CN107400137B - Compound with anti-tumor activity and its preparation method and application - Google Patents
Compound with anti-tumor activity and its preparation method and application Download PDFInfo
- Publication number
- CN107400137B CN107400137B CN201710452480.9A CN201710452480A CN107400137B CN 107400137 B CN107400137 B CN 107400137B CN 201710452480 A CN201710452480 A CN 201710452480A CN 107400137 B CN107400137 B CN 107400137B
- Authority
- CN
- China
- Prior art keywords
- compound
- tumor activity
- preparation
- formula
- culture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of compound with anti-tumor activity and its preparation method and application, the compound is Formulas I, structure shown in Formula II.Compound provided by the invention can be used for treating the cancers such as leukemia relevant to protein kinase inhibition, lymph cancer, breast cancer, lung cancer, AIDS, the drug of the diseases such as coronary heart disease, diabetes, senile dementia.The preparation method of present invention compound with anti-tumor activity, it is generated by marine actinomycete rice solid-substrate fermentation, the resulting tunning after ethyl acetate extracts, isolates and purifies to obtain using gel column chromatography and preparative liquid chromatography, easily operated and implementation.
Description
Technical field
The present invention relates to marine actinomycete cultures to prepare reactive compound field, and in particular to one kind has anti-tumor activity
Compound and its preparation method and application.
Background technique
From the isolated indole carbazole Alkaloid staurosporine from rod spore streptomycete (ATCC55006) in 1977
(STA) since, since its extensive pharmacological activity is paid close attention to, such as: antitumor, antibacterial, anti-hypertension, and to protein kinase
C (PKC), tyrosine kinase, topoisomerase, extracellular regulated protein kinase etc. have stronger inhibiting effect, especially prominent
Be inhibitory activity (IC to protein kinase C (PKC)50=2.7nM), but later period research discovery STA is to normal cell and tumour
The specific selectivity of cell is poor, can not patent medicine, therefore deepen continuously to the discovery and application study of its derivative.PKC be by
One group of phosphatide dependence Ca that Nishizuka et al. had found for the first time in 19772+The Protein Serine M/ threonine kinase 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 signal transmitting side
There is identical biological activity in face.And it is the high-affinity receptor of carcinogen phorbol exters (TPA), the overexpression of PKC
It will lead to abnormal growth of cells.Therefore, PKC is currently as an important target spot in tumor pharmacother research.It is currently the only
Natural UCN-01 is completed for treating T- cell lymphoma, 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 inhibits tumour growth
It can also inhibit Tumor Angiongesis in addition to directly acting on cell Proliferation, which has entered acute myeloid leukaemia II at present
Phase clinical research.And the analog Lestaurtinib (CEP-701) of K252a, show inhibit specific neurotrophic because
Sub- Trk receptor auto-phosphorylation, 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 abundant, and structure novel, condition of culture is simple, and star spore is generated especially in streptomyces
The bacterial strain example of streptozotocin derivative is more, and rice medium is full of nutrition, provides enough origin of amino acid, therefore pass through rice
Solid culture can get the activated product of more structure novels, can be used as the kinases inhibitor with specific selectivity, answers
For clinical treatments such as cancer relevant to protein kinase, tuberculosis, malaria, coronary heart disease, viruses.
Summary of the invention
The present invention provides a kind of compound with anti-tumor activity and its preparation method and application, the Formulas I, Formula II knot
The compound of structure is the intermediate product in microbial body in synthesis staurosporine metabolic process, and the present invention uses rice solid culture
Base fermented and cultured marine actinomycete, gained tunning obtain the compound of Formulas I, Formula II structure through isolating and purifying.
A kind of compound with anti-tumor activity is Formulas I, Formula II structure；
The present invention provides a kind of preparation methods of compound with anti-tumor activity, by marine actinomycete solid fermentation
It generates, through isolating and purifying to obtain, easily operated and implementation.
A kind of preparation method of compound with anti-tumor activity, comprising the following steps:
1) marine actinomycete is inoculated in Gause I fluid nutrient medium, shaking table culture, obtains seed liquor；
2) above-mentioned resulting seed liquor is inoculated in rice solid medium, stationary culture, extraction obtains tunning.
3) after being isolated and purified above-mentioned resulting tunning, the compound of Formulas I, Formula II structure 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,
Stationary culture 120 days at 28 DEG C.
In step 3), described isolating and purifying includes: the tunning obtained by ethyl acetate equal-volume extraction, through gel
Column chromatography, preparative liquid chromatography obtain the compound of Formulas I, Formula II structure.
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%
The volume ratio of liquid, i.e. methanol and water is 20:80 to 100:0；
The condition of the 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 the methanol-water solution of volume ratio percentage 40%-100%,
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 inhibit PC3 growth, absolutely prove such compound have protein kinase inhibiting activity to
Cytotoxic effect is played, therefore can be prepared as kinases inhibitor and anti-tumor drug.Provided by the inventionization
Closing object can be used for treating the cancers such as leukemia relevant to protein kinase inhibition, lymph cancer, breast cancer, lung cancer, AIDS
Disease, the drug of the diseases such as coronary heart disease, diabetes, senile dementia.The compound of the Formulas I, Formula II structure is preparing albumen
Application in kinase inhibitor and anti-tumor drug, before treating cancer related with protein kinase with application well
Scape.
Compared with prior art, the present invention has the advantage that
Compound with anti-tumor activity in the present invention, can be used for developing treatment and kinases inhibitor associated cancer
Drug；The compound is obtained by rice solid medium, to absolutely prove that intermediate product can be prepared in solid medium
The advantage of acquisition；Fertilizer utilization can be used as after simple process through solid medium extracted, it is environmentally protective, it is recycled benefit
With realization large-scale industrial production.
Detailed description of the invention
Fig. 1 is compound A68-13E with anti-tumor activity in formula I1H-NMR map；
Fig. 2 is compound A68-13E with anti-tumor activity in formula I13C-NMR map；
Fig. 3 is the HSQC map of compound A68-13E with anti-tumor activity in formula I；
Fig. 4 is the HMBC map of compound A68-13E with anti-tumor activity in formula I；
Fig. 5 is the NOESY map of compound A68-13E with anti-tumor activity in formula I；
Fig. 6 is compound A68-13H with anti-tumor activity in formula I1H-1H COSY map；
Fig. 7 is compound A68-13H with anti-tumor activity in Formula II1H-NMR map；
Fig. 8 is compound A68-13H with anti-tumor activity in Formula II13C-NMR map；
Fig. 9 is the HSQC map of compound A68-13H with anti-tumor activity in Formula II；
Figure 10 is the HMBC map of compound A68-13H with anti-tumor activity in Formula II；
Figure 11 is the NOESY map of compound A68-13H with anti-tumor activity in Formula II；
Figure 12 is compound A68-13H with anti-tumor activity in Formula II1H-1H COSY map.
Specific embodiment
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 (CICC 11027) is inoculated in 500mL conical flask, every bottle of liquid of Gause I containing 250mL
Culture medium, condition of culture be 28 DEG C, cultivate 3 days in the shaking table of 180rpm, acquisition can fermented and cultured seed liquor；
2) the resulting seed liquor of step 1) is seeded to rice medium (rice medium is made of the following components: rice
40g, seawater 60mL are placed in after 500ml conical flask through obtained by high pressure moist heat sterilization), inoculation volume is 12mL, condition of culture 28
Constant temperature stationary culture 120 days at DEG C 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 of percentage by volume 40%-100% with 10mL/min gradient elution, and TLC analysis, which merges, to be contained
There is the fraction of noval chemical compound, obtains 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 70% methanol/water system of percentage by volume with 10mL/min isocratic elution, collects the chromatographic peak of 20-22min, recycle molten
Agent obtains compound A68-13E, and as shown in Figures 1 to 6, according to nuclear magnetic resonance data, 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, specific structure are 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 60% methanol/water system of percentage by volume with 10mL/min isocratic elution, collects the chromatographic peak of 46-48min, recycle molten
Agent obtains compound A68-13H.As shown in Fig. 7 to 12, according to nuclear magnetic resonance data, 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 specific structure is as follows:
Compound nuclear-magnetism identification (1H 400MHz,13C 100.5MHz) as shown in table 1.
Table 1
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, is placed at room temperature for 20 minutes, removes supernatant, washed 5 times, be air-dried with 1% acetic acid of mass percent.Knot
The SRB of conjunction is vibrated with 100 hole μ l/ 10mmol/L Tris lye (pH=10.5) and is dissolved.It is placed in microplate reader and measures each hole light suction
It receives, measurement wavelength is 515nm.Drug cell proliferation inhibiting rate: inhibiting rate=[1- (OD is calculated according to each hole OD value515 dosing holes/
OD515 control wells)] × 100%, according to each concentration inhibiting rate calculation of half inhibitory concentration IC50, the results are shown in Table 2.
Table 2
| Compound | IC50(μM) |
| A68-13E | 0.81 |
| A68-13H | 16.24 |
The result shows that the present invention carries out active evaluation test, provided by the inventionization using Human carcinoma of prostate cell line PC3
Closing object Formulas I, Formula II can absolutely prove that such compound inhibits with protein kinase in the growth of different degrees of concentration inhibition PC3
Activity can be used for preparing kinases inhibitor and anti-tumor drug to play cytotoxic effect.
Claims (6)
1. a kind of preparation method of compound with anti-tumor activity, 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) above-mentioned resulting seed liquor is inoculated in rice solid medium, stationary culture, extraction obtains tunning；
3) after being isolated and purified above-mentioned resulting tunning, the compound of Formulas I, Formula II structure is obtained；
The compound with anti-tumor activity is Formulas I, Formula II structure；
2. the preparation method of compound with anti-tumor activity according to claim 1, which is characterized in that step 1)
In, the condition of the shaking table culture are as follows: cultivated 2~4 days in 26 DEG C~30 DEG C, the shaking table of 130rpm~230rpm.
3. the preparation method of compound with anti-tumor activity according to claim 1, which is characterized in that step 2)
In, the rice solid medium is made of rice and seawater, and the ratio between quality and the volume of seawater of the rice are
30g~50g:50mL~70mL.
4. the preparation method of compound with anti-tumor activity according to claim 1, which is characterized in that step 2)
In, the condition of the stationary culture are as follows: the stationary culture 100~140 days at 23 DEG C~33 DEG C.
5. the preparation method of compound with anti-tumor activity according to claim 1, which is characterized in that step 3)
In, described isolating and purifying includes: the tunning obtained by ethyl acetate equal-volume extraction, through gel column chromatography, preparation solution
Phase chromatography obtains the compound of Formulas I, Formula II structure.
6. the preparation method of compound with anti-tumor activity according to claim 5, which is characterized in that step 3)
In, the condition of the gel column chromatography: 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
Methanol-water solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710452480.9A CN107400137B (en) | 2017-06-15 | 2017-06-15 | Compound with anti-tumor activity and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710452480.9A CN107400137B (en) | 2017-06-15 | 2017-06-15 | Compound with anti-tumor activity and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107400137A CN107400137A (en) | 2017-11-28 |
| CN107400137B true CN107400137B (en) | 2019-10-15 |
Family
ID=60404602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710452480.9A Active CN107400137B (en) | 2017-06-15 | 2017-06-15 | Compound with anti-tumor activity and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107400137B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009125042A1 (en) * | 2008-04-08 | 2009-10-15 | 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. |
| US20120028309A1 (en) * | 2010-08-02 | 2012-02-02 | National Chiao Tung University | Method for producing indole derivative |
| CN106831898A (en) * | 2016-12-27 | 2017-06-13 | 杭州科兴生物化工有限公司 | Compound with protein kinase inhibiting activity and its preparation method and application |
-
2017
- 2017-06-15 CN CN201710452480.9A patent/CN107400137B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009125042A1 (en) * | 2008-04-08 | 2009-10-15 | Universidad De Oviedo | Glycosylated indolecarbazoles, method for obtaining same and uses thereof |
| US20120028309A1 (en) * | 2010-08-02 | 2012-02-02 | National Chiao Tung University | Method for producing indole derivative |
| 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. |
| CN106831898A (en) * | 2016-12-27 | 2017-06-13 | 杭州科兴生物化工有限公司 | Compound with protein kinase inhibiting activity and its preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| Deciphering the late steps in the biosynthesis of the anti-tumor indolocarbazole staurosporine: Sugar donor substrate flexibility of the StaG glycosyltransferase;Salas, Aaroa P.等;《Molecular Microbiology》;20050720;第58卷(第1期);参见全文 * |
| 拟诺卡菌及其次级代谢产物;高春燕等;《中国抗生素杂志》;20160229;第41卷(第2期);第81-97页，参见全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107400137A (en) | 2017-11-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107417751B (en) | Indole carbazole compound and its preparation method and application | |
| CN106831898B (en) | Compound and its preparation method and application with protein kinase inhibiting activity | |
| CN108358946A (en) | A kind of anthraquinone analog compound and preparation method thereof and the application in preparing treating cancer drug | |
| CN107400137B (en) | Compound with anti-tumor activity and its preparation method and application | |
| CN106518643B (en) | A kind of cyclopentene ketone compounds and its preparation method and application | |
| CN110066283B (en) | Indole diketopiperazine alkaloid and preparation method and application thereof | |
| CN108084205B (en) | A kind of indole carbazole Alkaloid and its preparation method and application | |
| CN107417559B (en) | A kind of sesquiterpenoids and its preparation method and application | |
| CN107417743A (en) | Staurosporine aldehyde radical substitutive derivative and its preparation method and application | |
| CN107446011A (en) | A kind of staurosporine class compound and its preparation method and application | |
| CN108299467A (en) | Indole carbazole Alkaloid with cytotoxic activity and preparation method, purposes | |
| CN107973769A (en) | A kind of benzodihydropyrone class compound and its preparation method and application | |
| CN107569491A (en) | A kind of application of staurosporine class compound | |
| CN107556323B (en) | A kind of amino replaces staurosporine class compound and its preparation method and application | |
| CN114213428B (en) | Indole alkaloid compound and preparation method and application thereof | |
| CN112500348B (en) | Geldanamycin derivatives, preparation method thereof and application thereof in preparing antitumor drugs | |
| CN111333659B (en) | Staurosporine derivatives and preparation method and application thereof | |
| CN112500340B (en) | Tetrahydroquinoline alkaloid with anti-prostate cancer activity and preparation method and application thereof | |
| CN107337612B (en) | Bisphenol compound and preparation method thereof and application in preparation of anti-tumor drugs | |
| CN108383889A (en) | Open loop staurosporine derivative and its preparation method and application | |
| CN108164538B (en) | The indole carbazole compound and its preparation method and application that N-13 tyrosine derivative replaces | |
| CN107098885A (en) | A kind of quianzolinones and its preparation method and application | |
| CN107903277B (en) | Mould chlorins compound of a kind of N- methyl-Mei Da and its preparation method and application | |
| CN108164537A (en) | A kind of staurosporine analog derivative of 3 substitutions and its preparation method and application | |
| CN107674105B (en) | Indole carbazole compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220223 Address after: 311400 No. 1, No. 13 Road, Dongzhou industrial functional zone, Dongzhou street, Fuyang District, Hangzhou City, Zhejiang Province Patentee after: Zhejiang Meixin Holding Co.,Ltd. Address before: 310000 No. 1, No. 13 Road, Dongzhou industrial functional zone, Fuyang District, Hangzhou City, Zhejiang Province Patentee before: HANGZHOU KEXING BIOCHEM Co.,Ltd. |