CN105777839A - Antitumor compound, extraction method therefor and application of antitumor compound - Google Patents
Antitumor compound, extraction method therefor and application of antitumor compound Download PDFInfo
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Abstract
The embodiments of the invention disclose an antitumor compound, an extraction method therefor and an application of the antitumor compound. The compound has a structure represented by a general formula (I) shown in the description or a general formula (II) shown in the description and an optical isomer of the general formula (I) or general formula (II). The compound disclosed by the invention and compositions thereof can be used for effectively inhibiting the growth of hormone-independent prostatic carcinoma cells, heterogeneous renal carcinoma cells and human malignant melanoma cells, so that the compound disclosed by the invention and the compositions thereof can serve as drugs for treating tumors and have a good research and development prospect.
Description
Technical field
The present invention relates to a kind of compound, the native compound particularly extracted from Physalis pubescens L., the extracting method of this compound, the pharmaceutical composition comprising this compound and this compound and this pharmaceutical composition purposes in preparing antitumor drug.
Background technology
Physalis pubescens L. PhysalispubescensL. is Solanaceae Physalis annual herb plant, and the band Constellation calyx fruit describing Physalis pubescens L. in " China's pharmacognosy " of Xu Guojun chief editor is medicinal as Fructus Seu Herba Pubescentis.Physalis pubescens L. nature and flavor acid is put down, and enters lung meridian, has effect of heat-clearing and toxic substances removing, pharynx-clearing throat-benefiting, diuresis hemostasis.Among the people notable for treating acute pharyngitis effect.(Xu Guojun. China's pharmacognosy. volume two [M]. Beijing: China Medical Science Press.1996:1161-1162.) method of " clots absorbing eliminating stagnation, tonneau water channel " that adopts of its tradition effect and Chinese traditional treatment carcinoma of prostate is just consistent.
To the chemical research of monkey flower it is shown that wherein mainly contain the compositions such as steroidal, alkaloid, flavone, terpenoid (Qiu Li. chemical Constituents from Physalis alkekengi and bioactivity research thereof. Shenyang Pharmaceutical University Ph.D. Dissertation .2007. tutor: Qiu Feng).The Analysis of Steroids contained in monkey flower, based on withanolide type, is a kind of Ergota steroid-lactone compound containing 28 carbon atoms, has many-sided pharmacologically actives such as antitumor, parasiticide, antibacterial, antiinflammatory, immunomodulating.Studies have reported that, withanolide compounds has the effect of anti-kinds of tumor cells: PhysalinsA and PhysalinsB can pass through to lower the expression of androgen receptor and active cell apoptosis thus effectively suppressing the growth (HanH.Y. of androgen-independent prostate cancer cell lines in vitro；QiuL.；WangX.H.；etal.Biol.Pharm.Bull.2011,34(10)1584—1588)；Withanolide compounds can growth (Subramanian, the C. of Selective depression adrenocortical carcinoma cells；Zhang,H.P.；Gallagher,R.；etal.WorldJ.Surg.2014,38,1343–1352.)；PhysalinA can the apoptosis of fibrin sarcoma cell and people's malignant melanoma cell and autophagy (HeH.；ZangL.H.；FengY.S.；etal.PhysalinAInducesApoptoticCellDeathandProtectiveAutophagyinHT1080HumanFibrosarcomaCells.JournalofNaturalProducts,2013,76,880–888；HeH.；FengY.S.；ZangL.H.；etal.Nitricoxideinducesapoptosisandautophagy；Autophagydown-regulatesNOsynthesisinphysalinA-treatedA37 5-S2humanmelanomacells.FoodandChemicalToxicology, 2014,71,128 135) etc..
But up to now, both at home and abroad the active component of Physalis pubescens L. is reported very few, for exploring whether this plant with medical value (i.e. Physalis pubescens L.) has anti-tumor active ingredient, inventor has studied having antineoplastic active component in Physalis pubescens L..
Summary of the invention
Primary and foremost purpose of the present invention is in that to provide in Physalis pubescens L. plant and has antineoplastic compound, its extracting method and the application in preparing antitumor drug thereof.
A further object of the present invention is in that to provide the compositions including above-claimed cpd and the application in preparing antitumor drug thereof.
The purpose of the present invention is achieved through the following technical solutions:
First aspect present invention provides a kind of antitumoral compounds, has the structure of logical formula I, logical formula II or both optical isomers:
Wherein, in logical formula I, 2-3 position, 5-6 position are singly-bound or double bond；R1For OH or carbonyl；R2For H, OH or group D, E；R3For H or OH；R4For OH or R4With R5It is combined into group B；R5For H, Cl or R5With R4It is combined into group B；R6For H or group C；R7For H or group C；R8For OH, group A or R8With R9It is combined into group B；R9For OH or R9With R8It is combined into group B；R10For OH, carbonyl or group A；
Described group A, group B, group C, group D and group E are respectively as follows:
In some preferred implementations of first aspect present invention, described compound includes:
nullPhysapubsideA(1)、PhysapubsideB(2)、PhysapubsideC(3)、PhysapubsideD(4)、PhysapubescinE(5)、PhysapubescinF(6)、PhysapubescinG(7)、PhysapubescinH(8)、PhysapubescinI(9)、PhysapubescinJ(10)、PhysapubescinK(11)、PhysapubescinL(12)、PhysapubescinM(13)、PhysapubescinN(14)、PhysapubescinO(15)、PhysapubescinP(16)、PhysapubescinQ(17)、Any one in PhysapubescinR (18)，It is respectively as follows: from the structural formula of compound 1-18
The preparation method of above-claimed cpd includes following operating procedure: adopting the dry stem and leaf of Physalis annual herb vegetable hair Calyx seu fructus physalis PhysalispubescensL. and/or fruit is raw material, by aqueous solution reflux, extract, 1-3 time of the ethanol that volume fraction is 1-99% or methanol, extract 1-48 hour every time, merge and obtain extracting solution, extracting solution is removed solvent and obtains total extractum；
Total extractum organic solvent is extracted, obtains organic extract liquid, after being concentrated by organic extract liquid, obtain organic solvent layer extractum；Described organic solvent is one or more in methanol, ethanol, acetone, ethyl acetate, chloroform, petroleum ether and n-butyl alcohol；
Organic solvent layer extractum is easily separated by chromatography, obtains above-mentioned compound；Described Extracting temperature is 20-100 DEG C, it is preferred to 40-90 DEG C.
Second aspect present invention provides a kind of vegetable hair Calyx seu fructus physalis extract including above-claimed cpd.
Third aspect present invention provides a kind of pharmaceutical composition, including one or more in above-claimed cpd.
Fourth aspect present invention provides a kind of pharmaceutical composition, and it includes the above-claimed cpd containing therapeutically effective amount or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier and/or excipient.
Fifth aspect present invention provides above-mentioned compound, vegetable hair Calyx seu fructus physalis extract and pharmaceutical composition application in preparing antitumor drug.
Described tumor includes but not limited to: various entity tumors and leukemia, such as pulmonary carcinoma, bronchogenic carcinoma, hepatocarcinoma, ovarian cancer, cervical cancer, bladder cancer, carcinoma of testis, renal cell carcinoma, cancer of pancreas, gastric cancer, osteocarcinoma, esophageal carcinoma, colon cancer, cancer of biliary duct, carcinoma of prostate, choriocarcinoma, melanoma, glioma, neurofibroma, fibrosarcoma, lymphangioma etc..
The medicine of the treatment genitourinary cancers containing compound of the present invention or compositions can be applicable to the application forms such as oral or injection, for instance, can be tablet, capsule, powder, syrup, injection etc..
Advantage of the present invention and effect: (1) provides compound and the compositions thereof of a series of novel structure；(2) external activity screening system is used to carry out activity rating, find that the compounds of this invention and compositions thereof can the growths of inhibitory hormone dependent/non-dependent prostate gland cancer cell, variety classes kidney cancer cell and people's malignant melanoma cell effectively, prompting the compounds of this invention and compositions thereof as the medicine for the treatment of tumor, can have good research and development prospect.
Detailed description of the invention
Below in conjunction with specific embodiment, technical scheme being described, described embodiment is only a part of embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention, the every other embodiment that those of ordinary skill in the art obtain under not making creative work premise, broadly fall into the scope of protection of the invention.
Embodiment 1: extract isolating active compound from Physalis pubescens L. stem and leaf
Solanaceae Physalis annual herb vegetable hair Calyx seu fructus physalis PhysalispubescensL. dries stem and leaf (9.3kg), by 75% ethanol water reflux, extract, 2 times, each 2 hours, united extraction liquid, decompression and solvent recovery, obtains total extractum (1170.0g) after concentration.Total extractum is distributed in the water of 4 times amount, and respectively with isopyknic petroleum ether, ethyl acetate, n-butanol extraction three times, decompression and solvent recovery obtains petroleum ether layer extractum 15.0g, ethyl acetate layer extractum 99.0g and n-butanol layer extractum 200.0g, remains water layer 850.0g.
Ethyl acetate layer extractum passes through silica gel column chromatography, methylene chloride-methanol (100:1～0:100) gradient elution, obtains 9 sub-fractions (Fr.1～Fr.9).Sub-fraction Fr.3 passes through silica gel column chromatography, dichloromethane-acetone (100:1～0:100) gradient elution, obtain 8 sub-fractions (Fr.31～Fr.38), Fr.35 is through SephadexLH-20 column chromatography, methylene chloride-methanol (1:1) eluting, then through preparative high-performance liquid chromatographic, methanol-water (70:30), obtain compound 9 (8.9mg)；Fr.36 is through SephadexLH-20 column chromatography, methylene chloride-methanol (1:1) eluting, obtain Fr.361, then through silica gel column chromatography (cyclohexane-ethyl acetate) gradient elution, obtain 2 sub-fractions (Fr.3611～Fr.3612), Fr.3611, through preparative high-performance liquid chromatographic, methanol-water (60:40), obtains compound 16 (17.9mg)；Fr.3612, through preparative high-performance liquid chromatographic, methanol-water (60:40), obtains compound 15 (85.0mg) and compound 8 (19.6mg)；Sub-fraction Fr.4 passes through silica gel column chromatography, cyclohexane-ethyl acetate (100:1～0:100) gradient elution, obtain 8 sub-fractions (Fr.41～Fr.48), Fr.44 is through SephadexLH-20 column chromatography, methylene chloride-methanol (1:1) eluting obtains sub-fraction Fr.441, then through ODS column chromatography, methanol-water (10:90～100:0) gradient elution obtains sub-fraction Fr.4413, Fr.4413 is through preparative high-performance liquid chromatographic, methanol-water (70:30), obtains compound 10 (75.2mg)；Fr.46 is through SephadexLH-20 column chromatography, methylene chloride-methanol (1:1) eluting obtains sub-fraction Fr.463, Fr.463 crosses preparative high-performance liquid chromatographic, methanol-water (60:40), obtains compound 11 (76.5mg) and compound 17 (252.0mg)；Fr.47 is through SephadexLH-20 column chromatography, and methylene chloride-methanol (1:1) eluting obtains sub-fraction Fr.471, Fr.471 and crosses preparative high-performance liquid chromatographic, methanol-water (50:50), obtains compound 12 (1600.0mg)；Fr.48 is through SephadexLH-20 column chromatography, and methylene chloride-methanol (1:1) eluting obtains sub-fraction Fr.481, Fr.481 and crosses preparative high-performance liquid chromatographic, methanol-water (50:50), obtains compound 13 (132.0mg).
N-butanol fraction (100g), by silica gel column chromatography, methylene chloride-methanol (100:1～0:100) gradient elution, there are 9 sub-fractions (B1～B9).B2 (7.5g) fraction passes through silica gel column chromatography, methylene chloride-methanol (30:1～0:1) gradient elution, obtain 3 sub-fractions (B21～B23), B22 is through SephadexLH-20 column chromatography, methanol-eluted fractions obtains B222, B222 is through preparing thin layer (methanol is developing solvent), open ODS column chromatography, methanol-water (10:90,30:70,40:60,80:20) gradient elution and preparative high-performance liquid chromatographic (methanol: water=50:50) purification obtain compound 14 (23.0mg)；B3 (15.2g) fraction passes through silica gel column chromatography, methylene chloride-methanol (50:1～10:1) gradient elution, obtains 6 sub-fractions (B31～B36).Sub-fraction B 35 is through open ODS column chromatography, methanol-water (10:90,30:70,50:50,80:20,100:0) gradient elution, obtain 8 sub-fractions (B351～B358), B356 has crystal precipitate out, after recrystallizing methanol, obtain compound 2 (101.0mg)；B6 (12g) fraction passes through silica gel column chromatography, methylene chloride-methanol (6:1) isocratic elution, obtains 3 sub-fractions (B61～B63).B63 is through mesolow ODS column chromatography, methanol-water (10:90～80:20) gradient elution, obtain 14 sub-fractions (B63-1～B63-14), B63-13 is through silica gel column chromatography, methylene chloride-methanol (5:1) isocratic elution and through SephadexLH-20 column chromatography, methanol-eluted fractions obtains B63-13-1, B63-13-1 through preparative high-performance liquid chromatographic, and methanol-water (72:28) separates and obtains compound 4 (75.0mg)；B7 (30g) fraction passes through silica gel column chromatography, methylene chloride-methanol (8:1～3:1) gradient elution, obtain 4 sub-fractions (B71～B74), B74 fraction is through polyamide column chromatography, 2 fractions (B741～B742) are obtained as eluant respectively using water and ethanol, B742 is repeatedly through SephadexLH-20 column chromatography, methanol-eluted fractions, then through preparative high-performance liquid chromatographic, methanol/water (60:40), separates and obtains compound 1 (43.0mg).B8 (19g) adopts repeatedly silica gel column chromatography with methylene chloride-methanol system ladder, after removing major part pigment, through SephadexLH-20 column chromatography repeatedly, methanol-eluted fractions purification, again through preparative high-performance liquid chromatographic, methanol-water (55:45), separates and obtains compound 3 (110.0mg).
Embodiment 2: extract isolating active compound from Physalis pubescens L. fruit
The fruit (17.5kg) of Solanaceae Physalis annual herb vegetable hair Calyx seu fructus physalis PhysalispubescensL., by 75% ethanol water reflux, extract, 2 times, each 2 hours, united extraction liquid, decompression and solvent recovery, obtains total extractum (1420.0g) after concentration.Total extractum is distributed in the water of 4 times amount, and respectively with isopyknic petroleum ether, ethyl acetate, n-butanol extraction three times, decompression and solvent recovery obtains petroleum ether layer extractum 49.0g, ethyl acetate layer extractum 46.0g and n-butanol layer extractum 70.0g, remains water layer 1246.0g.
Ethyl acetate layer extractum passes through silica gel column chromatography, methylene chloride-methanol (100:1～0:100) gradient elution, obtains 10 sub-fractions (E1～E10).Sub-fraction E3 passes through silica gel column chromatography, methylene chloride-methanol (100:0～0:100) gradient elution, obtain 6 sub-fractions (E31～E36), E32 is through SephadexLH-20 column chromatography, methylene chloride-methanol (1:1) eluting, obtain E322, then through silica gel column chromatography (cyclohexane-ethyl acetate) gradient elution, obtain 8 sub-fractions (E3221～E3228), E3227 is through preparative high-performance liquid chromatographic, methanol-water (67:33), obtains compound 11 (92.0mg)；Sub-fraction E5 passes through polyamide column chromatography, methanol-water (10:90～100:0) gradient elution, obtain 3 sub-fractions (E51～E53), E51 passes through silica gel column chromatography, (cyclohexane-acetone) gradient elution, obtain 12 sub-fractions (E51-1～E51-12), E51-8 passes through ODS column chromatography, methanol-water gradient elution, obtain 6 sub-fractions (E51-8-1～E51-8-6), E51-8-4, through preparative high-performance liquid chromatographic, methanol-water (52:48), obtains compound 12 (19.0mg)；E51-10 passes through ODS column chromatography, methanol-water gradient elution, obtain 4 sub-fractions (E51-10-1～E51-10-4), E51-10-3 obtains E51-10-3-3 through silica gel preparative thin layer chromatography (methylene chloride-methanol=10:1), then through preparative high-performance liquid chromatographic, methanol-water (48:52), obtains compound 18 (34.0mg)；E52 is through SephadexLH-20 column chromatography, methanol-eluted fractions, obtaining 5 sub-fractions (E521～E525), E523 obtains E5232 through silica gel preparative thin layer chromatography (hexamethylene: acetone=1:1), obtains compound 5 (20.0mg) through recrystallization (methanol-water).Sub-fraction E6 passes through polyamide column chromatography, methanol-water (10:90～100:0) gradient elution, obtain 6 sub-fractions (E61～E66), E61 is through SephadexLH-20 column chromatography, methanol-eluted fractions, obtain 3 sub-fractions (E611～E613), E612 passes through silica gel column chromatography, (dichloromethane-acetone) gradient elution, obtain 5 sub-fractions (E6121～E6125), E6123, through preparative high-performance liquid chromatographic, methanol-water (67:33), obtains compound 13 (64.0mg).Sub-fraction E7 is through silica gel preparative thin layer chromatography, dichloromethane-acetone (15:1～1:1) gradient elution, obtain 8 sub-fractions (E71～E78), E74 passes through ODS column chromatography, methanol-water gradient elution, obtains 6 sub-fractions (E741～E746), and E746 is through preparative high-performance liquid chromatographic, methanol-water (67:33), obtains compound 6 (77.0mg).Sub-fraction E8 is through SephadexLH-20 column chromatography, methanol-eluted fractions, obtain 6 sub-fractions (E81～E86), E83 passes through ODS column chromatography, methanol-water gradient elution, obtains 9 sub-fractions (E831～E839), and E839 is through preparative high-performance liquid chromatographic, methanol-water (55:45), obtains compound 2 (35.0mg).
N-butanol layer extractum passes through silica gel column chromatography, methylene chloride-methanol (100:1～0:100) gradient elution, obtains 12 sub-fractions (B1～B12).B2 passes through ODS column chromatography, methanol-water gradient elution, obtain 8 sub-fractions (B21～B28), B26 passes through silica gel column chromatography, methylene chloride-methanol (20:1) isocratic elution, obtains sub-fraction B 261, B261 through preparative high-performance liquid chromatographic, methanol-water (65:35), obtains compound 12 (12.2mg), 13 (44.2mg).B11 passes through silica gel column chromatography, methylene chloride-methanol (100:1～0:100) gradient degree eluting, obtain 6 sub-fractions (B11-1～B11-6), B11-5 passes through ODS column chromatography, methanol-water gradient elution, obtain 14 sub-fractions (B11-5-1～B11-5-14), B11-5-14 is through SephadexLH-20 column chromatography, methanol-eluted fractions, obtain sub-fraction B 11-5-14-2, B11-5-14-2 is through preparative high-performance liquid chromatographic, methanol-water (70:30), obtain compound 4 (19.0mg), compound 4 obtains its aglycon through cellulase hydrolysis, compound 7.B12 passes through silica gel column chromatography, methylene chloride-methanol (100:1～0:100) gradient degree eluting, obtain 5 sub-fractions (B12-1～B12-5), B12-5 passes through ODS column chromatography, methanol-water gradient elution, obtains 7 sub-fractions (B12-5-1～B12-5-7), and B12-5-4 is through preparative high-performance liquid chromatographic, methanol-water (50:50), obtains compound 3 (509.0mg)；B12-5-5, through SephadexLH-20 column chromatography, methanol-eluted fractions, obtains sub-fraction B 12-5-5-4, B12-5-5-4 through preparative high-performance liquid chromatographic, methanol-water (50:50), obtains compound 1 (24.0mg).
By physicochemical constant and the Modern spectroscopy section of learning to do (MS, NMR), in conjunction with document related data, identifying their structure, compound 1-18 is the noval chemical compound having no bibliographical information, as follows:
Physical chemistry and the constant of each noval chemical compound of gained are as follows:
The colourless platelet of compound 1 (methanol)；Fusing point: 241 DEG C；(c0.06, methanol)；IR(KBr)νmaxcm-1: 3458,2939,2898,1640,1459,1385,1062,1048；ESI-TOF-MS (Positive) m/z:818.4527 (calcd.forC40H64O16NH4, 818.4538), molecular formula is C40H64O16；1H-NMR(600MHz,Pyridine-d5) and13C-NMR(150MHz,Pyridine-d5) data are in Table 1.
Compound 2 white powder；(c=0.07, methanol)；IR(KBr)νmaxcm-1: 3448,2938,2858,1728,1630,1463,1385,1169,1103,1067,1021；ESI-TOF-MS (Positive) m/z:661.3560 (calcd.forC34H54NaO11: 661.3558), molecular formula is C34H54O11；1H-NMR(600MHz,Pyridine-d5) and13C-NMR(150MHz,Pyridine-d5) data are in Table 1.
Compound 3 white powder；(c0.07, methanol)；IR(KBr)νmaxcm-1: 3396,2940,2897,1658,1435,1076,1044,894；ESI-TOF-MS (Positive) m/z:825.4243 (calcdforC40H66O16Na, 825.4249), molecular formula is C40H66O16；1H-NMR(600MHz,Pyridine-d5) and13C-NMR(150MHz,Pyridine-d5) data are in Table 1.
Compound 4 white powder；(c0.06, methanol)；IR(KBr)νmaxcm-1: 3406,2941,2842,1658,1436,1051,1046,899；ESI-TOF-MS (Positive) m/z:853.4538 (calcd.forC42H70O16Na, 853.4562), molecular formula is C42H70O16；1H-NMR(600MHz,Pyridine-d5) and13C-NMR(150MHz,Pyridine-d5) data are in Table 1.
Compound 5 white powder；(c=0.07, methanol)；IR(KBr)νmaxcm-1: 3458,2942,2904,1721,1641,1462,1384,1262,1143,1054,1025；ESI-TOF-MS (Positive) m/z:499.3035 (calcd.forC28H44NaO6: 499.3036), molecular formula is C28H44O6；1H-NMR(600MHz,CDCl3) and13C-NMR(150MHz,CDCl3) data are in Table 2.
Compound 6 white powder (methanol)；(c=0.10, methanol)；IR(KBr)νmaxcm-1: 3422,2972,2937,2856,2825,1641,1463,1384,1109,1078,1050,1029；ESI-TOF-MS (Positive) m/z:501.3184 (calcd.forC28H46NaO6, 501.3192), molecular formula is C28H46O6；1H-NMR(600MHz,Pyridine-d5) and13C-NMR(150MHz,Pyridine-d5) data are in Table 2.
Compound 7 white powder (methanol)；(c=0.15, methanol)；IR(KBr)νmaxcm-1: 3422,2918,2847,1598,1384,1055,1032；ESI-TOF-MS (Positive) m/z:529.3501 (calcd.forC30H50NaO6, 529.3505), molecular formula is C30H50O6；1H-NMR(400MHz,Pyridine-d5) and13C-NMR(150MHz,Pyridine-d5) data are in Table 2.
Compound 8 colorless needle crystals (methanol)；Fusing point: 118 DEG C；(c=0.135, methanol)；IR(KBr)νmaxcm-1: 3455,2934,1716,1678cm-1；UVλmax(methanol) nm (log ε): 214 (3.73)；HR-ESI-MS(positive)m/z:553.2778(calcdforC30H42O8Na, 553.2777), molecular formula is C30H42O8；1H-NMR(300MHz,CD3OD) and13C-NMR(75MHz,CD3OD) data are in Table 2.
Compound 9 white powder；(c=0.10, methanol)；IR(KBr)νmaxcm-1: 3451,2925,1733,1675cm-1；UVλmax(methanol) nm (log ε): 222 (3.77)；HR-ESI-MS(positive)m/z:537.2817(calcdforC30H42O7Na,537.2828)；Molecular formula is C30H42O7；1H-NMR(600MHz,CDCl3) and13C-NMR(75MHz,CDCl3) data are in Table 3.
Compound 10 white powder；(c=0.215, methanol)；IR(KBr)νmaxcm-1: 3456,2930,1737,1673cm-1；UVλmax(methanol) nm (log ε): 213 (3.72)；HR-ESI-MS(positive)m/z:567.2928(calcdforC31H44O8Na, 567.2934), molecular formula is C31H44O8；1H-NMR(600MHz,CDCl3) and13C-NMR(150MHz,CDCl3) data are in Table 3.
Compound 11 white powder；(c=0.33, methanol)；IR(KBr)νmaxcm-1: 3466,2965,1746,1679cm-1；UVλmax(methanol) nm (log ε): 216 (3.71)；HR-ESI-MS(positive)m/z:611.2823(calcdforC32H44O10Na, 611.2827), molecular formula is C32H44O10；1H-NMR(600MHz,CDCl3) and13C-NMR(150MHz,CDCl3) data are in Table 3.
Compound 12 white powder；(c=0.545 methanol), IR (KBr) νmaxcm-1: 3442,2961,1733,1676cm-1,UVλmax(methanol) nm (log ε): 214 (3.77)；HR-ESI-MS(negative)m/z:547.2915(calcdforC30H43O9, 547.2907), molecular formula is C30H44O9；1H-NMR(600MHz,Pyridine-d5) and13C-NMR(150MHz,Pyridine-d5) data are in Table 3.
Compound 13 white powder；(c=0.135 methanol)；IR(KBr)νmaxcm-1: 3446,2978,1743,1676cm-1,UVλmax(methanol) nm (log ε): 213 (3.74)；HR-ESI-MS(positive)m/z:629.2936(calcd.forC32H46O11Na, 629.2938), molecular formula is C32H46O11；1H-NMR(600MHz,Pyridine-d5) and13C-NMR(150MHz,Pyridine-d5) data are in Table 4.
Compound 14 white powder,(c=0.045 methanol)；IR(KBr)νmaxcm-1: 3464,2972,2906,1734,1681,1453,1376,1257,1077,1040；HR-TOF-MS provides m/z:607.2636 (calcd.forC30H45ClO9Na, 607.2650), molecular formula is C30H42O8；1H-NMR(600MHz,Pyridine-d5) and13C-NMR(100MHz,Pyridine-d5) data are in Table 4.
Compound 15 white, needle-shaped crystals (methanol)；Fusing point: 195 DEG C；(c=0.145 methanol)；IR(KBr)νmaxcm-1: 3397,2942,1734,1663,1459,1372,1249,1107,1054cm-1,UVλmax(methanol) nm (log ε): 213 (3.60)；HR-ESI-MS(positive)m/z:567.2925(calcdforC31H44O8Na, 567.2934), molecular formula is C31H44O8；1H-NMR(300MHz,CDCl3) and13C-NMR(75MHz,CDCl3) data are in Table 4.
Compound 16 white powder,(c=0.25, methanol), IR (KBr) νmaxcm-1: 3461,2934,1735,1683,1462,1382,1260,1089,1044cm-1,UVλmax(methanol) nm (log ε): 216 (3.92), HR-ESI-MS (positive) m/z:589.2532 (calcdforC30H43O8ClNa, 589.2544), molecular formula is C30H43O8Cl；1H-NMR(600MHz,CDCl3) and13C-NMR(150MHz,CDCl3) data are in Table 4.
Compound 17 white powder；(c=0.345 methanol), IR (KBr) νmaxcm-1: 3450,2962,1734,1678,1461,1374,1249,1143,1117,1039cm-1,UVλmax(methanol) nm (log ε): 213 (3.80), HR-ESI-MS (positive) m/z:585.3033 (calcdforC31H46O9Na, 585.3040), molecular formula is C31H46O9；1H-NMR(600MHz,Pyridine-d5) and13C-NMR(150MHz,Pyridine-d5) data are in Table 5.
Compound 18 white powder；(c=0.075, methanol)；IR(KBr)νmaxcm-1: 3433,2942,1712,1640,1458,1376,1250,1115,1076,1043；ESI-TOF-MS (Positive): m/z:584.3435 (calcd.forC30H50O10N584.3435), molecular formula is C30H46O10；1H-NMR(600MHz,Pyridine-d5) and13C-NMR(150MHz,Pyridine-d5) data are in Table 5.
Embodiment 3: antitumor activity of compound detects
Adopt MTT method, compound disclosed in this invention is carried out Activity determination, with Human Prostate Cancer Cells (C4-2B and 22Rvl), human renal carcinoma cell (786-0, A-498, Caki-2, ACHN), human melanoma cell (A375 and A375-S2) is example.
Take the above-mentioned cell 100 μ L being in exponential phase, every hole 2 × 104It is inoculated in 96 orifice plates, puts CO2Incubator (37 DEG C, 5%CO2, saturated humidity) cultivate.Dosing 10 μ L/ hole after 12 hours, the working solution culture medium of sample is diluted to final concentration respectively 10,5,2.5,1.25,0.625,0.3125,0.15625 μMs, application of sample group and blank group and is all provided with 3 multiple holes.After continuing cultivation 72 hours, add MTT working solution, 20 μ L/ holes, after 3 hours, discard culture medium, add DMSO150 μ L/ hole, on plate shaker, 500rpm jolts 3 minutes, measures the OD value in each hole by microplate reader, and mensuration wavelength is 490nm, calculate cell proliferation inhibition rate, cell proliferation inhibition rate=(blank group OD value-administration group OD value)/blank group OD value × 100%.More than test all in triplicate, Activity Results (IC50) in Table 6.
The hydrogen spectrum of table 1 compound 1-4 and carbon modal data
Note: above-claimed cpd used test solvent is deuterated pyridine；The hydrogen spectrum test of compound 14 is 600MHz, and carbon spectrum test is 150MHz；* it is expressed as in a pair tautomer the data of 26S configurational isomer.
The hydrogen spectrum of table 2 compound 5-8 and carbon modal data
Note: above-claimed cpd 5 used test solvent is deuterochloroform, compound 6,7 used test solvent is deuterated pyridine, and compound 8 used test solvent is deuterated methanol；The hydrogen spectrum test of compound 5,6 is 600MHz, and the hydrogen spectrum test of compound 7 is 400MHz, and the carbon spectrum test that hydrogen spectrum test is 300MHz, compound 5-7 of compound 8 is 150MHz, and the carbon spectrum test of compound 8 is 75MHz；* it is expressed as in a pair tautomer the data of 26S configurational isomer.
The hydrogen spectrum of table 3 compound 9-12 and carbon modal data
Note: above-claimed cpd 9-11 used test solvent is deuterochloroform, and compound 12 used test solvent is deuterated pyridine；The hydrogen spectrum test of compound 9-12 is 600MHz, and the carbon spectrum test that carbon spectrum test is 75MHz, compound 10-12 of compound 9 is 150MHz；* it is expressed as in a pair tautomer the data of 26S configurational isomer.
The hydrogen spectrum of table 4 compound 13-16 and carbon modal data
Note: above-claimed cpd 13,14 used test solvent is deuterated pyridine, compound 15,16 used test solvent is deuterochloroform；The hydrogen spectrum test of compound 13,14,16 is 600MHz, and the carbon spectrum test of compound 15 is 75MHz, and the carbon spectrum test of compound 14 is 100MHz, and the carbon spectrum test of compound 13,16 is 150MHz；* it is expressed as in a pair tautomer the data of 26S configurational isomer.
The hydrogen spectrum of table 5 compound 17-18 and carbon modal data
Note: above-claimed cpd 17,18 used test solvent is deuterated pyridine；The hydrogen spectrum test of compound 17,18 is 600MHz, and the carbon spectrum test of compound 17,18 is 150MHz；* it is expressed as in a pair tautomer the data of 26S configurational isomer.
Anti-tumor activity result (the IC of table 6 compound50,μM)
By table 6 it can be seen that kinds of tumor cells propagation is had very good inhibitory activity, IC by compound disclosed by the invention50It is worth minimum up to 0.17 μM.By Structure-activity analysis it can be seen that work as in compound structure of the present invention containing α, alpha, beta-unsaturated ketone group (i.e. R1For carbonyl, 2-3 position is double bond) and/or 5 β, 6 beta epoxide group (i.e. R5With R4Be combined into group B), and 4 have hydroxyl replace (i.e. R3For hydroxyl) time, its anti-tumor activity is substantially better than the compound without above-mentioned group.
Effective functional group that above-mentioned structure activity relationship relates to all belongs to compound characteristic structure of the present invention, illustrates that compound of the present invention is one of effective ingredient of vegetable hair Calyx seu fructus physalis performance drug effect simultaneously.
Above antitumoral compounds provided by the present invention, its extracting method and application thereof are described in detail.Principles of the invention and embodiment are set forth by specific embodiment used herein, and the explanation of above example is only intended to help to understand method and the central idea thereof of the present invention.It should be pointed out that, for the person of ordinary skill of the art, under the premise without departing from the principles of the invention, it is also possible to the present invention carries out some improvement and modification, these improve and modify the protection also falling into the claims in the present invention.
Claims (10)
1. an antitumoral compounds, it is characterised in that there is the structure of logical formula I, logical formula II or both optical isomers:
Wherein, in logical formula I, 2-3 position, 5-6 position are singly-bound or double bond；R1For OH or carbonyl；R2For H, OH or group D, E；R3For H or OH；R4For OH or R4With R5It is combined into group B；R5For H, Cl or R5With R4It is combined into group B；R6For H or group C；R7For H or group C；R8For OH, group A or R8With R9It is combined into group B；R9For OH or R9With R8It is combined into group B；R10For OH, carbonyl or group A；
Described group A, group B, group C, group D and group E are respectively as follows:
2. compound as claimed in claim 1, it is characterised in that any one in compound 1-18 of described compound, the described structural formula from compound 1-18 is respectively as follows:
3. the extracting method of a compound as claimed in claim 1 or 2, it is characterised in that comprise the following steps:
Adopting the dry stem and leaf of Physalis pubescens L. and/or fruit is raw material, by aqueous solution reflux, extract, 1-3 time of the ethanol that volume fraction is 1-99% or methanol, extracts 1-48 hour every time, and merging obtains extracting solution, extracting solution is removed solvent and obtains total extractum；
Total extractum organic solvent is extracted, obtains organic extract liquid, after being concentrated by organic extract liquid, obtain organic solvent layer extractum；Described organic solvent is one or more in methanol, ethanol, acetone, ethyl acetate, chloroform, petroleum ether and n-butyl alcohol；
Organic solvent layer extractum is easily separated by chromatography, obtains compound as claimed in claim 1 or 2.
4. compound application in preparing antitumor drug as claimed in claim 1 or 2.
5. apply as claimed in claim 4, it is characterized in that, described tumor includes: pulmonary carcinoma, bronchogenic carcinoma, hepatocarcinoma, ovarian cancer, cervical cancer, bladder cancer, carcinoma of testis, renal cell carcinoma, cancer of pancreas, gastric cancer, osteocarcinoma, esophageal carcinoma, colon cancer, cancer of biliary duct, carcinoma of prostate, choriocarcinoma, melanoma, glioma, neurofibroma, fibrosarcoma or lymphangioma.
6. the vegetable hair Calyx seu fructus physalis extract comprising compound as claimed in claim 1 or 2.
7. vegetable hair Calyx seu fructus physalis extract application in preparing antitumor drug as claimed in claim 6, it is characterized in that, described tumor includes: pulmonary carcinoma, bronchogenic carcinoma, hepatocarcinoma, ovarian cancer, cervical cancer, bladder cancer, carcinoma of testis, renal cell carcinoma, cancer of pancreas, gastric cancer, osteocarcinoma, esophageal carcinoma, colon cancer, cancer of biliary duct, carcinoma of prostate, choriocarcinoma, melanoma, glioma, neurofibroma, fibrosarcoma or lymphangioma.
8. a pharmaceutical composition, it is characterised in that include one or more in compound described in claim 1 or 2.
9. a pharmaceutical composition, it is characterised in that comprise the compound described in claim 1 or 2 or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier and/or excipient.
10. compositions application in preparing antitumor drug as claimed in claim 8 or 9, it is characterized in that, described tumor includes: pulmonary carcinoma, bronchogenic carcinoma, hepatocarcinoma, ovarian cancer, cervical cancer, bladder cancer, carcinoma of testis, renal cell carcinoma, cancer of pancreas, gastric cancer, osteocarcinoma, esophageal carcinoma, colon cancer, cancer of biliary duct, carcinoma of prostate, choriocarcinoma, melanoma, glioma, neurofibroma, fibrosarcoma or lymphangioma.
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| ANTHONY C. WAISS JR. ET AL.: "Insect inhibitory steroidal saccharide esters from physalis peruviana", 《J.NAT. PROD.》 * |
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