1, wild chrysanthemum (Chrysanthemum indicum) aerial part (6kg), is dried, and is crushed, 95% ethanol water room temperature Extraction four times 72 hours every time, merges concentrate, obtains crude extract (700g), be extracted with ethyl acetate, the portion ethyl acetate (300g) Point directly through silica gel column chromatography (2500g, 200-300 mesh, 7.0 × 100cm), petrol ether/ethyl acetate gradient elution (10:0, 9:1,4:1,2:1,0:1), every 500mL collects portion, and 5 flow point Fr.A-E are obtained in TLC combining data detection same section.
2, Fr.D (30g) is partially through C18Reversed post separation obtains tri- flow points of Fr.D1-D3.Wherein, Fr.D1 group lease making silicon Rubber column gel column is eluted with petroleum ether-ethyl acetate (4:1-1:1), obtains 5 flow point Fr.D1a-D1e.The part Fr.D1a passes through half system Standby liquid phase separation obtains formula (II) 8 (1g), and the part 9 (600mg) .Fr.D1a passes through the half isolated formula of preparation liquid phase (II) 17 (162mg)。
3, Fr.D2 is eluted through petroleum ether-ethyl acetate (5:1-1:1, V/V), obtains 4 flow point Fr.D2a-D2d. Fr.D2d is through the half preparation isolated formula of liquid phase (II) 16 (5mg).
4, Fr.E (100g) is partially through C18Reversed-phase column column chromatographs (MeOH/H2O, 50% → 100%) obtain Fr.E1-E3. Fr.E1 is eluted with petroleum ether-ethyl acetate (4:1-1:2, V/V), obtains 3 flow point Fr.E1a-E1c.Fr.E1a warp Sephadex LH-20 elutes to obtain Fr.E1a-1-Fr.E1a-3 with methylene chloride-methanol (1:1).Fr.E1a-1 is through half preparation solution Mutually isolated formula (II) 10 (29.5mg), 11 (24.3mg) and 12 (15mg).Fr.E1a-2 is isolated through half preparation liquid phase Formula (II) 7 (15mg) and 15 (34.3mg).Fr.E2 is eluted with petroleum ether-ethyl acetate (4:1-1:2, V/V), obtains 5 flow points Fr.E2a-E2e.Fr.E2b elutes to obtain Fr.E2b ' through Sephadex LH-20, with methylene chloride-methanol (1:1), makes by half Standby liquid phase separation obtains formula (I) 1 (9mg), 2 (11mg), 3 (10.8mg), 4 (7mg), 5 (24.4mg), 6 (181mg), and 13 (10mg),14(5mg)。
Shown in structural formula such as formula (I) and formula (II).
New compound structure identification:
Table 1: the nuclear magnetic data of noval chemical compound 1-4
The nuclear magnetic data of 2. noval chemical compound 5-8 of table
The nuclear magnetic data of 3. noval chemical compound 9-12 of table
Compound 1 is clear crystal, being provided according to mass spectrum plus sodium ion peak 533.2507 [M+Na]+(calcd.for C30H38O7Na, 533.2510), thus it is speculated that molecular formula C30H38O7, degree of unsaturation 12.The infrared spectroscopy of compound 1 shows exist Hydroxyl (3414cm-1), carbonyl (1767,1736cm-1) and double bond (1459cm-1).The hydrogen spectrum and carbon spectrogram of compound 1 compose (table 1) it discloses, 30 carbon, including 4 methyl (δ is contained in compound structureH1.26,1.27,1.43 and 1.84), 3 oxygen-containing secondary first Base (δC/H68.7/4.04,79.6/3.84,80.5/4.14), 2 oxygen-containing tertiary carbon (δC73.4 and 75.7), an exocyclic double bond [δH5.32, d, J=3.2Hz, 6.04, overlap；δC118.8], 2 carbonyl carbon (δC171.2 with 179.5).According to reported Chemical structural type in mother chrysanthemum, thus it is speculated that compound 1 is a guainane type sesquiterpene dimers.Pass through a peacekeeping two-dimensional nucleus magnetic Atlas analysis, compound 1 with from the isolated deacetylhandelin of phoenix Mao Juzhong planar structure having the same. In NOESY spectrum, H-7/H-5, H-5/H-1, H-6/H-8, H-8/H2-13,H3- 15 '/H-6 ' has related to H-5 '/H-7 ', shows H-1, H-5, H-7, H-5 ' and H-7 ' are in same plane, it is determined as α direction, then H-6, H-8, H2- 13, H-6 ' and H3- 15 ' it is β court To.By the monocrystalline cultivated in methanol/water, it has been determined that its absolute configuration is 1R, 5R by X-ray single crystal diffraction, 6R,7R,8S,10R,11R,1′R,4′R,5′S,6′S,7′S,10′R。
Being provided according to mass spectrum plus sodium ion peak 633.3046 [M+Na]+(calcd.for C35H46O9Na, 633.3034), The molecular formula for obtaining compound 2 is C35H46O9.Find that compound 2 and the structure of compound 1 are much like by analysis nuclear magnetic data, There is no exocyclic double bond in compound 2, more a bimodal methyl and a tigloyl side chain substituents [δH1.79, d (J= 7.2Hz),1.82,s,6.85,m；δC167.1,128.6,138.7,14.8 with 12.3].By HMBC compose in H-8 ' (δH5.13) With C-1 " (δCAnd C-11 ' (δ 167.1)C42.4) related, illustrate that tigloyl unit is connected in the position C-8 '.1H-1In H COSY spectrum, H- 11 ' and H-7 '/H3H in -13 ' related and HMBC spectrum3-13′(δH1.14, d, J=7.2Hz)/C-12 ' (δC178.8) and H3- 13′(δH1.14)/C-7′(δC51.1) coherent signal shows that methyl is connected in the position C-11 '.By NOESY compose in H-7/H-5, H- 5/H-1,H-6/H-8,H-8/H2-13,H3-15′/H-6′,H-8′/H-6′,H3- 13 '/H-7 ', H-11 '/H-8 ' and H-5 '/H- 7 ' coherent signal, show compound 2 relative configuration be the R of rel-1R, 5R, 6R, 7R, 8S, 11R, 1 ', 4 ' R, 5 ' S, 6 ' R ,- 7 ' R, 8 ' S, 11 ' S, in conjunction with its test ECD and calculate ECD map, it was demonstrated that the compound absolute configuration be 1R, 5R, 6R, 7R, 8S,10R,11R,1′R,4′R,5′S,6′R,7′R,8′S,10′R,11′S。
Compound 3 is named 8'-tigloyl chrysanolide D, determines that its molecular formula is C by mass spectrum35H44O9.It is logical The nuclear magnetic data discovery for comparing compound 3 and 2 is crossed, in addition to more exocyclic double bond (δ in compound 3H5.34, d, J= 3.2Hz；6.06, d, J=3.2Hz；δC120.7) and a bimodal methyl (δ has been lackedH1.14, d, J=7.2Hz；δC14.8), Remaining is all about the same.Pass through H in HMBC map2-13′(δH5.34,6.06) and C-7 ' (δCAnd C-12 ' (δ 51.1)C170.1) Correlation determines that the exocyclic double bond is located at C-11 '.Equally, pass through NOESY coherent signal H-7/H-5, H-5/H-1, H-6/H-8, H- 8/H2-13,H3- 15 '/H-6 ', H-8 '/H-6 ', and H-5 '/H-7 ' determined the compound relative configuration be rel-1R, 5R, 6R,7R,8S,10R,11R,1′R,4′R,5′S,6′R,7′R,8′S,10′R。
The molecular formula of compound 4 (8-angeloyl-8'-hydroxy chrysanolide D) can by ms fragment from Sub- peak m/z 631.2890 [M+Na]+(calcd.for C35H44O9Na, 631.2878) it is determined as C35H44O9Its nuclear magnetic data with Compound 3 is closely similar, and difference is in compound 4 that side chain is substituted by angeloyl unit, and is in compound 3 tigloyl.It is related to H-8 by NOE coherent signal H-3 "/H-4 " and H-3 "/H-5 " and COSY map H-7, and combine γ- The presence of the provable angeloyl of Ponds effect, two of them methyl are in trans- position.Based on NOESY coherent signal H-7/ H-5,H-5/H-1,H-6/H-8,H-8/H2-13,H3- 15 '/H-6 ', H-8 '/H-6 ' and H-5 '/H-7 ', the opposite structure of compound 4 Type is accredited as the R of rel-1R, 5R, 6R, 7R, 8S, 10R, 11R, 1 ', 4 ' R, 5 ' S, 6 ' R, 7 ' R, 8 ' S, 10 ' R.
Based on high resolution mass spectrum, the molecular formula of compound 5 (8,8'-ditigloyl chrysanolide D) is determined as C40H50O10.It is analyzed by one-dimensional nuclear magnetic data (table 2), it is found that the compound is similar to compound 3, difference is the chemical combination Object C-8 have connected a tigloyl unit (δH1.72, d, J=7.2Hz, 1.79, s, 6.85, overlap；δC166.6, 129.0,139.8,14.8 with 12.2), HMBC coherent signal H-8 (δH5.51)/C-1″(δC166.6) this provable point.Compound 5 NOESY correlation is as compound 3, so the relative configuration of the compound is set to rel-1R, 5R, 6R, 7R, 8S, 10R, 11R,1′R,4′R,5′S,6′R,7′R,8′S,10′R。
The molecular formula of compound 6 is by adding sodium ion peak m/z 615.2939 [M+Na]+(calcd.for C35H44O8Na, 615.2928) it is determined as C35H44O8.Find that the compound is similar to 1 structure by one-dimensional nuclear magnetic data analysis (table 2), wherein Compound 6 compared with 1 in the C-8 more tigloyl segment segments substitution can be composed by HMBC in coherent signal H-8/C- 1 "/C-11 is proved.NOESY correlation shows that compound 6 and compound 1 have same relative configuration.Therefore the structure of compound 6 It is accredited as the R of rel-1R, 5R, 6R, 7R, 8S, 10R, 11R, 1 ', 4 ' R, 5 ' S, 6 ' S, 7 ' S, 10 ' R are named 8-tigloyl chrysanolide D。
Compound 7 (chrysanolide F) be colourless powder, molecular formula by high resolution mass spectrum provide plus sodium from Sub- peak m/z 289.1405 [M+Na]+(calcd.for C15H22O4Na, 289.1410) it is determined as C15H22O4, amount to 5 insatiable hungers And degree.Its one-dimensional nuclear magnetic data (table 2) shows that compound 7 is the epimer of known compound chrysanolide B. NOESY coherent signal H3-13/H-8,H-6/H3- 13, H-5/H-7 and H-5/H-1 show that H-1, H-5, H-7 and H-11 are coplanar, For α direction, then H-6, H-8 and H3- 13 (Fig. 7) are β direction.Therefore, the structure of compound 7 is set to rel-1R, 5R, 6R, 7R, 8S,10R,11R。
Compound 8 is colorless oil compound, molecular formula C20H28O5.By analyzing one-dimensional nuclear magnetic data (table 2) hair Existing compound 8 be reported 8 α-angeloyloxy-10 β-hydroxy-slov-3-en-6,12-olideD of compound it is poor to Isomers.Difference is that the compound C-8 are connected with a tigloyl unit.Based on NOESY coherent signal H3-13/H-8, H-6/H3- 13, H-5/H-7 and H-5/H-1, compound 8 can be accredited as rel-1R, 5R, 6R, 7R, 8S, 10R, 11R, be named as 8- tigloyl chrysanolide F。
Fragment ion peak m/z 369.1656 [M+Na] based on high resolution mass spectrum+(calcd.for C20H26O5Na, 369.1672), the molecular formula of compound 9 is determined as C20H26O5.Its hydrogen spectrum and carbon modal data (table 3) compound with it is reported Compound a ngeloylcumambrin B (16) is much like, in addition to C-8 more tigloyl segments in compound 9 It is angeloyl in compound 16.It is found by the two-dimentional nuclear magnetic spectrum of compound 9, which is the monoploid of 1-6 and 13. Therefore by NOESY coherent signal H-5/H-7 and H-5/H-1, compound 9 is determined as rel-1R, and 5R, 6R, 7R, 8S, 10R is simultaneously It is named as chrysanolide G.
The molecular formula of compound 10 (chrysanolide H) is C20H26O6.Its hydrogen spectrum and carbon modal data show the compound There are 5 methyl, the methine of two company's oxygen, company's oxygen tertiary carbon, an olefinic carbon proton, two methylene, three methines, One ketone group and two carbonyls.These are statistics indicate that compound 10 is the analog of compound 8.The ketone group that compound is C-3 with And the double bond of C-4/C-5 interdigit can confirm (Fig. 7) through coherent signal H-15/C-3/C-5 in HMBC.H in NOESY spectrum3-13/H- 7, H-11/H-8, H-11/H-6, H-8/H-6 and H-1/H-7 coherent signal show that H-1 and H-7 is α direction.H-6, H-8 and H-11 It is then β direction.Compared by calculating ECD and experiment ECD map, determine the compound absolute configuration for 1R, 6S, 7R, 8S, 10R, 11S。
11 molecular formula of compound is C20H26O6.By nuclear magnetic data (Table 4) analysis find the structure of the compound with 10 is similar, and difference is in compound 11 that C-8 are angeloyl unit.Same NOESY related (Fig. 7) shows the two changes Closing object has same relative configuration.So compound 11 (8-angeloyl chrysanolide H) is confirmed as rel-1R, 6S,7R,8S,10R,11S。
Compound 12 (chrysanolide I)1H spectrum and13C modal data (Table 3) shows the compound containing there are five first Base, three company's oxygen methines, company's oxygen tertiary carbon, an olefinic carbon proton, two methylene, three methines and two carbonyls. The nuclear magnetic data of compound 12 and indicumolide A are very much like.In addition to compound indicumolide A C-8 Angeloyl unit is replaced by tigloyl.This point of correlation HMBC signal susceptible of proof in Fig. 7.Signal H in NOESY spectrum3-13/H-7, H-11/H-8,H-11/H-6,H-6/H-8,H3- 15/H-5, H-5/H-7 and H-3/H3- 15 show H-3, H-5, H-7, H3- 13 and H3- 15 be same plane, it is determined as α direction, then H-6, H-8 and H-11 are β direction.Based on same biosynthetic pathway, chemical combination Object 12 is determined as 3S, 4R, 5S, 6S, 7R, 8S, 11S, by calculating and testing ECD map susceptible of proof (Fig. 6).
Chrysanolide D (1): clear crystal；[α]20 D+9.4(c0.1,MeOH)；UV(MeOH)λmax(logε)202 (4.23)nm；ECD(MeOH)λmax(logε)222(-0.43)nm；IR(KBr)νmax3414,2963,2927,2858,1767, 1736,1459,1378,1261,1088,1025,914,796,732,and 522cm-1；1H and13C NMR data,see Table 1；HRESIMS m/z 533.2507[M+Na]+(calcd.for C30H38O7Na,533.2510).
Chrysanolide E (2): colorless oil；[α]20 D+41.5(c0.1,MeOH)；UV(MeOH)λmax(logε)203 (4.12)nm；ECD(MeOH)λmax(logε)214(-0.18)nm；IR(KBr)νmax3474,2968,2924,2854,1756, 1699,1455,1377,1261,1082,1015,919,863,799,737,and 545cm-1；1H and13CNMR data,see Table 1；HRESIMS m/z 633.3046[M+Na]+(calcd.for C35H46O9Na,633.3034).
8'-Tigloyl chrysanolide D (3): colorless oil；[α]20 D+42.1(c0.1,MeOH)；UV(MeOH) λmax(logε)202(4.52)nm；ECD(MeOH)λmax(logε)210(-0.44),225(+0.13)nm；IR(KBr)νmax3474,2968,2931,2860,1756,1703,1458,1379,1262,1082,1021,913,797,731,and 545cm-1；1H and13C NMR data,see Table 1；HRESIMS m/z 631.2876[M+Na]+(calcd.for C35H44O9Na,631.2878).
8-Angeloyl-8'-hydroxy chrysanolide D (4): colorless oil；[α]20 D+24.1(c0.1, MeOH)；UV(MeOH)λmax(logε)202(4.25)nm；ECD(MeOH)λmax(logε)219(-0.78)nm；IR(KBr)νmax3482,2968,2927,2854,1748,1705,1457,1375,1354,1261,1157,1091,1022,969,908, 797,732,667,and 548cm-1；1H and13C NMR data,see Table 1；HRESIMS m/z 631.2890[M+ Na]+(calcd.for C35H44O9Na,631.2878).
8,8'-Ditigloyl chrysanolide D (5): colorless oil；[α]20 D+54.4(c0.1,MeOH)；UV (MeOH)λmax(logε)202(4.40)nm；ECD(MeOH)λmax(logε)210(-0.98),229(+0.25)nm；IR(KBr) νmax3489,2966,2927,2860,1766,1688,1641,1457,1415,1377,1261,1085,1015,866,797, 736,and 699cm-1；1H and13C NMR data,see Table 2；HRESIMS m/z 713.3300[M+Na]+ (calcd.for C40H50O10Na,713.3296).
8-Tigloyl chrysanolide D (6): colorless oil；[α]20 D+4.0(c0.1,MeOH)；UV(MeOH)λmax (logε)202(4.37)nm；ECD(MeOH)λmax(logε)217(-0.99)nm；IR(KBr)νmax3499,2963,2933, 1753,1699,1648,1454,1378,1345,1260,1146,1086,1030,908,804,727,and 521cm-1；1H and13C NMR data,see Table 2；HRESIMS m/z 615.2939[M+Na]+(calcd.for C35H44O8Na, 615.2928).
Chrysanolide F (7): colorless solid；[α]20 D+92.4(c0.1,MeOH)；UV(MeOH)λmax(logε)201 (3.76)nm；ECD(MeOH)λmax(logε)213(-0.12)nm；IR(KBr)νmax3258,2966,2921,2854,1772, 1684,1454,1384,1261,1217,1146,1033,1000,924,798,721,and 539cm-1；1H and13C NMR data,see Table 2；HRESIMS m/z 289.1405[M+Na]+(calcd.for C15H22O4Na,289.1410).
8-Tigloyl chrysanolide F (8): colorless oil；[α]20 D+86.3(c0.1,MeOH)；UV(MeOH) λmax(logε)203(4.07)nm；ECD(MeOH)λmax(logε)204(+0.25)nm；IR(KBr)νmax3455,3401,2962, 2929,2913,2854,1772,1753,1702,1648,1446,1376,1267,1224,1182,1147,1116,1074, 1024,1002,941,806,738,and 673cm-1；1H and13C NMR data,see Table 2；HRESIMS m/z 371.1804[M+Na]+(calcd.for C20H28O5Na,371.1829).
Chrysanolide G (9): colorless oil；[α]20 D+116.2(c 0.1,MeOH)；UV(MeOH)λmax(logε) 203(4.37)nm；ECD(MeOH)λmax(logε)209(+0.42),222(+5.22),264(-0.46)nm；IR(KBr)νmax3434,2964,2921,2850,1760,1741,1702,1687,1646,1450,1382,1336,1263,1157,1133, 1070,1010,941,912,815,740,and 674cm-1；1H and13C NMR data,see Table 3；HRESIMS m/ z 369.1656[M+Na]+(calcd.for C20H26O5Na,369.1672).
Chrysanolide H (10): colorless oil；[α]20 D+143.9(c 0.1,MeOH)；UV(MeOH)λmax(logε) 201(3.88),230(3.95)nm；ECD(MeOH)λmax(logε)236(+0.62),323(-0.30)nm；IR(KBr)νmax3493,2969,2936,1787,1693,1643,1459,1373,1253,1192,1095,1060,1009,973,797, 734,and 545cm-1；1H and13C NMRdata,see Table 3；HRESIMS m/z 385.1613[M+Na]+ (calcd.for C20H26O6Na,385.1622).
8-Angeloyl chrysanolide H (11): colorless oil；[α]20 D+114.3(c0.1,MeOH)；UV (MeOH)λmax(logε)201(3.95),231(4.16)nm；ECD(MeOH)λmax(logε)208(-0.36),238(+0.95), 323(-0.06)nm；IR(KBr)νmax3482,2963,2937,2880,1784,1681,1639,1448,1373,1302, 1207,1160,1091,1004,949,798,737,and 556cm-1；1H and13C NMRdata,see Table 3； HRESIMS m/z 385.1624[M+Na]+(calcd.for C20H26O6Na,385.1622).
Chrysanolide I (12): colorless oil；[α]20 D+9.3(c0.1,MeOH)；UV(MeOH)λmax(logε)202 (4.11)nm；ECD(MeOH)λmax(logε)206(-0.94),222(+0.75)nm；IR(KBr)νmax3570,2968,2942, 2856,1756,1700,1505,1446,1383,1259,1171,1083,1048,1014,971,925,801,733,627, and 522cm-1；1H and13C NMR data,see Table 3；HRESIMS m/z 387.1790[M+Na]+ (calcd.for C20H28O6Na,387.1778).
The analysis of 1 X-ray single crystal diffraction of compound: the crystal structure and its absolute configuration of compound 1 are by single crystal diffraction point Analysis determines.Crystal passes through Xcalibur, Onyx, Nova diffractometer, gather data at a temperature of 100K.By XS and Olex2.refine software is handled and is optimized to crystal.Monocrystalline figure is drawn using ORTEP.The single crystal data of compound 1 It is as follows: C30H38O7(M=510.60)；Colourless bulk, space group P212121(no.0), Z=2, T =100K, μ (CuK α)=0.755mm-1,Dcalc=1.320g/cm3, 24724 reflection measurements, 5045unique (Rint= 0.0512).Suitable for all calculating.Final R1 value is that 0.0326, wR2 is 0.0849 (all data).Flack Parameter=-0.10 (7).
Embodiment 2
Formula (I) and formula (II) are first made as described in Example 1, routinely plus water for injection, refined filtration, encapsulating sterilizing are made Injection.
Embodiment 3
Formula (I) and formula (II) are first made as described in Example 1, is dissolved in sterile water for injection, stirring makes molten, use Sterile suction funnel filtering.Sterile refined filtration again is sub-packed in 2 ampoules, sterile after frozen drying to seal to obtain powder-injection.
Embodiment 4
Formula (I) and formula (II) are first made as described in Example 1, in its with excipient weight than being added for the ratio of 5:1 Excipient, pelletizing press sheet.
Embodiment 5
Formula (I) and formula (II) are first made as described in Example 1, in its with excipient weight than being added for the ratio of 5:1 Capsule is made in excipient.
Embodiment 6
Formula (I) and formula (II) is first made by the method for implementation column 1, in its with excipient weight than being added for the ratio of 3:1 Capsule is made in excipient.
Application test example:
The compounds of this invention formula (I) and formula (II) measure nasopharyngeal carcinoma cell inhibitory activity.
(1) cell culture.In vitro culture human nasopharyngeal epithelioma 1 CNE1, CNE2, HONE-1 and SUNE1 cell.Using containing 10% fetal calf serum, streptomysin (100 mcg/ml), the RPMI1640 culture medium of penicillin (100 units per ml), 37 DEG C, conventional maintenance culture and passage are carried out under the conditions of 5% gas concentration lwevel.
(2) cytotoxic activity test method.Before 96 orifice plate kind plates, to cell count (2000-4000/hole), every hole adds 100 μ L culture mediums, after being incubated for 1 day, dosing, wherein blank control group is culture medium, and negative control group is the thin of not agent-feeding treatment Born of the same parents add cisplatin treated as positive controls.After 48 hours, the 20 μ L of MTT for using the configured 5mg/mL of PBS, processing 4 is added Hour.Culture medium is discarded again, and the DMSO of 120 μ L is added in every hole, vibrates 10min, finally measures it at 492nm with microplate reader OD value.Each drug concentration is calculated to the inhibiting rate of cell according to OD value, and by GraphPad Prism software, use is non-linear The IC of each compound of calculated50Value.
(3) cell apoptosis assay method.By the HONE1 cell in logarithmic growth phase with 2 × 105/ hole, every hole 10% FBS culture medium, is laid in 6 orifice plates, is placed in 37 DEG C, 5%CO2Incubator in, be incubated for for 24 hours；It changes liquid and adds various concentration Compound incubation cell 48h；It sucks supernatant (being stored in 5mL centrifuge tube), 4 DEG C of the every hole 200 μ L PBS is washed twice, and every hole adds Enter pancreatin of the 200 μ L without EDTA to digest, cell is collected in centrifugation；Every pipe is added 1mL Binding buffer and is suspended；Take 400 μ Each 5 μ L of FITC, PI is added in L cell suspension；400 μ L Binding buffer Beckman flow cytometers point are added in every pipe Analysis, 10000 cells of each sample collection.Experimental result is analyzed with Flowjo software.
(4) cell cycle experimental method.2×105/ hole HONE1 cell kind is cultured in 6 orifice plates for 24 hours.Compound is with difference Concentration handles HONE1 cell 48h, and then the pancreatin without EDTA digests, and cell is collected in centrifugation.With 70% ethyl alcohol of frost at 4 DEG C Lower fixation is stayed overnight, and is then washed with cold PBS, is then protected from light 30 points of dyeing at 37 DEG C with Cellular cycle and apoptosis detection kit Clock.The sample handled well Beckman flow cytometry analysis, 10000 cells of each sample collection.Experimental result is used The analysis of Modfit software.Active list is shown in Table 4.
The inhibition nasopharyngeal carcinoma cell proliferation activity of 4 compound formula (I) of table and formula (II)
As shown in table 4, Fig. 1 and Fig. 2, compound provided by the invention has good inhibitory activity to nasopharyngeal carcinoma cell, especially It is that the effect of some compounds is better than cis-platinum.
As can be known from Fig. 1, after 0,1,3,5,10,20 μM of compound 5 handles 48h, HONE1 apoptosis rate is respectively 3.61%, 3.34%, 3.46%, 17.61%, 33.99%, 37.18%, apoptosis rate is apparently higher than blank group, present dosage according to Lai Xing prompts compound to play the role of promoting apoptosis in nasopharyngeal carcinoma cells.
As can be known from Fig. 2, after 0,1,3,5,10,20 μM of compound 5 handles 48h, G0/G1 phase cell proportion is respectively 55%, 44.75%, 50.22%, 40.89%, 14.01%, overall ratio is on a declining curve, and S phase cell proportion is substantially not Become, G2/M phase cell percentage is respectively 0.3%, 5.93%, 7.52%, 16.52%, 38.22%, and dose-dependant is presented Property increase, prompt compound 5 to can induce nasopharyngeal carcinoma cell and block in the G2/M phase.

Claims (10)

1. a kind of Flos Chrysanthemi Indici extract, which is characterized in that the structural formula of the Flos Chrysanthemi Indici extract such as formula (I) and formula (II) institute Show:
Wherein, R1For hydrogen, hydroxyl or C1 ~ C5 is saturated or unsaturated alkyl, wherein R1In hydrogen can be replaced by cyano, nitro, carboxyl, amide or ester, R2For hydrogen, hydroxyl Or C1 ~ C5 saturation or unsaturated alkyl, wherein R2In hydrogen can be replaced by cyano, nitro, carboxyl, amide or ester, R3For hydrogen, hydroxyl Base or C1 ~ C5 saturation or unsaturated alkyl.
2. Flos Chrysanthemi Indici extract according to claim 1, which is characterized in that R1For hydrogen, hydroxyl or C1 ~ C5 saturated alkyl, wherein R1In hydrogen can be by-CO-R ' replace, R ' be C1 ~ C5 saturated alkyl or C1 ~ C5 unsaturated alkyl；R2It is full for hydrogen, hydroxyl or C1 ~ C5 And/or unsaturated alkyl, wherein R2In hydrogen can be by-CO-R ' replace, R ' be C1 ~ C5 saturated alkyl or C1 ~ C5 unsaturated alkyl.
3. Flos Chrysanthemi Indici extract according to claim 2, which is characterized in that unsaturated alkyl is alkenyl.
4. Flos Chrysanthemi Indici extract according to claim 3, which is characterized in that R ' is-C (CH3)=CH(CH3) or-CH=C (CH3)2。
5. Flos Chrysanthemi Indici extract according to claim 1 or claim 2, which is characterized in that when the Flos Chrysanthemi Indici extract is formula (I) institute When showing structural formula, R1For hydrogen, hydroxyl or C1 ~ C3 saturated alkyl, wherein R1In hydrogen can be by-CO-R ' replace, R ' be-C (CH3)= CH(CH3) or-CH=C (CH3)2；R2For hydrogen, hydroxyl or C1 ~ C3 saturated alkyl, wherein R2In hydrogen can be by-CO-R ' replace, R ' For-C (CH3)=CH(CH3) or-CH=C (CH3)2, R3For H, C1 ~ C3 saturated alkyl or=CH2。
6. Flos Chrysanthemi Indici extract according to claim 1 or claim 2, which is characterized in that when the Flos Chrysanthemi Indici extract is formula (II) When shown structural formula, R1For hydrogen, hydroxyl or C1 ~ C3 saturated alkyl, wherein R1In hydrogen can be by-CO-R ' replace, R ' be-C (CH3) =CH(CH3) or-CH=C (CH3)2；R2For H, C1 ~ C3 saturated alkyl or=CH2。
7. Flos Chrysanthemi Indici extract according to claim 1, which is characterized in that the Flos Chrysanthemi Indici extract is in following structural formula One kind:、、
、、、。
8. a kind of preparation method of Flos Chrysanthemi Indici extract described in claim 1, which is characterized in that by wild chrysanthemum aerial part, shine It is dry, it crushes, is extracted four times with 95% ethanol water room temperature, 72 hours every time, merge concentrate, be extracted with ethyl acetate, be recovered under reduced pressure Ethyl acetate obtains ethyl acetate portion medicinal extract, and ethyl acetate portion crosses normal phase silicagel column, and petrol ether/ethyl acetate presses hundred respectively Divide and cross column than 10:0,9:1,4:1,2:1,0:1, fraction is through repeatedly isolated.
9. application of the Flos Chrysanthemi Indici extract described in claim 1 in preparation prevention and treatment medicine for nasopharyngeal.
10. applying according to claim 9, which is characterized in that the drug further include in pharmaceutics acceptable carrier or Auxiliary material.
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