CN107417751B - 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, the compound is Formulas I, Formula II, structure shown in formula III.Compound provided by the invention, which can be used for treating, inhibits the cancers such as related leukemia, lymph cancer, breast cancer, lung cancer, gastric cancer, AIDS, the drug of the diseases such as coronary heart disease, diabetes, senile dementia with protein kinase.The invention also discloses the preparation methods of the compound of anti-tumor activity, it is generated by marine actinomycete rice solid-substrate fermentation, the resulting fermentation material after ethyl acetate extracts, purifies to obtain using gel column chromatography and high performance liquid chromatography separation, easily operated and implementation.
Description
Technical field
The present invention relates to marine actinomycetes to cultivate prepare compound technical field, and in particular to three indole carbazole class chemical combination
Object and preparation method thereof and preparing the application in drug with anti-tumor activity.
Background technique
Indole carbazole compound is a kind of alkaloid in microbial fermentation solution, first isolated day
Right indole carbazole compound is the alkaloid by separating in the culture solution of streptomyces AM-2282 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 Union ammonia of activation
Acid kinase is an important component during Porcine HGF signal transduction, and plays important work in tumour growth
With.Therefore, it can be used as effective target treatment for the relevant cancer of protein kinase.Studies have found that staurosporine specifically selects
Selecting property is poor, clinical treatment can not be entered directly as drug, therefore deepen continuously for the excavation of STA derivative exploitation.
STA derivative isolated from microorganism at present, it is most of that there is preferable anti-tumor activity.Such as unique day
The UCN-01 in right source is completed for treating T- cell lymphoma, melanoma, II phase of non-small cell lung cancer clinical treatment.
Midostaurin (PKC412) is that artificial semi-synthetic obtained STA analog derivative is living with high inhibition to PKC, VEGF, FLT3
Property, Tumor Angiongesis can also be inhibited in addition to being able to suppress tumor cell proliferation, which has entered acute myelogenous white at present
Blood disease II phase clinical research.K252a derivative L estaurtinib (CEP-701), show inhibit specific neurotrophic because
Sub- Trk receptor auto-phosphorylation, FLT3, RET tyrosine kinase activity, U.S. FDA approval in 2006 are acute myelogenous as treating
Leukemia medicament.In addition to this, the related kinases of such compound also cell cycle, nucleus topoisomerase have preferable
Activity, it will be appreciated, however, that either artificial synthesized or structural modification, is not natural generation other than UCN-01
Thank to product.
Now it is known that marine actinomycete metabolite is abundant, structure novel, condition of culture is simple, therefore therefrom obtains structure
Novel STA derivative, and it is applied to the treatments such as cancer relevant to protein kinase, tuberculosis, malaria, coronary heart disease, virus tool
There is good development prospect.
Summary of the invention
It is with anti-tumor activity the present invention provides three indole carbazole compounds and preparation method thereof and preparing
Application in drug.The Formulas I, Formula II, III structure of formula compound be the novel chemical combination of structure feature in microbial metabolic products
Object, the present invention use rice solid medium cultivation and fermentation marine actinomycete, finally by tunning isolate and purify obtain Formulas I,
The compound of Formula II, III class formation of formula.
Indole carbazole compound is Formulas I, Formula II, III structure of formula:
The preparation method of the indole carbazole compound is generated by marine actinomycete solid fermentation, through isolating and purifying
It obtains, easily operated and implementation.
The preparation method of the indole carbazole compound, comprising the following steps:
1) marine actinomycete is inoculated in Gause I fluid nutrient medium, shaking table culture, obtains seed liquor；
2) resulting seed liquor is inoculated in rice solid medium, stationary culture, extraction obtains tunning；
3) after being isolated and purified resulting tunning, the compound of Formulas I, Formula II, III structure of formula is obtained.
In step 1), commercial product is specifically can be used in the marine actinomycete, such as uses Chinese industrial microorganism fungus kind
The streptomycete Streptomyces sp.CICC 11027 that preservation administrative center is sold orders network address: http://www.china-
cicc.org/。
The condition of the shaking table culture are as follows: it is cultivated 2~4 days in 26 DEG C~30 DEG C, the shaking table of 130rpm~230rpm,
Further preferably, it is cultivated 3 days in 28 DEG C, the shaking table of 180rpm.
In step 2), the rice solid medium is made of rice and seawater, the quality and seawater of the rice
The ratio between volume be 30g~50g:50mL~70mL, further preferably, the ratio between quality and the volume of seawater of the rice 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 the stationary culture are as follows: the stationary culture 100~140 days at 23 DEG C~33 DEG C, further preferably, In
Stationary culture 120 days at 28 DEG C.
In step 3), described isolating and purifying includes: to impregnate the tunning that extraction obtains by ethyl acetate, through gel column
Chromatography, high pressure preparative liquid chromatography obtain the compound of Formulas I, Formula II, III structure of formula.
The condition of the 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 the methanol-water of methanol percentage by volume 20%-100%
Liquid.
The condition of the 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 the methanol-water solution of 40%-100%, 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 absolutely prove that such compound has protein kinase inhibiting activity in the growth of different degrees of concentration inhibition PC3
It to play cytotoxic effect, therefore can prepare as anti-tumor drug, can be used as antitumor, AntiHIV1 RT activity and albumen
The application of kinase inhibitors drug, is particularly used in treatment and protein kinase inhibits related leukemia, lymph
The cancers such as cancer, breast cancer, lung cancer, gastric cancer.The Formulas I, Formula II, III structure of formula compound preparing anti-tumor drug and egg
Application in white kinase inhibitors drug has a good application prospect for treating cancer related with protein kinase.
Compared with prior art, the present invention has the advantage that
Three indole carbazole compounds in the present invention, can be used for developing the drug for the treatment of Yu protein kinase associated cancer；
The Formulas I, Formula II, III structure of formula compound can be used for studying between indole carbazole Alkaloid and protein kinase effect
Structure-activity relationship；Experimental implementation of the present invention is simple, is easily enlarged production, with good application prospect.
Detailed description of the invention
Fig. 1 is formula I with active compound for anti tumor A68-29A's1H-NMR map；
Fig. 2 is formula I with active compound for anti tumor A68-29A's13C-NMR map；
Fig. 3 is the HSQC map that formula I has active compound for anti tumor A68-29A；
Fig. 4 is the HMBC map that formula I has active compound for anti tumor A68-29A；
Fig. 5 is the NOESY map that formula I has active compound for anti tumor A68-29A；
Fig. 6 is formula I with active compound for anti tumor A68-29A's1H-1H COSY map；
Fig. 7 is formula III with active compound for anti tumor A68-18G's1H-NMR map；
Fig. 8 is formula III with active compound for anti tumor A68-18G's13C-NMR map；
Fig. 9 is the HSQC map that formula III has active compound for anti tumor A68-18G；
Figure 10 is the HMBC map that formula III has active compound for anti tumor A68-18G；
Figure 11 is formula III with active compound for anti tumor A68-18G's1H-1H COSY map.
Specific embodiment
Embodiment 1
One, the fermentation of compound
The streptomycete Streptomyces that marine actinomycete uses China General Microbiological culture presevation administrative center to sell
sp.CICC 11027；
1) marine actinomycete is inoculated in 500mL conical flask, every bottle of fluid nutrient medium of Gause I containing 250mL, is cultivated
Condition is 28 DEG C, cultivates 3 days in the shaking table of 180rpm, obtains the seed liquor that can be used for fermented and cultured；
2) the resulting seed liquor of step 1) is seeded to rice medium (rice medium is made of the following components: rice
Quality 40g；Seawater 60mL is placed in after 500ml conical flask through obtained by high pressure moist heat sterilization), inoculation volume is 12mL, at 28 DEG C
Stationary culture 120 days, obtain the solid fermentation product containing present invention compound with anti-tumor activity.
Two, the preparation of compound
Solid fermentation product ethyl acetate containing present invention compound with anti-tumor activity is impregnated into extraction 3
Secondary, solvent recovery concentration obtains runic object.Gained runic object is carried out gel column chromatography, and (filler is hydroxypropyl sephadex
LH-20), eluant, eluent is the methanol-water solution gradient elution of percentage by volume 20%-100%, and every 1/4 column volume is one and evaporates
Point, TLC analysis merges the fraction containing target compound.To the standby chromatographic isolation (Sepax of compacting in target components use
Amethyst C-18 (10 μm, 30 × 400mm) chromatographic column, Detection wavelength 292nm, filler are octadecylsilane bonded silica
Glue), mobile phase is the methanol-water solution gradient elution of percentage by volume 40%-100%, and TLC analysis, which merges, contains noval chemical compound
Fraction, obtain the component containing noval chemical compound.
Component of the gained containing noval chemical compound separates (Agilent Pursuit C-18 using high performance preparative liquid chromatography
(10 μm, 21.2 × 250mm) chromatographic column, Detection wavelength 292nm, filler is octadecylsilane chemically bonded silica), the flowing of use
Mutually it is percentage by volume 30%-60% acetonitrile/water system with 10mL/min isocratic elution, collects the chromatographic peak of 18-19min, return
Solvent is received, compound A68-29A is obtained.As shown in Figures 1 to 6, according to nuclear magnetic resonance data, 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, specific structure
It is as follows:
Component of the gained containing noval chemical compound separates (Agilent Pursuit C-18 using high performance preparative liquid chromatography
(10 μm, 21.2 × 250mm) chromatographic column, Detection wavelength 292nm, filler is octadecylsilane chemically bonded silica), the flowing of use
Mutually it is percentage by volume 30%-60% acetonitrile/water system with 10mL/min gradient elution, collects 23-24min chromatographic peak, recycling
Solvent obtains compound A68-29B.According to nuclear magnetic resonance data, structure is as follows, is II structure of formula.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
Object 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 separates (Agilent Pursuit C-18 using high performance preparative liquid chromatography
(10 μm, 21.2 × 250mm) chromatographic column, Detection wavelength 292nm, filler is octadecylsilane chemically bonded silica), the flowing of use
Mutually it is 50% methanol/water system with 10mL/min gradient elution, collects 45-54min chromatographic peak, recycling design obtains compound
A68-18G.As shown in Fig. 7 to 11, according to nuclear magnetic resonance data, 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
For 9-hydroxyl-K252c, referred to as A68-18G, specific structure is as follows:
Compound nuclear-magnetism identification (1H 500MHz,13C 125.7MHz) result is as shown in Table 1 and Table 2.
Table 1
Table 2
Three, anti-tumor activity is tested
Using Sulforhodamine B (Sulforhodamine B, SRB) colorimetric determination compound to Human Prostate Cancer Cells
The inhibited proliferation of strain PC3 cell.The cell of logarithmic growth phase, is configured to 5 × 104A/mL is laid on 96 with 100 holes μ l/
Well culture plate, CO2It is cultivated 24 hours in incubator, the sample to be tested of various concentration is added after taking-up culture plate in every hole, often
A 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 refrigerators pre-cooling is added in every hole is fixed, stands after five minutes, then
Culture plate is moved into 4 DEG C of refrigerator overnights.Fixer is outwelled, every hole is washed with deionized 5 times, and drying is air-dried.Every hole adds
Enter 70 μ l SRB solution, 25 DEG C of room temperature are placed 20 minutes, are removed supernatant, are washed 5 times with 1% acetic acid of mass percent, and air is dry
It is dry.In conjunction with SRB with 100 hole μ l/ 10mmol/L Tris lye (pH=10.5) vibrate dissolve.It is placed in microplate reader and measures respectively
Hole light absorption, measurement wavelength are 515nm.Drug cell proliferation inhibiting rate: inhibiting rate=[1- is calculated according to each hole OD value
(OD515 dosing holes/OD515 control wells)] × 100%, according to each concentration inhibiting rate calculation of half inhibitory concentration IC50It is, specific that see Table 3 for details.
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 absolutely prove that such compound inhibits with protein kinase in the growth of different degrees of concentration inhibition PC3
Activity can prepare to play cytotoxic effect as anti-tumor drug.
Claims (8)
1. indole carbazole compound, which is characterized in that be Formulas I, Formula II, III structure of formula:
2. the preparation method of indole carbazole compound according to claim 1, which comprises the following steps:
1) marine actinomycete is inoculated in Gause I fluid nutrient medium, shaking table culture, obtains seed liquor；
The streptomycete that the marine actinomycete uses Chinese industrial Microbiological Culture Collection administrative center to sell
Streptomyces sp.CICC 11027；
2) resulting seed liquor is inoculated in rice solid medium, stationary culture, extraction obtains tunning；
3) after being isolated and purified resulting tunning, Formulas I, Formula II, the indole carbazole compound of III structure of formula are obtained.
3. the preparation method of indole carbazole compound according to claim 2, which is characterized in that described in step 1)
Shaking table culture condition are as follows: cultivated 2~4 days in 26 DEG C~30 DEG C, the shaking table of 130rpm~230rpm.
4. the preparation method of indole carbazole compound according to claim 2, which is characterized in that described in step 2)
Rice solid medium, be made of rice and seawater, the ratio between volume of quality of the rice and seawater is 30g~50g:
50mL~70mL.
5. the preparation method of indole carbazole compound according to claim 2, which is characterized in that described in step 2)
Stationary culture condition are as follows: the stationary culture 100~140 days at 23 DEG C~33 DEG C.
6. the preparation method of indole carbazole compound according to claim 2, which is characterized in that described in step 3)
Isolate and purify include: by ethyl acetate impregnate extraction obtain tunning, through gel column chromatography, high pressure preparative liquid chromatography
Obtain the compound of Formulas I, Formula II, III structure of formula.
7. the preparation method of indole carbazole compound according to claim 6, which is characterized 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 the 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.
8. indole carbazole compound application in preparation of anti-tumor drugs according to claim 1.
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| CN108069985B (en) * | 2018-01-08 | 2019-12-31 | 杭州科兴生物化工有限公司 | 3-O-demethyl-4-N-acetyl staurosporine and preparation method and application thereof |
| CN108048369B (en) * | 2018-01-26 | 2020-06-19 | 中国医学科学院医药生物技术研究所 | Marine streptomycete for producing staurosporine and preparation method thereof |
| CN108299467B (en) * | 2018-02-27 | 2020-04-28 | 中国海洋大学 | Indolocarbazole alkaloid with cytotoxic activity, preparation method and application thereof |
| 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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| US20110136753A1 (en) * | 2008-04-08 | 2011-06-09 | Universidad De Oviedo | Glycosylated indolecarbazoles, method for obtaining same and uses thereof |
| CN102181387A (en) * | 2011-03-17 | 2011-09-14 | 中国科学院南海海洋研究所 | Streptomyces sp. and method for preparing straurosporine and K-252d by utilizing Streptomyces sp. |
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| WO1991009034A1 (en) * | 1989-12-14 | 1991-06-27 | Schering Corporation | Indolocarbazoles from saccharothrix aerocolonigenes subsp. copiosa subsp. nov. scc 1951 atcc 53856 |
| US20110136753A1 (en) * | 2008-04-08 | 2011-06-09 | Universidad De Oviedo | Glycosylated indolecarbazoles, method for obtaining same and uses thereof |
| CN102181387A (en) * | 2011-03-17 | 2011-09-14 | 中国科学院南海海洋研究所 | Streptomyces sp. and method for preparing straurosporine and K-252d by utilizing Streptomyces sp. |
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