CN107569491A - A kind of application of staurosporine class compound - Google Patents
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Abstract
The invention discloses a kind of application of staurosporine class compound in the medicine for preparing treating cancer, inflammation or AIDS.The compounds of this invention is to isolate and purify to obtain from a kind of actinomyces, it is identified as staurosporine class compound, found through functional study, these compound on prostate cancer cells have higher activity, also there is higher inhibitory action to Brd4 albumen simultaneously, illustrate that the compounds of this invention has a good application prospect in terms of the medicine of the diseases such as treatment tumour, HIV, leukaemia is prepared.
Description
Technical field
The present invention relates to biological technical field, more particularly to a kind of application of staurosporine class compound.
Background technology
Cancer is to endanger one of major disease of human life and health, has the characteristics of long death rate of the course of disease is high.Prostate
Cancer is a kind of malignant tumour for being common in male genitourinary system, and its incidence of disease has male tumor in west American-European countries shelter
First of, the death rate is only second to lung cancer, occupies second.Compared with western countries, the incidence of disease of China's prostate cancer is substantially relatively low, but
It is in notable growing trend due to being influenceed by various factors in recent years.WHO Report, global cancer is suffered within 2012
Person and death are all constantly increasing, and newly-increased cases of cancer has nearly half to appear in Asia, wherein most in China, in
State increases cases of cancer newly and is in first.Therefore, the prevention and treatment of cancer are most important.
Staurosporine (STA) is isolated indole carbazole compound from soil actinomycete earliest, afterwards successively
Found from a variety of marine actinomycetes and invertebrate.Research show protein kinase C (PKC) be mediate tumor cell propagation,
Vital effect is played in the signal path of differentiation, apoptosis and angiogenesis, PKC has become one of antineoplaston
Target spot.STA is strong pkc inhibitor (IC50=2.7nM), it is different to mainly act on various kinases in intracellular signal transduction pathway, topology
Structure enzyme and Cell cycle regulatory proteins, but the kinase inhibitor of wide spectrum is then proved, poor selectivity, thus can not patent medicine.
And the derivative of multiple staurosporines is just being in clinical research as antineoplastic at present.The staurosporine of natural origin derives
Thing UCN-01 is currently in the II phase clinical researches for the treatment of breast cancer and lymph cancer.The staurosporine derivative that structural modification obtains
PKC-412 is in the phase of clinic II of the third stage of acute myeloid leukaemia, NHL and chronic lymphocytic leukemia；
Oral lestaurtinib was ratified as the Orphan drug for treating acute myelocytic leukemia in 2006 by FDA；CEP-
2563 have been completed the I phase clinical research for the treatment of solid tumor；The III phase clinic that Enzastaurin is in treatment lymthoma is ground
Study carefully.Examples detailed above shows that staurosporine class compound has wide patent medicine prospect.
BRD4 albumen is under the jurisdiction of the BET subfamilies in bromine domain protein family, total length totally 1362 amino acid residues, its
First bromine domain of nitrogen end, i.e. BRD4 (44-168).It can identify the lysine with reference to acetylation modification, and therefore special
Property the nucleosome that regulating DNA methylates, chromatin reconstitution is related to translation posttranscriptional modification, so as to further controlling gene
Expression.BRD4 is a very potential drug targets, and a large amount of article reports show that BRD4 is tumour, HIV and leukaemia etc.
The very promising target spot of disease treatment.
The content of the invention
The present invention isolates and purifies to obtain 5 kinds of staurosporine class compounds by studying actinomyces.
A kind of application of staurosporine class compound in the medicine for preparing treating cancer, inflammation or AIDS, the star
The structural formula of spore bacteriums compound is Formulas I or the structure of formula II：
R1=H or Me；
R2=OH, N (Me) COH or N (Me) COMe；
R3=O or NOH.
The structural formula of the staurosporine class compound is one kind in following five kinds：
The cancer is prostate cancer, colon cancer, non-small cell lung cancer, leukaemia, liver cancer, kidney, thyroid cancer, skin
Cancer, cancer of pancreas, oophoroma, breast cancer, celiothelioma or Peripheral Nerve Sheath Tumours.
The cancer is prostate cancer.
The inflammation is arthritis or dermatitis.
Invention further provides a kind of application of staurosporine class compound in Brd4 protein inhibitors are prepared, the star
The structural formula of spore bacteriums compound is Formulas I or the structure of formula II：
R1=H or Me；
R2=OH, N (Me) COH or N (Me) COMe；
R3=O or NOH.
Brd4 albumen is the very promising target spot of the disease treatments such as tumour, HIV and leukaemia, illustrates the compounds of this invention
Had a good application prospect in the medicine for preparing the diseases such as treatment tumour, HIV and leukaemia.
The structural formula of the staurosporine class compound is one kind in following five kinds：
The compounds of this invention is identified as staurosporine class compound, passed through to isolate and purify to obtain from a kind of actinomyces
Functional study finds that these compound on prostate cancer cells have higher activity, while also has to Brd4 albumen higher
Inhibitory action, it is good to illustrate that the compounds of this invention has in terms of the medicine for the treatment of tumour, HIV, the disease such as leukaemia is prepared
Application prospect.
Brief description of the drawings
Fig. 1 is the structural formula schematic diagram of compound 1.
Fig. 2 is the structural formula schematic diagram of compound 2.
Fig. 3 is the structural formula schematic diagram of compound 3.
Fig. 4 is the structural formula schematic diagram of compound 4.
Fig. 5 is the structural formula schematic diagram of compound 5.
Embodiment
Strain source
Actinomyces are streptomycete (Streptomyces sp.), and preserving number is CICC No.172617, and purchase is from positioned at north
The Chinese industrial Microbiological Culture Collection administrative center (CICC) in No. 6 building of No. 24 institutes in Jing Shi Chaoyang Districts winebibber's bridge Road, order net
Location：http://www.china-cicc.org/.
Culture medium
Gause I fluid nutrient medium：In terms of fermentation medium 1L, soluble starch 20g, KNO31g, K2HPO40.5g,
MgSO4·7H2O 0.5g, NaCl 0.5g, FeSO4·7H2O 0.01g, 1L is added water to, adjust pH 7.2.
Gause I solid medium：In terms of fermentation medium 1L, soluble starch 20g, KNO31g, K2HPO40.5g,
MgSO4·7H2O 0.5g, NaCl 0.5g, FeSO4·7H2O 0.01g, 12g agar, 1L is added water to, adjust pH 7.2.
Rice medium：Rice and sea salt water press following mass volume ratio：Rice 40g, 25% sea salt water 60mL are that is, big
Rice: 25% sea salt water=40g: 60mL.
Embodiment 1
1st, seed liquor
Above-mentioned streptomycete is inoculated in the 500mL conical flasks containing 250mL fluid nutrient mediums, every bottle of Gao Shi containing 250mL
No.1 fluid nutrient medium, seed liquor was obtained with 180rpm shaken cultivations 4 days at 28 DEG C in shaking table.
2nd, ferment
Above-mentioned seed liquor is inoculated into rice fermentation culture medium with every bottle of inoculation 8mL amount (to be made up of following components by weight percent：
Rice 40g, 25% sea salt water 60mL) in, 28 DEG C of quiescent cultures terminate fermentation after 60 days.
3rd, slightly carry
Every bottle of solid fermentation thing EA (ethyl acetate) about 300mL soaked overnights, three layers of filtered through gauze remove mycelium, received
Collect filtrate, be concentrated under reduced pressure to obtain crude extract (oily medicinal extract).
4th, isolate and purify
Crude extract is dissolved with 90% methanol-water, and after isometric petroleum ether extraction three times, 90% methanol-water, which mutually depressurizes, to be concentrated to give
To alcohol phase, after methanol is mutually dissolved with methanol, after 1200rpm centrifuges 8min, entered using Sephadex LH-20 gel column chromatographies
Row separation, eluting solvent are the aqueous solution of volume fraction containing methanol 20%~100%, are merged similar flow point after TLC analyses, altogether
Obtain 14 component Fr.A~Fr.N.
Preparative liquid chromatography gradient elution 210min is pressed in Fr.J (365.0mg) warps, and (eluting solvent is the body of acid adding containing methanol
The aqueous solution of fraction 50%~100%, flow velocity 10mL/min, Detection wavelength 292nm), a flow point is connect every 10min,
Similar flow point is merged to obtain 3 component Fr.J-1~Fr.J-3 after TLC analyses.Fr.J-3 washes through high pressure preparative liquid chromatography gradient
(eluting solvent is the aqueous solution of volume fraction containing acetonitrile 40%~60%, flow velocity 10mL/min, and Detection wavelength is by de- 70min
292nm), compound 1 (1.5mg, t are obtainedR=29min), 4 (6.2mg, tR=43min) and 5 (9.5mg, tR=45min).
Preparative liquid chromatography gradient elution 210min is pressed in Fr.I (299.8mg) warps, and (eluting solvent is the body of acid adding containing methanol
The aqueous solution of fraction 50%~100%, flow velocity 10mL/min, Detection wavelength 292nm), a flow point is connect every 10min,
Similar flow point is merged to obtain 3 component Fr.I-1~Fr.I-3 after TLC analyses.Fr.I-2 washes through high pressure preparative liquid chromatography gradient
(eluting solvent is the aqueous solution of volume fraction containing acetonitrile 40%~60%, flow velocity 10mL/min, and Detection wavelength is by de- 60min
292nm), compound 2 (2.5mg, t are obtainedR=33min) and 3 (1.2mg, tR=22min).
Embodiment 2
(1) Structural Identification of compound 1
White powder (CH3OH), there is bluish violet fluorescence under ultraviolet light.According to1H and13C NMR datas speculate that its molecular formula is
C29H26N4O4,1H NMR(CD3OD, 400MHz)：δH7.26 (1H, d, J=7.8Hz, H-1), 7.49 (1H, br t, H-2), 7.39
(1H, br t, H-3), 9.43 (1H, d, J=7.9Hz, H-4), 5.03 (1H, d, J=14.7Hz, H-7a), 5.04 (1H, d, J=
14.7Hz, H-7b), 7.93 (1H, d, J=7.8Hz, H-8), 7.36 (1H, br t, H-9), 7.50 (1H, br t, H-10),
7.76 (1H, d, J=7.9Hz, H-11), 4.02 (1H, d, J=2.0Hz, H-3 '), 5.02 (1H, m, H-4 '), 2.52 (1H, d, J
=4.4Hz, H-5 ' a), 2.68 (1H, m, H-5 ' b), 6.75 (1H, dd, J=6.2＆7.1Hz, H-6 '), 2.52 (3H, s, H-2 '-
CH3), 3.42 (3H, s, H-3 '-OCH3), 2.86 (3H, s, H-N-CH3), 8.14 (1H, s, H-1 "),13C NMR(CD3OD,
100MHz)：δC107.8 (C-1), 125.6 (C-2), 120.4 (C-3), 126.8 (C-4), 123.6 (C-4a), 116.5 (C-
4b), 119.0 (C-4c), 173.3 (C-5), 46.2 (C-7), 132.6 (C-7a), 114.7 (C-7b), 124.7 (C-7c),
121.7 (C-8), 120.8 (C-9), 125.2 (C-10), 112.4 (C-11), 138.6 (C-11a), 130.7 (C-12a), 126.6
(C-12b), 136.7 (C-13a), 94.5 (C-2 '), 84.7 (C-3 '), 47.7 (C-4 '), 27.7 (C-5 '), 82.4 (C-6 '),
29.2(C-2’-CH3), 60.5 (C-3 '-OCH3), 163.5 (C-1 "), 32.4 (N-CH3).According to above-mentioned data inspection document, really
It is N-Formyl-staurosporine to determine compound 1, and structural formula is as shown in Figure 1.
(2) Structural Identification of compound 2
White powder (CH3OH), there is bluish violet fluorescence under ultraviolet light.1H NMR(CD3OD, 400MHz)：δH7.33 (1H, d,
J=8.1Hz, H-1), 7.42 (1H, br t, H-2), 7.26 (1H, br t, H-3), 9.24 (1H, d, J=7.9Hz, H-4),
4.89 (1H, d, J=17.7Hz, H-7a), 4.92 (1H, d, J=17.7Hz, H-7b), 7.94 (1H, d, J=7.9Hz, H-8),
7.33 (1H, br t, H-9), 7.47 (1H, br t, H-10), 7.87 (1H, d, J=8.5Hz, H-11), 4.05 (1H, t, J=
2.0Hz, H-3 '), 5.10 (1H, ddd, J=13.6＆5.1＆2.0Hz, H-4 '), 2.37 (1H, m, H-5 ' a), 2.62 (1H, m, H-
5 ' b), 6.69 (1H, dd, J=8.9＆4.8Hz, H-6 '), 2.43 (3H, s, H-2 '-CH3), 2.41 (3H, s, H-3 '-OCH3),
2.82 (3H, s, H-N-CH3), 2.12 (3H, s, H-COCH3).According to above-mentioned data inspection document, it is N- to determine compound 2
Acetyl-staurosporine, structural formula are as shown in Figure 2.
(3) Structural Identification of compound 3
White powder (CH3OH), there is bluish violet fluorescence under ultraviolet light.1H NMR(CD3OD, 400MHz)：δH7.50 (1H, d,
J=7.0Hz, H-1), 7.47 (1H, br t, H-2), 7.29 (1H, br t, H-3), 9.26 (1H, d, J=8.1Hz, H-4),
5.06 (1H, d, J=17.7Hz, H-7a), 5.07 (1H, d, J=17.7Hz, H-7b), 8.06 (1H, d, J=9.2Hz, H-8),
7.36 (1H, br t, H-9), 7.49 (1H, br t, H-10), 8.03 (1H, d, J=8.7Hz, H-11), 4.49 (1H, d, J=
3.7Hz, H-3 '), 4.28 (1H, m, H-4 '), 2.65 (1H, m, H-5 ' a), 2.65 (1H, m, H-5 ' b), 6.79 (1H, dd, J=
3.8＆6.8Hz, H-6 '), 2.37 (3H, s, H-2 '-CH3).According to above-mentioned data inspection document, it is defined as the structure of compound 3
Formula is as shown in Figure 3.
(4) Structural Identification of compound 4
Pale yellow powder (CH3OH), there is bluish violet fluorescence under ultraviolet light.According to1H and13C NMR datas speculate its molecular formula
For C27H22N4O4。1H NMR(DMSO–d4, 400MHz)：δH7.72 (1H, d, J=8.2Hz, H-1), 7.45 (1H, br t, H-2),
7.31 (1H, br t, H-3), 9.30 (1H, d, J=7.9Hz, H-4), 4.96 (2H, s, H-7a), 8.02 (1H, d, J=8.6Hz,
H-8), 7.32 (1H, br t, H-9), 7.50 (1H, br t, H-10), 7.98 (1H, d, J=7.8Hz, H-11), 4.75 (1H, s,
H-3 '), 3.02 (1H, dd, J=5.6＆14.4Hz, H-5 ' a), 3.62 (1H, d, J=14.4Hz, H-5 ' b), 7.05 (1H, d, J
=5.2Hz, H-6 '), 2.47 (3H, s, H-2 '-CH3), 3.42 (3H, s, H-3 '-OCH3), 10.45 (1H, s, H-N-OH),13C
NMR((DMSO–d4, 100MHz)：δC109.0 (C-1), 125.3 (C-2), 119.6 (C-3), 125.7 (C-4), 122.9 (C-
4a), 115.0 (C-4b), 119.2 (C-4c), 171.8 (C-5), 45.4 (C-7), 132.3 (C-7a), 114.1 (C-7b),
123.9 (C-7c), 120.8 (C-8), 120.2 (C-9), 124.7 (C-10), 115.7 (C-11), 139.9 (C-11a), 128.1
(C-12a), 124.6 (C-12b), 136.0 (C-13a), 96.3 (C-2 '), 83.6 (C-3 '), 145.2 (C-4 '), 29.8 (C-
5 '), 82.3 (C-6 '), 28.7 (C-2 '-CH3), 58.4 (C-3 '-OCH3).According to above-mentioned data inspection document, compound 4 is determined
It is as shown in Figure 4 for TAN-1030A, structural formula.
(5) Structural Identification of compound 5
Pale yellow powder (CH3OH), there is bluish violet fluorescence under ultraviolet light.1H NMR(CDCl3, 400MHz)：δH7.27 (1H,
D, J=8.5Hz, H-1), 7.43 (1H, br t, H-2), 7.33 (1H, br t, H-3), 9.41 (1H, d, J=7.9Hz, H-4),
4.97 (2H, s, H-7a), 7.95 (1H, d, J=8.6Hz, H-8), 7.39 (1H, br t, H-9), 7.50 (1H, br t, H-10),
7.84 (1H, d, J=7.7Hz, H-11), 4.55 (1H, s, H-3 '), 3.60 (1H, dd, J=7.0＆14.0Hz, H-5 ' a), 3.62
(1H, d, J=14.0Hz, H-5 ' b), 7.09 (1H, d, J=7.0Hz, H-6 '), 2.57 (3H, s, H-2 '-CH3), 3.57 (3H,
S, H-3 '-OCH3).According to above-mentioned data inspection document, it is Des (hydroxyimino)-TAN-1030A to be defined as compound 5,
Structural formula is as shown in Figure 5.
Embodiment 3
The proliferation inhibition test of Human carcinoma of prostate cell line PC3 cell.
Take the logarithm the cell in growth period, be configured to 5 × 104Individual/mL, 96 well culture plates, CO are laid on 100 μ L/ holes2Culture
Cultivated 24 hours in case, take out culture plate and set 3 multiple holes after the testing sample that various concentrations are added in every hole, each concentration,
After the completion of dosing, CO is placed in2Culture plate is taken out after continuing culture in incubator 72 hours, discards nutrient solution, 100 μ are added per hole
10% trichloroacetic acid (TCA) of L4 DEG C of refrigerator precooling is fixed, and standing moves to 4 DEG C of refrigerator overnights after 5 minutes, then by culture plate.
Fixer is outwelled, is washed with deionized 5 times per hole, dries, is air-dried.70 μ L SRB solution are added per hole, room temperature is placed
20 minutes, supernatant is removed, is washed 5 times, is air-dried with 1% acetic acid.With reference to SRB with 100 μ L/ holes 10mmol/L Tris alkali
Liquid (pH=10.5) vibration dissolving.It is placed in ELIASA and determines each hole light absorbs, measure wavelength is 515nm.According to each hole OD values
Calculate medicine cell proliferation inhibiting rate：Inhibiting rate=[1- (OD515 dosing holes/OD515 control wells)] × 100%, suppressed according to each concentration
Rate calculation of half inhibitory concentration IC50。
As a result the IC of each compound50Value is as shown in table 1.
Table 1
| Compound | IC50(μg/mL) |
| 1 | 1.72 |
| 2 | 2.03 |
| 3 | 5.24 |
| 4 | 9.84 |
| 5 | 10.14 |
Embodiment 4
Using BRD4bromodomain 1TR-FRET assay kit (Cisbio), determined with (+)-JQ1 positions positive drug
Inhibitory activity of each compound to BRD4 albumen.TR-FRET values are by determining BRD4 albumen after 340nm ultraviolet excitations
620nm and 665nm fluorescence ratio obtains, i.e. TR-FRET values T=[F665nm/F620nm] × 104.BRD4 albumen % suppresses
Rate=((T is to be measured)-(Tmin))/((Tmax)-(Tmin)) × 100, Tmax is the TR-FRET values of reaction solution, and Tmin is not have
The blank reaction solution TR-FRET values of BRD4 albumen.Each compound is 10 μ g/mL to the inhibiting rate of Brd4 albumen respectively such as in concentration
Shown in table 2.
Table 2
| Compound | Inhibiting rate % |
| 1 | 41% |
| 2 | 37% |
| 3 | 5% |
| 4 | 33% |
| 5 | 60% |
Claims (7)
1. a kind of application of staurosporine class compound in the medicine for preparing treating cancer, inflammation or AIDS, the star spore
The structural formula of bacteriums compound is Formulas I or the structure of formula II：
R1=H or Me；
R2=OH, N (Me) COH or N (Me) COMe；
R3=O or NOH.
2. application as claimed in claim 1, it is characterised in that the structural formula of the staurosporine class compound is following five kinds
In one kind：
3. application as claimed in claim 1, it is characterised in that the cancer is prostate cancer, colon cancer, non-small cell lung
Cancer, leukaemia, liver cancer, kidney, thyroid cancer, cutaneum carcinoma, cancer of pancreas, oophoroma, breast cancer, celiothelioma or peripheral nerve sheath
Film knurl.
4. application as claimed in claim 3, it is characterised in that the cancer is prostate cancer.
5. application as claimed in claim 1, it is characterised in that the inflammation is arthritis or dermatitis.
6. a kind of application of staurosporine class compound in Brd4 protein inhibitors are prepared, the staurosporine class compound
Structural formula is Formulas I or the structure of formula II：
R1=H or Me；
R2=OH, N (Me) COH or N (Me) COMe；
R3=O or NOH.
7. application as claimed in claim 6, it is characterised in that the structural formula of the staurosporine class compound is following five kinds
In one kind：
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299467A (en) * | 2018-02-27 | 2018-07-20 | 中国海洋大学 | Indole carbazole Alkaloid with cytotoxic activity and preparation method, purposes |
| CN110498801A (en) * | 2019-09-19 | 2019-11-26 | 杭州科兴生物化工有限公司 | A kind of staurosporine analog derivative and its preparation method and application |
| CN114437109A (en) * | 2022-03-08 | 2022-05-06 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Halogenated derivative of staurosporine, preparation method and application thereof |
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| JPH01246288A (en) * | 1987-11-25 | 1989-10-02 | Takeda Chem Ind Ltd | Tan-1030a and its derivative, production and use thereof |
| CN101505760A (en) * | 2006-06-23 | 2009-08-12 | 诺瓦提斯公司 | Combinations comprising staurosprorines |
| CN102348708A (en) * | 2009-03-11 | 2012-02-08 | 奥克兰联合服务有限公司 | Prodrug forms of kinase inhibitors and their use in therapy |
| 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 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01246288A (en) * | 1987-11-25 | 1989-10-02 | Takeda Chem Ind Ltd | Tan-1030a and its derivative, production and use thereof |
| CN101505760A (en) * | 2006-06-23 | 2009-08-12 | 诺瓦提斯公司 | Combinations comprising staurosprorines |
| CN102348708A (en) * | 2009-03-11 | 2012-02-08 | 奥克兰联合服务有限公司 | Prodrug forms of kinase inhibitors and their use in therapy |
| 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 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299467A (en) * | 2018-02-27 | 2018-07-20 | 中国海洋大学 | Indole carbazole Alkaloid with cytotoxic activity and preparation method, purposes |
| CN110498801A (en) * | 2019-09-19 | 2019-11-26 | 杭州科兴生物化工有限公司 | A kind of staurosporine analog derivative and its preparation method and application |
| CN114437109A (en) * | 2022-03-08 | 2022-05-06 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Halogenated derivative of staurosporine, preparation method and application thereof |
| CN114437109B (en) * | 2022-03-08 | 2023-09-29 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Philippine halogenated derivative and preparation method and application thereof |
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Application publication date: 20180112 |