CN107400137A - Compound with antitumor activity and its preparation method and application - Google Patents
Compound with antitumor activity and its preparation method and application Download PDFInfo
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- CN107400137A CN107400137A CN201710452480.9A CN201710452480A CN107400137A CN 107400137 A CN107400137 A CN 107400137A CN 201710452480 A CN201710452480 A CN 201710452480A CN 107400137 A CN107400137 A CN 107400137A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention discloses a kind of compound with antitumor activity and its preparation method and application, and described compound is Formulas I, the structure shown in Formula II.Compound provided by the invention can be used for the medicine for treating the diseases such as the cancers such as the leukemia related to protein kinase suppression, lymph cancer, breast cancer, lung cancer, AIDS, coronary heart disease, diabetes, senile dementia.The present invention has the preparation method of the compound of antitumor activity, produced by marine actinomycete rice solid-substrate fermentation, the tunning of gained, isolates and purifies to obtain using gel column chromatography and preparative liquid chromatography after ethyl acetate extracts, easily operated and implementation.
Description
Technical field
The present invention relates to marine actinomycete culture to prepare reactive compound field, and in particular to one kind has antitumor activity
Compound and its preparation method and application.
Background technology
From the isolated indole carbazole Alkaloid staurosporine from rod spore streptomycete (ATCC55006) in 1977
(STA) since, because its extensive pharmacological activity is paid close attention to, such as：Antitumor, antibacterial, anti-hypertension, and to protein kinase
C (PKC), EGFR-TK, topoisomerase, extracellular regulated protein kinase etc. have stronger inhibitory action, especially prominent
Be inhibitory activity (IC to protein kinase C (PKC)50=2.7nM), but later stage research finds STA to normal cell and tumour
The specific selectivity of cell is poor, can not patent medicine, therefore discovery to its derivative and application study deepen continuously.PKC be by
One group of phosphatide dependence Ca that Nishizuka et al. had found first in 19772+The Protein Serine M/ threonine kinases of activation,
It is an important component during Porcine HGF signal transduction, it plays an important role in malignant growth, PKC
With known proto-oncogene structurally and functionally much like, and many oncogene products are in PKC signals transmission side
There is identical biological activity in face.And it is carcinogen phorbol exters (TPA) high-affinity receptor, PKC overexpression
Abnormal growth of cells can be caused.Therefore, an important target spot during PKC studies currently as tumor pharmacother.It is currently the only
The UCN-01 of natural origin has completed to be used to treat T- cell lymphomas, melanoma, II phase of non-small cell lung cancer clinical treatment.People
The semi-synthetic Midostaurin of work (PKC412) has strong inhibitory activity to PKC, VEGF, FLT3, and PKC412 suppresses tumour growth
Tumor Angiongesis can also be suppressed except directly acting on cell propagation, the medicine has been enter into acute myeloid leukaemia II at present
Phase clinical research.And K252a analog Lestaurtinib (CEP-701), show suppress specific neurotrophic because
Sub- Trk receptor auto-phosphorylations, FLT3, RET tyrosine kinase activity, U.S. FDA approved is as the acute myelogenous white blood for the treatment of
Medicine.
Marine actinomycete metabolite is enriched, and structure is novel, and condition of culture is simple, and star spore is produced especially in streptomyces
The bacterial strain example of streptozotocin derivative is more, and rice medium is nutritious, there is provided enough origin of amino acid, therefore pass through rice
Solid culture can obtain the novel activated product of more structures, can be as the kinases inhibitor with specific selectivity, should
For clinical treatments such as the cancer related to protein kinase, tuberculosis, malaria, coronary heart disease, viruses.
The content of the invention
The invention provides a kind of compound with antitumor activity and its preparation method and application, the Formulas I, Formula II knot
The compound of structure is that the intermediate product in synthesis staurosporine metabolic process, the present invention use rice solid culture in microbial body
Base fermented and cultured marine actinomycete, gained tunning obtain Formulas I, the compound of Formula II structure through isolating and purifying.
A kind of compound with antitumor activity, it is Formulas I, Formula II structure；
The invention provides a kind of preparation method of the compound with antitumor activity, by marine actinomycete solid fermentation
Produce, through isolating and purifying to obtain, easily operated and implementation.
A kind of preparation method of the compound with antitumor activity, 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 above-mentioned gained is inoculated in rice solid medium, quiescent culture, extraction obtains tunning.
3) after the tunning of above-mentioned gained is isolated and purified, Formulas I, the compound of Formula II structure 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 obtained by ethyl acetate equal-volume extraction, through gel
Column chromatography, preparative liquid chromatography obtain Formulas I, the compound of Formula II structure.
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
The volume ratio of liquid, i.e. methanol and water is 20：80 to 100：0；
The condition of described preparative liquid chromatography：The filler used is octadecylsilane chemically bonded silica, the flowing of use
It is mutually methanol-water solution, further preferably, the mobile phase of use is volume ratio percentage 40%-100% methanol-water solution,
I.e. the volume ratio of methanol and water is 40：60 to 100：0.
The present invention carries out active evaluation test using Human carcinoma of prostate cell line PC3, Formula I provided by the invention,
Formula II can different degrees of concentration suppress PC3 growth, absolutely prove such compound have protein kinase inhibiting activity so as to
Cytotoxic effect is played, therefore can be prepared as kinases inhibitor and antineoplastic.Provided by the inventionization
Compound can be used for treating the cancers such as the leukemia related to protein kinase suppression, lymph cancer, breast cancer, lung cancer, AIDS
The medicine of the disease such as disease, coronary heart disease, diabetes, senile dementia.Described Formulas I, the compound of Formula II structure are preparing albumen
Application in kinase inhibitor and antineoplastic, before treating the cancer relevant with protein kinase with application well
Scape.
Compared with prior art, the invention has the advantages that：
There is the compound of antitumor activity, available for exploitation treatment and kinases inhibitor associated cancer in the present invention
Medicine；The compound is obtained by rice solid medium, so as to absolutely prove that intermediate product can be prepared in solid medium
The advantage of acquisition；Solid medium after extraction can be used as fertilizer utilization after simple process, green, be recycled profit
With realizing large-scale industrial production.
Brief description of the drawings
Fig. 1 is the compound A68-13E for having in formula I antitumor activity1H-NMR collection of illustrative plates；
Fig. 2 is the compound A68-13E for having in formula I antitumor activity13C-NMR collection of illustrative plates；
Fig. 3 is the HSQC collection of illustrative plates of the compound A68-13E in formula I with antitumor activity；
Fig. 4 is the HMBC collection of illustrative plates of the compound A68-13E in formula I with antitumor activity；
Fig. 5 is the NOESY collection of illustrative plates of the compound A68-13E in formula I with antitumor activity；
Fig. 6 is the compound A68-13H for having in formula I antitumor activity1H-1H COSY collection of illustrative plates；
Fig. 7 is the compound A68-13H for having in Formula II antitumor activity1H-NMR collection of illustrative plates；
Fig. 8 is the compound A68-13H for having in Formula II antitumor activity13C-NMR collection of illustrative plates；
Fig. 9 is the HSQC collection of illustrative plates of the compound A68-13H in Formula II with antitumor activity；
Figure 10 is the HMBC collection of illustrative plates of the compound A68-13H in Formula II with antitumor activity；
Figure 11 is the NOESY collection of illustrative plates of the compound A68-13H in Formula II with antitumor activity；
Figure 12 is the compound A68-13H for having in Formula II antitumor activity1H-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 (CICC 11027) is inoculated in 500mL conical flasks, every bottle of liquid of Gause I containing 250mL
Culture medium, condition of culture is 28 DEG C, cultivate 3 days in 180rpm shaking table, acquisition can fermented and cultured seed liquor；
2) seed liquor obtained by step 1) is seeded into rice medium (rice medium, to be made up of following components：Rice
40g, seawater 60mL, it is placed in after 500ml conical flasks through obtained by high pressure moist heat sterilization), inoculation volume is 12mL, condition of culture 28
Constant temperature quiescent culture 120 days at DEG C, 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), the methanol-water solution that mobile phase is percentage by volume 40%-100% is contained with 10mL/min gradient elutions, TLC analysis merging
There is the cut of noval chemical compound, 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 the methanol/water system of percentage by volume 70% with 10mL/min isocratic elutions, collects 20-22min chromatographic peak, recovery is molten
Agent, compound A68-13E is obtained, as shown in Figures 1 to 6, according to nuclear magnetic resonance data, its structure is as follows, is Formulas I structure.
Molecular formula is calculated as C according to high resolution mass spectrum HR-ESI-MS28H26N4O4(m/z=[M+H]+483.2018,
Calculated483.2027), therefore authenticating compound is 3 '-O-acetyl-4 '-epi-holyrineA), referred to as A68-
13E, concrete structure are 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 the methanol/water system of percentage by volume 60% with 10mL/min isocratic elutions, collects 46-48min chromatographic peak, recovery is molten
Agent, obtain compound A68-13H.As shown in Fig. 7 to 12, according to nuclear magnetic resonance data, its structure is as follows, is Formula II knot
Structure.Molecular formula is calculated as C according to high resolution mass spectrum HR-ESI-MS28H26N4O4(m/z=[M+H]+483.2045,calculated
483.2027), therefore authenticating compound is 4 '-N-acetyl-holyrineA, referred to as A68-13H, and concrete structure is as follows：
Compound nuclear-magnetism identification (1H 400MHz,13C 100.5MHz) as shown in table 1.
Table 1
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, room temperature is placed 20 minutes, removes supernatant, washed 5 times, be air-dried with the acetic acid of mass percent 1%.Knot
The SRB of conjunction is vibrated with 100 μ l/ holes 10mmol/L Tris alkali lye (pH=10.5) and dissolved.It is placed in ELIASA and determines each hole light suction
Receive, measure wavelength is 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, its result is as shown in table 2.
Table 2
| Compound | IC50(μM) |
| A68-13E | 0.81 |
| A68-13H | 16.24 |
As a result show, the present invention carries out active evaluation test, provided by the inventionization using Human carcinoma of prostate cell line PC3
Compound Formulas I, Formula II can suppress PC3 growth in different degrees of concentration, absolutely prove that such compound has protein kinase suppression
Activity can be used for preparing kinases inhibitor and antineoplastic so as to play cytotoxic effect.
Claims (10)
1. a kind of compound with antitumor activity, it is characterised in that for Formulas I, Formula II structure；
2. the compound according to claim 1 with antitumor activity, 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 above-mentioned gained is inoculated in rice solid medium, quiescent culture, extraction obtains tunning；
3) after the tunning of above-mentioned gained is isolated and purified, Formulas I, the compound of Formula II structure are obtained.
3. the compound according to claim 2 with antitumor activity, it is characterised in that in step 1), described sea
Foreign actinomyces use the streptomycete Streptomyces sp.CICC that Chinese industrial Microbiological Culture Collection administrative center is sold
11027。
4. the compound according to claim 2 with antitumor activity, it is characterised in that in step 1), described shakes
Bed culture condition be：Cultivated 2~4 days in 26 DEG C~30 DEG C, 130rpm~230rpm shaking table.
5. the compound according to claim 2 with antitumor activity, it is characterised in that in step 2), described is big
Rice solid medium, is made up of, the ratio between the quality of described rice and the volume of seawater are 30g~50g rice and seawater：50mL
~70mL.
6. the compound according to claim 2 with antitumor activity, it is characterised in that in step 2), described is quiet
The condition for putting culture is：The quiescent culture 100~140 days at 23 DEG C~33 DEG C.
7. the compound according to claim 2 with antitumor activity, it is characterised in that in step 3), described point
Include from purifying：The tunning obtained by ethyl acetate equal-volume extraction, formula is obtained through gel column chromatography, preparative liquid chromatography
I, the compound of Formula II structure.
8. the compound according to claim 7 with antitumor activity, it is characterised in that in step 3), described is solidifying
The condition of glue column chromatography：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
Methanol-water solution.
9. application of the compound according to claim 1 with antitumor activity in kinases inhibitor is prepared.
10. application of the compound according to claim 1 with antitumor activity in antineoplastic is prepared.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
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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 |
| 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 |
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