CN108191937A - A kind of polyenoid androstane ketone compound and its application - Google Patents
A kind of polyenoid androstane ketone compound and its application Download PDFInfo
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- CN108191937A CN108191937A CN201810000419.5A CN201810000419A CN108191937A CN 108191937 A CN108191937 A CN 108191937A CN 201810000419 A CN201810000419 A CN 201810000419A CN 108191937 A CN108191937 A CN 108191937A
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- Prior art keywords
- androstane
- compound
- polyenoid
- cell
- ketone compound
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- -1 androstane ketone compound Chemical class 0.000 title claims abstract description 20
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 10
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 5
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 4
- 125000003368 amide group Chemical group 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical group 0.000 claims abstract 2
- 238000002360 preparation method Methods 0.000 claims description 5
- 229940124589 immunosuppressive drug Drugs 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 239000003814 drug Substances 0.000 abstract description 10
- 241000196324 Embryophyta Species 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 5
- 241001408435 Epigynum auritum Species 0.000 abstract description 4
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 4
- 241001529246 Platymiscium Species 0.000 abstract description 2
- 150000002611 lead compounds Chemical class 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 27
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- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 2
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- 238000011068 loading method Methods 0.000 description 2
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- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical group CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 description 1
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 1
- JWMFYGXQPXQEEM-NUNROCCHSA-N 5β-pregnane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-NUNROCCHSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
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- 235000011996 Calamus deerratus Nutrition 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 241001408451 Epigynum Species 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 102100028999 High mobility group protein HMGI-C Human genes 0.000 description 1
- 101000986379 Homo sapiens High mobility group protein HMGI-C Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
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- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000003409 anti-rejection Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000004500 asepsis Methods 0.000 description 1
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- 238000000006 cell growth inhibition assay Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
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- 210000003743 erythrocyte Anatomy 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 125000002350 geranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
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- 230000036210 malignancy Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- WXNOCMKVJXUPOC-UHFFFAOYSA-N octadec-2-yne Chemical compound CCCCCCCCCCCCCCCC#CC WXNOCMKVJXUPOC-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
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- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0007—Androstane derivatives not substituted in position 17
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a kind of polyenoid androstane ketone compound and its applications；The compound is to be extracted from Epigynum Auritum platymiscium isolated, and structural formula is shown below：Wherein, R1、R2、R3It is selected from hydrogen, hydroxyl, methyl, halogen, aliphatic group, fat amido；Experiment proves that the compound reported in the present invention has very strong immunosuppressive activity；The compounds of this invention provides lead compound to develop immunosuppressor and anti-tumor agent, is conducive to develop and use plant medicine resource.
Description
Technical field
A kind of application the present invention relates to polyenoid androstane ketone compound and its in immunosupress, antitumor drug is prepared.
Background technology
Steroidal drug is clinical most common immunosuppressor, such as prednisone, dexamethasone, methylprednisolone.Its energy
Effectively inhibit inflammatory factor, reduce various immunocytes.Immunosuppressor is after clinic is autoimmunity disease and organ transplant
Rejection provides effective medicine, and commonly used to the rejection for inhibiting to occur after organ transplant, treatment marrow moves
The autoimmune diseases such as the graft versus host disease(GVH disease) occurred after plant or treatment rheumatoid arthritis, disease.
It is currently understood that there are about 100 Several Kinds of Malignancy, cancer occurrence numbers account for about whole world disease death number 13% is died of；
It is expected that whole world cancer mortality will continue to increase, the year two thousand thirty estimation will have 12,000,000 people to die of cancer；The occurrence and development of tumour
It fails with entire body's immunity closely related, tumour once occurs that the suppression to body's immunity can be deepened in turn again
System, the development of tumor promotion.Tumour cell is transferred to other position continued growths from primary portion, is the weight of tumour life-threatening
Want reason.In the factors of tumor invasion, various types of immunosuppression molecules are in the formation and evolution of tumour
Key effect is played, can be as the novel targets of antitumor medicine, the biological therapy for tumour provides new approaches.
Autoimmune disease and cancer are mostly chronic or progressive disease needs long-term administration, and existing sugared cortex
Hormone（Such as dexamethasone）With immunosuppressor long-term administration generally existing toxic side effect it is big, inconvenient to use the shortcomings of.Chinese medicine
As a kind of natural products, have many advantages, such as and people's tissue compatible property is good, Small side effects, in immunosuppressor and antitumor system
It is increasingly valued by people in the research of agent.Thus, it is found from natural products thin with immunosupress and malignant tumour
The compound of born of the same parents' inhibited proliferation has using valency the neotype immunosuppressant and anti-tumor agent of developing high-efficiency low-toxicity
Value.Polyenoid androstane ketone compound provided by the invention and its conduct immunosuppressive drug are not yet reported.
Simao Calamus（Epigynum）It is one of Apocynaceae Epigynum Auritum race category, according to the result of study of our early periods,
Androstane, pregnane and its glucosides are mainly contained in Epigynum Auritum platymiscium.Under the interest drive for finding new drug lead compound,
We have carried out these noval chemical compounds a large amount of bioactivity screening experiment, find wherein polyenoid androstane ketone compound（12β-
Hydroxy-androstane -3,5,14 (15)-triolefin -16- ketone）There is immunosuppressive activity at a concentration of 12.5 μM, a concentration of 25,50
μM when compared with model group significant difference（P<0.05）, there is better immunosuppressive activity.In antitumor experiment, I
For human body acute lymphoblastic leukemia cell, chronic myeloid leukemia cell, malignant melanoma cell, starlike thin
Born of the same parents' oncocyte, adenocarcinoma cell, carcinoma cell, pleomorphism Gliblastoma cell, Lung Squamous Carcinoma Cells, ovary
Cell, breast cancer cell, lung carcinoma cell etc. carry out cell growth inhibition assay room, the results showed that at a concentration of 25 μM and positive
It is suitable to compare dexamethazone active, and there are 5 plants of cells to show drug resistance to dexamethasone.
Invention content
The purpose of the present invention is to provide a kind of polyenoid androstane ketone compound of structural formula as shown in formula I：
Ⅰ
Wherein, R1、R2、R3It is selected from hydrogen, hydroxyl, methyl, halogen, aliphatic group, fat amido.
Fatty substituents in above-mentioned aliphatic group and fat amido refer to saturation or unsaturated fat substituent group, wherein,
Saturated fat substituent group refers to straight chain or alkyl with branch, cycloalkyl, for example, methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl group, tertiary butyl, sec-butyl, cyclopropyl rings dodecyl etc., and unsaturated fat base refers to alkenyl, alkynyl or alkadiene
Base, alkenyl such as pi-allyl, isopentene group, 1- laurylene bases, alkynyl such as 1- octadecynes base, 2- octadecyne bases, alkadienyl is such as
Geranyl, 1,3- octadecylenes base, 9- octadecylene bases etc..
Another object of the present invention is to provide a kind of 12 beta-hydroxy androstane -3,5,14 (15)-triolefins-of structural formula such as formula II
16- ketone：
Ⅱ。
It is another object of the present invention to apply above-mentioned polyenoid androstane ketone compound in immunosuppressive drug is prepared.
Specifically immunosuppressive drug is applied in the medicine for preparing autoimmune disease or is applied in preparing device
Official is transplanted in the medicine of anti-rejection.
The present invention is another object is that applying above compound in antitumor drug is prepared.
One or more pharmaceutically acceptable auxiliary materials can also be added in application of the present invention, the auxiliary material includes medicine
Filler, diluent, adhesive, excipient, sorbefacient, filler, surfactant and the stabilizer of field routine
Deng can also be added if necessary flavouring agent, pigment and sweetener etc..
Pill, pulvis, tablet, granula, oral liquid and injection can also be made in addition to capsule is made in application of the present invention
The diversified forms such as liquid.
It is used to test to prepare splenocyte with the Balb/c mouse of health in the present invention.After the completion of prepared by splenocyte, pass through
ConA or LPS are induced, while add in various concentration test compound in test group, after cultivating 72 h, are tried by CCK-8
Agent method measures test group, induction control group and does not induce the light absorption value of control group respectively, so as to evaluate compound stimulation T cell or
The ability of person's B cell proliferation；The experimental results showed that polyenoid androstane ketone compound of the present invention：12 beta-hydroxy androstanes -3,5,14 (15) -
Triolefin -16- ketone, to ConA（ConA）The Balb/c mice spleen lymphocytes proliferations of stimulation have apparent inhibiting effect,
Compared with the control group for being not added with the compound significant difference (p < 0.05)。
It takes and is adjusted to certain density cell suspension inoculation in exponential phase human body tumour cell and is cultivated in 96 holes
Plate, 90 μ l/ holes, 24 hours compounds that various concentration is added in after its is adherent of culture, 10 μ l/hole, each concentration are all provided with 3
Multiple holes.Cell count simultaneously uses the survival rate of desk tray indigo plant Determination Staining cell, survival rate=uncolored cell number/total number of cells
For testing, cell suspension is adjusted to 1 × 10 by × 100%, survival rate ＞6A/mL.If cell blank control group, the positive
Control group（Dexamethasone）And sample sets（Concentration is set to 25 μm of olL according to trial test result-1, the DMSO containing isoconcentration）.
Negative control is isometric culture medium, while sets corresponding a concentration of Vehicle controls of DMSO during 25 μ g/mL of compound, to eliminate
Influences of the DMSO to cell growth.Continue to be placed in 37 DEG C after dosing, 5%CO2Incubator culture, act on 1 respectively in drug, 3,6,
12nd, after 18,24 hours, MTT is added in per hole（5mg/mL）20 μ l continue culture 4 hours, and three liquid [10%SDS- are added in per hole
5% isobutanol -0.012mol/L HCl (W/V/V)] 100 μ l Rong Xie formazans.Each hole is measured under 570nm wavelength with microplate reader
OD values deduce cell proliferation inhibition rate.
Specific embodiment
The present invention is described in further detail, but present disclosure is not limited thereto below by embodiment, this
Method operating according to a conventional method unless otherwise specified in embodiment, agents useful for same unless otherwise specified use conventional commercial
Reagent or the reagent being configured according to a conventional method.
Embodiment 1：The preparation of 12 beta-hydroxy androstanes -3,5,14 (15)-triolefin -16- ketone
Laos little Hua Epigynum Auritum plant samples aerial part (stem and leaf) dry powder 11.0kg is taken, is extracted 3 times with 75% alcohol reflux,
Each 48h merges the filtrate extracted three times after being filtered to remove filter residue, is extracted with ethyl acetate again after reduced pressure 3 times, concentrates second
Acetoacetic ester extract layer is weighed to obtain 352g；Ethyl acetate layer extract is subjected to rough segmentation with C18 columns, respectively with percent by volume 20%,
40%th, 50%, 60%, 80%, 100% methanol aqueous solution elute always be obtained 6 parts (Fr.A, Fr.B, Fr.C, Fr.D,
Fr.E).Fr.D obtains four parts by preparing liquid phase with the methanol aqueous solution progress gradient elution of percent by volume 40%-80%
Fr.B1-B4.Again by Fr.B2 therein by the silicagel column of 200-300 mesh, with chloroform-acetone（Volume ratio 20:1-3:1）To wash
De- liquid is eluted, and four part Fr.B2a-Fr.B2d are always obtained.Fr.B2b is prepared into efficient liquid phase by half（Acetonitrile-
Water, 70:30）Purifying obtains the compound in formula II（20mg）.Identified, the polyenoid androstane ketone compound in formula II is new chemical combination
Object；Qualification result is as follows：
II compound of formula, 12 beta-hydroxy androstane -3,5,14 (15)-triolefin -16- ketone are faint yellow indefinite form powder, are soluble in chloroform
Methyl alcohol mixed liquor（Chloroform：Methanol=1:1）, pyridine etc..[α]26 D - 98.5 (c 0.04, MeOH); UV (MeOH) λ max
(log ε): 203 nm (3.5); IR (KBr) ν max 3473 2902, 2831, 1733, 1717, 1458, 1375,
1329, 1047, 962 cm–1;HR-ESI-MS m/z 284.1846 [M+H]+With reference to13CNMR spectrums infer its molecular formula
C19H24O2。1H NMR (CDCl3, 500Mz) and13C NMR(CDCl3, 125Mz) and it is shown in Table 1；NMR points of data above combination 2D
Analysis confirms the chemical structural formula of the compound shown in formula II, to be a new natural organic-compound.
Table 1：12 beta-hydroxy androstanes -3,5,14 (15)-triolefin -16- ketone1H NMR and13C NMR datas
。
Embodiment 2：The preparation of 12 beta-hydroxy androstanes -3,5,14 (15)-triolefin -16- ketone
11 kg Simao, Yunnan rattan samples after air-drying are taken, are extracted 3 times with methanol eddy after crushing, recycling design is concentrated into small
Volume, then be extracted with ethyl acetate 3 times, ethyl acetate layer is concentrated, weigh to obtain 1.2kg；Ethyl acetate layer segment is inhaled with macropore
Attached resin D101 carries out rough segmentation, elute always there are with the methanol aqueous solution of percent by volume 40%, 60%, 80%, 100% respectively
To 5 parts (Fr.A, Fr.B, Fr. C, Fr.D, Fr.E).Fr.E (280g) admix 1.5 times amount silica gel, mix sample silica gel into
Row conventional drying fills column, with chloroform-acetone（0:100-95:5）Two-phase system carries out gradient elution for mobile phase, according to TLC
It inspects merging and obtains three part Fr.E1-E3.Fr.E2 mixes reverse phase C18 columns methanol-water gradient elution on sample with C18 fillers and obtains
To two parts, Fr.E2a-E2b.Fr.E2a is eluted by silicagel column with petroleum ether-acetone system, then passes through gel
Use chloromethane（1:1, V/V）System elution prepares efficient liquid phase by half again and obtains compound in formula II after purification（7 mg）.
Identified, the androstane hydride compounds in formula II are new natural organic-compound.
Embodiment 3：Immunosupress detection experiment
（1）The preparation of splenic lymphocytes suspension
The healthy BABL/c mouse sacrificed by exsanguination of 18 ~ 22g is taken, is placed in soaking disinfection 5 minutes in 75% alcohol, takes out, is placed in sterile
In pallet, left side upward, in super-clean bench, picks up fur in the middle part of abdomen with the tweezers sterilized, makees a kerf, with other set device
Tool cuts off each layer of stomach wall, is taken out spleen with third set instrument, and removal fat and connective tissue are put into PBS（Phosphate buffer）
In, wash away floating blood.Then spleen tissue is moved in the plate for filling 1640 endless full nutrient solutions of RPMI, is cut into small pieces with scissors,
Spleen is ground in 200 mesh stainless steel mesh with asepsis injector core, is repeatedly rinsed on a small quantity with PBS, suspension pipettor is turned
It moves in 15mL centrifuge tubes；1000r/min rotating speeds centrifuge 5min；Supernatant is abandoned in suction, adds in 3mL erythrocyte cracked liquids（Tris-
NH4Cl）Mixing adds in 10 mL PBS termination reactions after standing 2min, centrifuges (1200rpm, 5min), remove supernatant, precipitation is used
5mL PBS are washed twice, and are centrifuged under similarity condition；Precipitation is hanged with 1640 complete culture solutions of RPMI of the 5mL containing 10% fetal calf serum
It is floating；Expect that blue living cells is refused dye method and counted with 0.8%, viable count is no less than 95%, and 1640 complete culture solutions of RPMI is added to dilute,
Cell concentration is adjusted to 1 × 106A/mL or so.
（2）The preparation of test liquid
Precision weighs monomeric compound 2mg, adds in DMSO and dissolves, and is diluted to required concentration with PBS before loading, and so that after loading
DMSO final concentrations be no more than 0.1%.
（3）Experiment packet
Normal group：+ 10 μ LPBS of+10 1640 complete mediums of μ L RPMI of 100 μ L splenocyte suspensions
Model group：+ 10 μ LConA of 100 μ L splenocyte suspensions (final concentration of 10 μ g/mL)+10 μ LPBS
Sample sets：+ 10 μ LConA of 100 μ L splenocyte suspensions (final concentration of 10 μ g/mL)+10 μ L samples
In 96 orifice plates, lymphocyte suspension is added in per hole（1×106A/mL）100 10 μ L (final concentration of 10 μ of μ L, ConA
G/mL), 10 μ L of various concentration reagent chemical compound diluted liquid (final concentration is respectively 12.5,25,50 μ g/mL), dexamethasone
Three corresponding concentration groups are done, Normal group hole is respectively with 1640 complete culture solutions of 10 μ L（Containing 10% fetal calf serum）With 10
The PBS polishings of μ L, each concentration group set 4 it is parallel.
（4）Culture：37 DEG C are placed in, 5 % CO2Culture 72 hours in incubator.
（5）CCK-8 methods measure cell OD values
After culture 72 hours, the CCK-8 reagents (the green skies) of 10 μ L are added in every hole, are placed in 37 DEG C, 5 % CO2Incubator
After inside continuing culture 4 hours, the light absorption value per hole is measured at 450nm to calculate cell proliferative conditions, and thorn is calculated as follows
Swash index（SI）：
SI（Stimulus index）=plus OD values of mitogen culture/is not added with the OD values of mitosis stock culture；
（6）Data processing
Experimental data OD values represent that mathematical statistics and variance analysis work are soft using Origin using " average ± standard deviation "
Part is completed.
（7）Experimental result
Table 2：The stimulus index of Balb/c mice spleen lymphocytes proliferations that II compound of formula stimulates ConA
Stimulus index of 12 beta-hydroxy androstanes -3,5,14 (15)-triolefin -16- ketone at a concentration of 12.5,25,50 μM in formula II
Respectively 2.90,2.52,1.79；Significance analysis shows middle concentration and high concentration the group significant difference compared with model group
（P<0.05）.
Positive control result is：
Table 3：The stimulus index of Balb/c mice spleen lymphocytes proliferations that dexamethasone stimulates ConA
Stimulus index of the dexamethasone at a concentration of 12.5,25,50 μM is respectively 1.62,1.41,1.21；Significance analysis table
It is bright, each concentration group significant difference compared with model group（P<0.05）.
The experimental results showed that 12 beta-hydroxy androstanes -3,5,14 (15)-triolefin -16- ketone has at a concentration of 12.5 μM exempts from
Epidemic disease inhibitory activity, at a concentration of 25,50 μM compared with model group significant difference（P<0.05）, there is preferably immune suppression
System activity.
Embodiment 4：Anti tumor activity in vitro is tested
（1）Material
DMSO（Sigma Co., USA）, fetal calf serum（HyClone companies of the U.S.）, RPMI-1640 culture solutions（U.S. HyClone
Company）, phosphate buffer（Shanghai beyotime companies）, it is dual anti-（HyClone companies of the U.S.）、CCK-8（Eastern Renhua subject skill
Co., Ltd）, human body tumour cell（CCRF-CEM、MOLT-4、K-562、MALME-3M、UACC-62、SNB-75、OVCAR8、
EKVX、U0-31、SF-295、NCI-H226、SK-OV3、MDA_MB-468、Hop92）, the compounds of this invention and dexamethasone are equal
It is prepared with DMSO.
（2）Method
It takes and is adjusted to certain density cell suspension inoculation in 96 well culture plates in exponential phase human body tumour cell,
90ml/ holes, 24 hours compounds that various concentration is added in after its is adherent of culture, 10ml/ holes, each concentration are all provided with 3 multiple holes.
Cell count and the survival rate for using desk tray indigo plant Determination Staining cell, survival rate=uncolored cell number/total number of cells ×
For testing, cell suspension is adjusted to 1 × 10 by 100%, survival rate ＞6A/mL.If cell blank control group, the positive are right
According to group（Dexamethasone）And sample sets（Concentration is set to 25 μm of olL according to trial test result-1, the DMSO containing isoconcentration）.It is cloudy
Property control for isometric culture medium, while corresponding a concentration of Vehicle controls of DMSO during compound 25mg/ml are set, to eliminate DMSO
Influence to cell growth.
（3）Culture
Continue to be placed in 37 DEG C after dosing, 5%CO2Incubator culture.
（4）Mtt assay measures OD values
After drug acts on 1,3,6,12,18,24 hour respectively, MTT is added in per hole（5mg/ml）20ml continues culture 4 hours,
Three liquid [10%SDS-5% isobutanol -0.012mol/L HCl (W/V/V)] 100ml Rong Xie formazans, usual feelings are added in per hole
, formazan growing amounts are directly proportional to viable count under condition, therefore can deduce the number of living cells, and press according to optical density OD values
Following formula calculates cell inhibitory rate：
Inhibiting rate（%）=（OD valuesControl wells- OD valuesWell）/ OD valuesControl wells× 100%；
（5）Data processing
Experimental data OD values represent that mathematical statistics and variance analysis work are soft using Origin using " average ± standard deviation "
Part is completed.
（6）Experimental result
II compound of formula has preferable inhibition to 14 kinds of human tumor cell lines；As a result showing wherein has 5 plants of human bodies to swell
Oncocyte（MOLT-4、K-562、SNB-75、SF-295、NCI-H226）There is drug resistance to dexamethasone, formula II is changed
Closing object has preferable cytotoxic activity；In addition II compound of formula is to other 9 plants of tumour cells（SK-OV3、MDA_MB-468、
Hop92、EKVX、U0-31、OVCAR8、UACC-62、MALME-3M、CCRF-CEM）Have inhibiting effect and with positive control activity
Quite.
Table 4：Influence of II compound of formula to 5 kinds of human body tumour cell survival rates
Claims (4)
1. the polyenoid androstane ketone compound that structural formula is shown below：
Wherein, R1、R2、R3It is selected from hydrogen, hydroxyl, methyl, halogen, aliphatic group, fat amido.
2. the polyenoid androstane ketone compound according to claim 1, it is characterised in that：Polyenoid androstane ketone compound for 12 β-
Hydroxy-androstane -3,5,14 (15)-triolefin -16- ketone, structural formula are as follows：
。
3. application of the polyenoid androstane ketone compound in immunosuppressive drug is prepared described in claims 1 or 2.
4. the polyenoid androstane ketone compound application in preparation of anti-tumor drugs described in claims 1 or 2.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103073608A (en) * | 2013-02-26 | 2013-05-01 | 昆明理工大学 | Androstane-4, 6, 8 (9), 13 (14)-tetraene-3, 11, 16-triketone and application thereof |
| CN103073607A (en) * | 2013-02-26 | 2013-05-01 | 昆明理工大学 | 12[beta]-hydroxyandrostane-4,6,8(9),13(14)-tetraene-3,11,16-triketone and application thereof |
| CN103142621A (en) * | 2013-03-28 | 2013-06-12 | 昆明理工大学 | Medical applications of four buxus alkaloids compounds |
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| CN103073608A (en) * | 2013-02-26 | 2013-05-01 | 昆明理工大学 | Androstane-4, 6, 8 (9), 13 (14)-tetraene-3, 11, 16-triketone and application thereof |
| CN103073607A (en) * | 2013-02-26 | 2013-05-01 | 昆明理工大学 | 12[beta]-hydroxyandrostane-4,6,8(9),13(14)-tetraene-3,11,16-triketone and application thereof |
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