CN107417751A - Indole carbazole compound and its preparation method and application - Google Patents
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Abstract
The invention discloses three indole carbazole compounds and its preparation method and application, and described compound is Formulas I, the structure shown in Formula II, formula III.Compound provided by the invention can be used for the medicine for treating the diseases such as the cancers such as the leukemia relevant with protein kinase suppression, lymph cancer, breast cancer, lung cancer, stomach cancer, AIDS, coronary heart disease, diabetes, senile dementia.The invention also discloses the preparation method of the compound of antitumor activity, produced by marine actinomycete rice solid-substrate fermentation, the fermentate of gained, purifies to obtain using gel column chromatography and high performance liquid chromatography separation after ethyl acetate extracts, easily operated and implementation.
Description
Technical field
The present invention relates to marine actinomycete to cultivate prepare compound technical field, and in particular to three indole carbazole class chemical combination
Thing and preparation method thereof and the application in the medicine with antitumor activity is prepared.
Background technology
Indole carbazole compound is a kind of alkaloid derived from microbial fermentation solution, first isolated day
Right indole carbazole compound is the alkaloid by being separated in streptomyces AM-2282 nutrient solution in 1986
Staurosporine (STA), research find that the compound has antibacterial, anti-hypertension, antitumor and stronger protein kinase
(PKC) inhibitory activity (IC50=2.7nM).Protein kinase C is one group of phosphatide dependence Ca2+The Protein Serine M/ Soviet Unions ammonia of activation
Acid kinase, it is an important component during Porcine HGF signal transduction, and important work is played in tumour growth
With.Therefore, effective target treatment can be used as the related cancer of protein kinase.Studies have found that staurosporine specifically selects
Selecting property is poor, clinical treatment can not be entered directly as medicine, therefore the excavation exploitation for STA derivatives deepens continuously.
STA derivatives isolated from microorganism at present, it is most of that there is preferable antitumor activity.Such as unique day
The UCN-01 in right source has completed to be used to treat T- cell lymphomas, melanoma, II phase of non-small cell lung cancer clinical treatment.
Midostaurin (PKC412) is that artificial semi-synthetic obtained STA analog derivatives have high inhibition work to PKC, VEGF, FLT3
Property, Tumor Angiongesis can also be suppressed except tumor cell proliferation can be suppressed, the medicine has been enter into acute myelogenous white at present
Blood disease II phase clinical research.K252a derivative Ls estaurtinib (CEP-701), show suppress specific neurotrophic because
Sub- Trk receptor auto-phosphorylations, FLT3, RET tyrosine kinase activity, U.S. FDA approval in 2006 are acute myelogenous as treating
Leukemia medicament.In addition, the relevant kinases of such compound also cell cycle, nucleus topoisomerase have preferable
Activity, it is not the generation of natural origin in addition to UCN-01 it will be appreciated, however, that either artificial synthesized or structural modification
Thank to product.
Now, it is known that marine actinomycete metabolite enriches, structure is novel, and condition of culture is simple, therefore therefrom obtains structure
Novel STA derivatives, and applied to the treatments such as the cancer related to protein kinase, tuberculosis, malaria, coronary heart disease, virus tool
There is good development prospect.
The content of the invention
The invention provides three indole carbazole compounds and preparation method thereof and preparing with antitumor activity
Application in medicine.The Formulas I, Formula II, the compound of the structure of formula III are the chemical combination that architectural feature is novel in microbial metabolic products
Thing, the present invention use rice solid medium cultivation and fermentation marine actinomycete, finally by tunning isolate and purify acquisition Formulas I,
The compound of Formula II, the class formation of formula III.
Indole carbazole compound, it is Formulas I, Formula II, the structure of formula III：
The preparation method of described indole carbazole compound, produced by marine actinomycete solid fermentation, through isolating and purifying
Obtain, easily operated and implementation.
The preparation method of described indole carbazole compound, comprises the following steps：
1) marine actinomycete is inoculated in Gause I fluid nutrient medium, shaking table culture, obtains seed liquor；
2) seed liquor of gained is inoculated in rice solid medium, quiescent culture, extraction obtains tunning；
3) after the tunning of gained is isolated and purified, Formulas I, Formula II, the compound of the structure of formula III are obtained.
In step 1), described marine actinomycete, commercially available prod can be specifically used, such as use Chinese industrial microorganism fungus kind
The streptomycete Streptomyces sp.CICC 11027 that preservation administrative center is sold, order network address：http://www.china-
cicc.org/。
The condition of described shaking table culture is：Cultivated 2~4 days in 26 DEG C~30 DEG C, 130rpm~230rpm shaking table,
Further preferably, cultivated 3 days in 28 DEG C, 180rpm shaking table.
In step 2), described rice solid medium, it is made up of rice and seawater, the quality and seawater of described rice
The ratio between volume be 30g~50g：50mL~70mL, further preferably, the ratio between the quality of described rice and the volume of seawater are
40g：60mL, i.e., through obtained by high pressure moist heat sterilization after being matched by rice quality 40g and seawater bulk 60mL.
The condition of described quiescent culture is：The quiescent culture 100~140 days at 23 DEG C~33 DEG C, further preferably,
Quiescent culture 120 days at 28 DEG C.
In step 3), it is described isolate and purify including：The tunning of extraction acquisition is soaked by ethyl acetate, through gel column
Chromatogram, high pressure preparative liquid chromatography obtain Formulas I, Formula II, the compound of the structure of formula III.
The condition of described gel column chromatography：The filler used is hydroxypropyl sephadex (LH-20), the elution of use
Agent is methanol-water solution, and further preferably, the eluant, eluent used is molten for methanol percentage by volume 20%-100% methanol-water
Liquid.
The condition of described preparative liquid chromatography：The filler used is octadecylsilane chemically bonded silica, the flowing of use
It is mutually for the solution of methanol-water solution, acetonitrile-water.Further preferably, the mobile phase used is for methanol percentage by volume
The solution of 40%-100% methanol-water solution, the acetonitrile-water that acetonitrile percentage by volume is 20% to 60%.
The present invention carries out active evaluation test using Human carcinoma of prostate cell line PC3, Formula I provided by the invention,
Formula II, formula III can suppress PC3 growth in different degrees of concentration, absolutely prove that such compound has protein kinase inhibiting activity
It so as to play cytotoxic effect, therefore can prepare as antineoplastic, antitumor, AntiHIV1 RT activity and albumen can be used as
The application of kinase inhibitors drug, it is particularly used in and treats the leukemia relevant with protein kinase suppression, lymph
The cancers such as cancer, breast cancer, lung cancer, stomach cancer.Described Formulas I, Formula II, the compound of the structure of formula III are preparing antineoplastic and egg
Application in white kinase inhibitors drug, the cancer for treating relevant with protein kinase have good application prospect.
Compared with prior art, the invention has the advantages that：
Three indole carbazole compounds in the present invention, available for exploitation treatment and the medicine of protein kinase associated cancer；
Described Formulas I, Formula II, the compound of the structure of formula III can be used between research indole carbazole Alkaloid and protein kinase effect
Structure-activity relationship；Experimental implementation of the present invention is simple, is easily enlarged production, has preferable application prospect.
Brief description of the drawings
Fig. 1 is formula I with active compound for anti tumor A68-29A1H-NMR collection of illustrative plates；
Fig. 2 is formula I with active compound for anti tumor A68-29A13C-NMR collection of illustrative plates；
Fig. 3 is the HSQC collection of illustrative plates that formula I has active compound for anti tumor A68-29A；
Fig. 4 is the HMBC collection of illustrative plates that formula I has active compound for anti tumor A68-29A；
Fig. 5 is the NOESY collection of illustrative plates that formula I has active compound for anti tumor A68-29A；
Fig. 6 is formula I with active compound for anti tumor A68-29A1H-1H COSY collection of illustrative plates；
Fig. 7 is formula III with active compound for anti tumor A68-18G1H-NMR collection of illustrative plates；
Fig. 8 is formula III with active compound for anti tumor A68-18G13C-NMR collection of illustrative plates；
Fig. 9 is the HSQC collection of illustrative plates that formula III has active compound for anti tumor A68-18G；
Figure 10 is the HMBC collection of illustrative plates that formula III has active compound for anti tumor A68-18G；
Figure 11 is formula III with active compound for anti tumor A68-18G1H-1H COSY collection of illustrative plates.
Embodiment
Embodiment 1
First, the fermentation of compound
Marine actinomycete uses the streptomycete Streptomyces that China General Microbiological culture presevation administrative center is sold
sp.CICC 11027；
1) marine actinomycete is inoculated in 500mL conical flasks, every bottle of fluid nutrient medium of Gause I containing 250mL, cultivated
Condition is 28 DEG C, is cultivated 3 days in 180rpm shaking table, obtains the seed liquor available for fermented and cultured；
2) seed liquor obtained by step 1) is seeded into rice medium (rice medium, to be made up of following components：Rice
Quality 40g；Seawater 60mL, it is placed in after 500ml conical flasks through obtained by high pressure moist heat sterilization), inoculation volume is 12mL, at 28 DEG C
Quiescent culture 120 days, obtain the solid fermentation product of compound that there is antitumor activity containing the present invention.
2nd, the preparation of compound
By the ethyl acetate immersion extraction 3 of the solid fermentation product of the compound containing the present invention with antitumor activity
It is secondary, solvent recovery concentration, obtain runic thing.Gained runic thing is carried out into gel column chromatography, and (filler is hydroxypropyl sephadex
LH-20), eluant, eluent is percentage by volume 20%-100% methanol-water solution gradient elution, and every 1/4 column volume is one and evaporated
Point, TLC analyses merge the cut containing target compound.Standby chromatographic isolation (Sepax is suppressed in being used to target components
Amethyst C-18 (10 μm, 30 × 400mm) chromatographic column, Detection wavelength 292nm, filler are octadecylsilane bonded silica
Glue), mobile phase is percentage by volume 40%-100% methanol-water solution gradient elution, and TLC analysis merging contains noval chemical compound
Cut, obtain the component containing noval chemical compound.
Component of the gained containing noval chemical compound is using high performance preparative liquid chromatography separation (Agilent Pursuit C-18
(10 μm, 21.2 × 250mm) chromatographic column, Detection wavelength 292nm, filler is octadecylsilane chemically bonded silica), the flowing of use
It is mutually percentage by volume 30%-60% acetonitrile/waters system with 10mL/min isocratic elutions, collects 18-19min chromatographic peak, return
Solvent is received, obtains compound A68-29A.As shown in Figures 1 to 6, according to nuclear magnetic resonance data, its structure is as follows, is Formulas I knot
Structure.Molecular formula is calculated as C according to high resolution mass spectrum HR-ESI-MS28H27N4O5([M+H]+499.1966,calculated
499.1976), authenticating compound is 9-hydroxy-4 '-N-acetyl-holyrineA, referred to as A68-29A, concrete structure
It is as follows：
Component of the gained containing noval chemical compound is using high performance preparative liquid chromatography separation (Agilent Pursuit C-18
(10 μm, 21.2 × 250mm) chromatographic column, Detection wavelength 292nm, filler is octadecylsilane chemically bonded silica), the flowing of use
Phase is percentage by volume 30%-60% acetonitrile/waters system with 10mL/min gradient elutions, collection 23-24min chromatographic peaks, recovery
Solvent, obtain compound A68-29B.According to nuclear magnetic resonance data, its structure is as follows, is the structure of formula II.Molecular formula according to
High resolution mass spectrum HR-ESI-MS is calculated as C28H25N4O5([M+H]+4971809, calculated 497.1819) chemical combination, is identified
Thing is 9-hydroxyl- (3 '-O-dimethyl) -4 '-N-acetyl-staurosporine), referred to as A68-29B, specifically
Structure is as follows：
Component of the gained containing noval chemical compound is using high performance preparative liquid chromatography separation (Agilent Pursuit C-18
(10 μm, 21.2 × 250mm) chromatographic column, Detection wavelength 292nm, filler is octadecylsilane chemically bonded silica), the flowing of use
It is mutually 50% methanol/water system with 10mL/min gradient elutions, collects 45-54min chromatographic peaks, recycling design, obtain compound
A68-18G.As shown in Fig. 7 to 11, according to nuclear magnetic resonance data, its structure is as follows, is formula III structure.Molecular formula according to
High resolution mass spectrum HR-ESI-MS is C20H14N3O2([M+H]+328.1076 calculated 328.1081), authenticating compound
It is as follows for 9-hydroxyl-K252c, referred to as A68-18G, concrete structure：
Compound nuclear-magnetism identification (1H 500MHz,13C 125.7MHz) result is as shown in Table 1 and Table 2.
Table 1
Table 2
3rd, antitumor activity is tested
Using Sulforhodamine B (Sulforhodamine B, SRB) colorimetric determination compound to Human Prostate Cancer Cells
The inhibited proliferation of strain PC3 cells.Take the logarithm the cell in growth period, be configured to 5 × 104Individual/mL, 96 are laid on 100 μ l/ holes
Well culture plate, CO2Cultivated 24 hours in incubator, take out testing sample of the culture plate after addition various concentrations in every hole, often
Individual concentration sets 3 multiple holes, after the completion of dosing, is placed in CO2Culture plate is taken out after continuing culture in incubator 72 hours, discards culture
Liquid, the trichloroacetic acid (TCA) that the mass percent 10% of 100 μ l4 DEG C refrigerator precoolings is added per hole is fixed, after standing 5 minutes, then
Culture plate is moved into 4 DEG C of refrigerator overnights.Fixer is outwelled, is washed with deionized 5 times per hole, dries, is air-dried.Add per hole
Enter 70 μ l SRB solution, 25 DEG C of room temperature is placed 20 minutes, removes supernatant, washed 5 times with the acetic acid of mass percent 1%, air is done
It is dry.With reference to SRB with 100 μ l/ holes 10mmol/L Tris alkali lye (pH=10.5) vibrate dissolve.It is placed in ELIASA and determines respectively
Hole light absorbs, measure wavelength are 515nm.Medicine cell proliferation inhibiting rate is calculated according to each hole OD values：Inhibiting rate=[1-
(OD515 dosing holes/OD515 control wells)] × 100%, according to each concentration inhibiting rate calculation of half inhibitory concentration IC50, specifically refer to table 3.
Table 3
| Compound | IC50(μg/ml) |
| A68-29A | 10~30 |
| A68-29B | 10~30 |
| A68-18G | 10~30 |
Therefore, the present invention carries out active evaluation test, compound provided by the invention using Human carcinoma of prostate cell line PC3
Formulas I, Formula II, formula III can suppress PC3 growth in different degrees of concentration, absolutely prove that such compound has protein kinase suppression
Activity can be prepared as antineoplastic so as to play cytotoxic effect.
Claims (10)
1. indole carbazole compound, it is characterised in that for Formulas I, Formula II, the structure of formula III：
2. the preparation method of indole carbazole compound according to claim 1, it is characterised in that comprise the following steps：
1) marine actinomycete is inoculated in Gause I fluid nutrient medium, shaking table culture, obtains seed liquor；
2) seed liquor of gained is inoculated in rice solid medium, quiescent culture, extraction obtains tunning；
3) after the tunning of gained is isolated and purified, Formulas I, Formula II, the indole carbazole compound of the structure of formula III are obtained.
3. the preparation method of indole carbazole compound according to claim 2, it is characterised in that described in step 1)
Marine actinomycete use Chinese industrial Microbiological Culture Collection administrative center sell streptomycete Streptomyces
sp.CICC 11027。
4. the preparation method of indole carbazole compound according to claim 2, it is characterised in that described in step 1)
The condition of shaking table culture be：Cultivated 2~4 days in 26 DEG C~30 DEG C, 130rpm~230rpm shaking table.
5. the preparation method of indole carbazole compound according to claim 2, it is characterised in that described in step 2)
Rice solid medium, be made up of rice and seawater, the ratio between the quality of described rice and the volume of seawater are 30g~50g：
50mL~70mL.
6. the preparation method of indole carbazole compound according to claim 2, it is characterised in that described in step 2)
The condition of quiescent culture be：The quiescent culture 100~140 days at 23 DEG C~33 DEG C.
7. the preparation method of indole carbazole compound according to claim 2, it is characterised in that described in step 3)
Isolate and purify including：The tunning of extraction acquisition is soaked by ethyl acetate, through gel column chromatography, high pressure preparative liquid chromatography
Obtain Formulas I, Formula II, the compound of the structure of formula III.
8. the preparation method of indole carbazole compound according to claim 7, it is characterised in that described in step 3)
Gel column chromatography condition：The filler used is hydroxypropyl sephadex, and the eluant, eluent used is methanol-water solution；
The condition of described preparative liquid chromatography：For octadecylsilane chemically bonded silica, the mobile phase of use is the filler used
For methanol-water solution, the solution of acetonitrile-water.
9. application of the indole carbazole compound according to claim 1 in kinases inhibitor is prepared.
10. application of the indole carbazole compound according to claim 1 in antineoplastic is prepared.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108048369A (en) * | 2018-01-26 | 2018-05-18 | 中国医学科学院医药生物技术研究所 | A kind of marine streptomyces for producing staurosporin and preparation method thereof |
| CN108069985A (en) * | 2018-01-08 | 2018-05-25 | 杭州科兴生物化工有限公司 | 3-O- demethyl -4-N- demethyl -4-N- acetyl group staurosporines and its preparation method and application |
| CN108299467A (en) * | 2018-02-27 | 2018-07-20 | 中国海洋大学 | Indole carbazole Alkaloid with cytotoxic activity and preparation method, purposes |
| CN108586489A (en) * | 2018-03-22 | 2018-09-28 | 杭州科兴生物化工有限公司 | A kind of 7- carbonyls staurosporine class compound and preparation method thereof and the application in preparing anticancer medicine |
| CN114835628A (en) * | 2021-02-02 | 2022-08-02 | 上海交通大学医学院附属仁济医院 | Chloro-carbazole compound and preparation method and application thereof |
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| CN108069985A (en) * | 2018-01-08 | 2018-05-25 | 杭州科兴生物化工有限公司 | 3-O- demethyl -4-N- demethyl -4-N- acetyl group staurosporines and its preparation method and application |
| CN108048369A (en) * | 2018-01-26 | 2018-05-18 | 中国医学科学院医药生物技术研究所 | A kind of marine streptomyces for producing staurosporin and preparation method thereof |
| CN108299467A (en) * | 2018-02-27 | 2018-07-20 | 中国海洋大学 | Indole carbazole Alkaloid with cytotoxic activity and preparation method, purposes |
| CN108586489A (en) * | 2018-03-22 | 2018-09-28 | 杭州科兴生物化工有限公司 | A kind of 7- carbonyls staurosporine class compound and preparation method thereof and the application in preparing anticancer medicine |
| CN108586489B (en) * | 2018-03-22 | 2019-12-03 | 杭州科兴生物化工有限公司 | A kind of 7- carbonyl staurosporine class compound and preparation method thereof and the application in preparation anticancer medicine |
| CN114835628A (en) * | 2021-02-02 | 2022-08-02 | 上海交通大学医学院附属仁济医院 | Chloro-carbazole compound and preparation method and application thereof |
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