CN101342158A - Application of two bromine phenolic compounds in preparing medicament for treating malignant tumor - Google Patents
Application of two bromine phenolic compounds in preparing medicament for treating malignant tumor Download PDFInfo
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- CN101342158A CN101342158A CNA2007100152964A CN200710015296A CN101342158A CN 101342158 A CN101342158 A CN 101342158A CN A2007100152964 A CNA2007100152964 A CN A2007100152964A CN 200710015296 A CN200710015296 A CN 200710015296A CN 101342158 A CN101342158 A CN 101342158A
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Abstract
The invention relates to a medicine for treating malignant tumor, in particular to an application of two bromophenol compounds to the preparation of the medicine for treating malignant tumor. The bromophenol compounds of the invention and the derivatives thereof such as salt, ester, aether, etc. have favorable inhibition effect on protein tyrosine kinase, and thus can be used for preventing and treating the malignant tumor of high expression C-kit receptor.
Description
Technical field
The present invention relates to treat the medicine of malignant tumor, specifically the preparation method of two kinds of ocean bromine phenol compounds, pharmacologically active, purposes and pharmaceutically acceptable salt, ester, ether and other tangible chemical equivalence thing; (protein tyrosinekinase, PTK) inhibitor can be used for treating the malignant tumor of various high expressed C-kit receptors as protein tyrosine kinase for this chemical compound and derivant thereof.
Background technology
Along with the development that molecular weight tumor is learned, the research of antitumor drug also acts on the newtype drug of molecular target from traditional cell toxicity medicament trend.Protein tyrosine kinase (PTK) is one of target of treatment of cancer, proto-oncogene C-kit is the congener of HZ4 cat family sarcoma virus kit oncogene, be positioned at No. 4 chromosomes long-armed on, the coding 145-165kDa transmembrane receptor (CD117), have tyrosine kinase activity.Its product is an III type tyrosine protein kinase growth factor receptors, its similar is in M-CSF and platelet-derived thing growth factor receptors, belong to the immunoglobulin superfamily member, have outer 5 the immunoglobulin-like similar structures of born of the same parents ligand binding domain, stride membrane-proximal region and tyrosine protein kinase district in film district, the film.In normal structure, C-kit albumen is expressed at mastocyte, Interstitial cell, melanocyte and galactophore epithelial cell.The autocrine of C-kit signal path and paracrine stimulate the generation of participant's tumor, and play the effect of oncogene in kinds of tumors.C-kit albumen is somatomedin and stem cell factor (SCF) receptor, and the interaction between it and part stem cell factor can activate intrinsic tyrosine kinase, makes the intracellular protein phosphorylation thereupon, causes the activation of signal transduction path in the cell.Proto-oncogene C-kit sudden change can cause that the proteic extracellular fragment of C-kit or born of the same parents' inner segment change, cause C-kit protein receptor continuous openness, the continuous autophosphorylation of various substrate proteins, make the conducted signal cascade of characteristics such as regulating cell differentiation, propagation, apoptosis, chemotactic and adhesion discharge and expansion, promoted the cell growth by this approach, suppressed apoptosis, the normal biological characteristics of cell disappears and develops into tumor cell.The oncogenic potential of C-kit is confirmed in many experiments, discoveries such as Hines, transfection the MCF-7 breast cancer cell of the C-kit growth and the multiplication rate that tie up in the culture medium speed, and this propagation can be prevented by anti-C-kit antibody; Caruana etc. to transfection the reorganization NIH3T3 fibroblast of C-kit gene cultivate, find that the activation of C-kit can promote cell proliferation and produce the Phenotype of a variation that this has obtained confirmation in cell clone and nude mice tumor model.In recent years, more and more researchers research is sought the small molecular protein tyrosine kinase inhibitor, thereby is developed new type anticancer medicine efficiently about the tumor of C-kit receptor as molecule target treatment high expressed C-kit receptor.
From modern medicines research and development historical as seen, the Application and Development of each original new drug, at first from the discovery of certain class new type natural lead compound, the ocean is origin of life ground, in the unique ecological environment of ocean, Sargassum can produce some very distinctive active substances mostly.The inventor obtains the bromine phenolic compound of two novel structures from a kind of marine red alga, active testing shows that it has very strong inhibition activity to the PTK enzyme, can be used for the control of the malignant tumor of high expressed C-kit receptor, comprise gastrointestinal stromal tumor (GIST), Mastocytosis type leukemia, germ cell tumor, small cell lung cancer, acute leukemia, neuroblastoma, melanoma, ovarian cancer and breast carcinoma etc.
Summary of the invention
The object of the invention has provided two kinds of bromine phenols medicine application in preparation treatment high expressed C-kit receptor malignant tumor medicine, derivants such as bromine phenolic compound and salt thereof, ester and ether have good inhibitory effect to protein tyrosine kinase, can be used for the control of the malignant tumor of high expressed C-kit receptor.
For achieving the above object, the technical solution used in the present invention is:
Two kinds have acceptable salt, ester, ether and other tangible chemical equivalence thing on protein tyrosine kinase (PTK) active ocean bromine phenol compounds of inhibition and the materia medica thereof, can be used for the control of the malignant tumor of high expressed C-kit receptor.
The bromine phenolic compound structure is as follows respectively:
3-bromo-4-[3-bromo-4, the 5-dihydroxy phenyl] methyl-5-(ethyoxyl)-1, the 2-biphenol
3-bromo-4-[3-bromo-4，5-dihydroxyphenyl]
methyl-5-(ethoxymethyl)-1，2-benzenediol
5R, 10R-2,7-two bromo-3,8-dihydroxy-5,10-dimethoxy-5,10-dihydro-.alpha.-5:6-benzopyran is also
[5,4,3-cde] .alpha.-5:6-benzopyran
5R，10R-2，7-dibromo-3，8-dihydroxy-5，10-dimethoxyl-5，10-dihydro-chromen
o[5，4，3-cde]chromene
The extraction of bromine phenolic compound, separation and structure are identified:
Air-dry multitube algae sample is pulverized back 95% ethanol extraction, extracting solution concentrating under reduced pressure; Concentrate adopts ethyl acetate extraction, concentrating under reduced pressure after suspending with distilled water.Silica gel column chromatography is carried out at the ethyl acetate extraction position, with petroleum ether-acetone gradient elution, is 1: 1 until the two volume ratio, use the chloroform-methanol gradient elution instead, use 95% ethanol elution at last, the thin layer chromatography inspection, be merged into eluent like the phase-splitting, concentrating under reduced pressure gets 8 partial L
1～L
8Get L4 and partly go up silicagel column, with chloroform-acetone gradient elution, the thin layer chromatography inspection is merged into eluent like the phase-splitting, and concentrating under reduced pressure gets 3 part F
1～F
3
Get F
2Silicagel column on the part, carry out eluting with chloroform-methanol, and get The compounds of this invention 1 with gel Sephadex-LH 20 purification, through Spectrum Analysis, this chemical compound is: 3-bromo-4-[3-bromo-4,5-dihydroxyphenyl] methyl-5-(ethoxymethyl) 1,2-benPTP1Benediol (English); 3-bromo-4-[3-bromo-4, the 5-dihydroxy phenyl] methyl-5-(ethyoxyl)-1,2-biphenol (Chinese).
Get F1 and partly go up silicagel column, carry out eluting, and get The compounds of this invention 2, through Spectrum Analysis with gel Sephadex-LH20 purification with petroleum ether-acetone, this chemical compound is: 5R, 10R-2,7-dibromo-3,8-dihydroxy-5,10-dimethoxyl-5,10-dihydro-chromeno[5,4,3-cde] chromene (English), 5R, 10R-2,7-two bromo-3,8-dihydroxy-5,10-dimethoxy-5,10-dihydro-.alpha.-5:6-benzopyran is [5,4,3-cde] .alpha.-5:6-benzopyrans (Chinese) also.
Above-claimed cpd has following physicochemical property:
Chemical compound 1 waxy solid; Ultraviolet spectra UV (MeOH) λ
Max(log ε) 289.50 (3.76), 207.50 (4.76) nm; Infrared spectrum IR (KBr) v
Max3388 (OH), 2924,2870,1662,1608,1583,1490,1427,1348,1284,1095,981,754cm
-1. Low Resolution Mass Spectra EIMS m/z (%) 450,448,446[M]
+(1.5,3,1.5), 404 (43), 402 (86), 400 (43), 387 (20), 385 (40), 383 (20), 323 (52), 221 (52), 277 (18), 275 (18), 242 (100), 213 (18), 139 (10), 121 (18), 57 (11). high resolution mass spectrum HREIMS m/z 445.9357 (value of calculation C
16H
16 79Br
2O
5445.9364). nuclear magnetic resonance, NMR
1H NMR (500MHz, acetone-d
6) data: 3.43 (2H, q, J=7.2, CH
2-9), 1.10q (3H, t, J=7.2, CH
3-10), 4.32 (2H, s, CH
2-8), 4.08 (2H, s, CH
2-7), 6.49 (1H, d, J=2.4, CH-6 '), 6.73 (1H, d, J=2.4, CH-2 '), 6.97 (1H, s, CH-6). nuclear magnetic resonance, NMR
13C NMR (125MHz, acetone-d
6) data: 133.1 (s, C-1 '), 123.2 (d, C-2 '), 109.6 (s, C-3 '), (141.4 s, C-4 '), 146.1 (s, C-5 '), 114.7 (d, C-6 '), 36.1 (t, C-7), 129.7 (s, C-4), 114.5 (s, C-3), 142.9 (s, C-2), 144.2 (s, C-1), 115.8 (d, C-6), 130.5 (s, C-5), 70.9 (t, C-8), 65.7 (t, C-9), 15.1 (q, C-10).
Chemical compound 2 colourless prisms (petroleum ether/acetone 3: 1); Mp 188.5-189.5 ℃, UV
Max(MeOH): 229.0 (log ε 4.65), 289.0 (4.35), 318.5 (3.89) nm; Infrared spectrum IR (KBr) v
Max: 3491,2920,1618,1479,1419,1342,1242,1093,1018,955,928,879cm
-1. Low Resolution Mass Spectra EIMS m/z (%) 462,460,458 (M+, 18%/36%/18%), 431 (50), 429 (100), 399 (37), 397 (74), 395 (37), 149 (8); High resolution mass spectrum HREIMS m/z457.9003 (M+), (value of calculation C
16H
12 79Br
2O
6457.9001). nuclear magnetic resonance, NMR
1H NMR (500MHz, acetone-d
6) data: 3.55 (6H, s, OCH
3), 6.22 (2H, s, CH-5, CH-10), 7.32 (2H, s, CH-1, CH-6), 9.10 (2H, s, OH). nuclear magnetic resonance, NMR
13C NMR (125MHz, acetone-d
6) data: 56.0 (q, OCH
3), 123.6 (d, C-1), 109.9 (s, C-2), 144.4 (s, C-3), 136.2 (s, C-3a), 99.2 (d, C-5), 113.8 (s, C-5a), 123,6 (d, C-6), 109.9 (s, C-7), 144.4 (s, C-8), 136.2 (s, C-8a), 99.2 (d, C-10), 113.8 (s, C-10a), 120.4 (s, C-10b), 120.4 (s, C-10c).
Tyrosine kinase activity suppresses active testing:
Adopt enzyme-linked immunosorbent assay (ELISA), receptor kinase is C-kit, positive control medicine Glivic (imatinib mesylate).
The vicious transformation of cell and growth are relevant with tyrosine kinase expression in the cell, and tyrosine kinase inhibitor can be blocked those growths that has tyrosine kinase overexpression and the active tumor cell that increases, and suppress the propagation of tumor cell.The most cells growth factor receptors contains the peptide chain-ordering of tyrosine kinase, so this receptoroid is commonly referred to as tyrosine kinase receptor.According to the similarity and the construction features of peptide chain-ordering, these receptors are divided into some families: the 1st class is representative with epithelial growth factor receptor (EGFR), and the high expressed of this receptoroid is common in the epithelial cell tumor; The 2nd class is an Insulin Receptor Family, comprises Insulin receptor INSR, IGF-1 (IGF-R) and insulin associated receptor (IRR) etc., the high expressed of common this receptoroid in the blood cell tumor; The 3rd class is platelet-derived growth factor receptors (PDGFR) family, comprises PDGFR α, PDGF β, and clone's stimulating factor (CSF-1a), C-kit etc., this receptoroid is common high expressed in the cerebral tumor and blood cell tumor etc.; The 4th class is bfgf receptor (FGFR) family, includes FGFR1, FGFR2, and FGFR3, FGFR4 and keratinocyte growth factor receptor etc., this receptoroid plays an important role aspect angiogenesis; The 5th class is vascular endothelial growth factor receptor (VEGFR), is the important positivity regulatory factor of angiogenesis; In addition, also have C-MET HGFr (HGFR) class, Fibroneetin III receptor class and nerve growth factor acceptor (NGFR) family etc.
The C-kit receptor is as type iii protein tyrosine kinase receptor superfamily member, utilize protein tyrosine kinase inhibitor can suppress the kinds of tumors that its kinase activity is treated high expressed C-kit receptor, by effect C-kit receptor, suppress the tyrosine receptor phosphorylation, suppress the tyrosine kinase abnormal activation, thereby suppress the kinds of tumors of high expressed C-kit receptor effectively.
The present invention has following advantage: (1), source are abundant: China is ocean big country, has abundant living marine resources.(2), evident in efficacy: as the multi-halogenated compounds that has the ocean characteristic, bromine phenols medicine is a kind of novel, tyrosine kinase inhibitor efficiently, shows significant antitumor curative effect in the mice body.(3), side effect is little: bromine phenols medicament sources Yu Haiyang Sargassum, the genus pure natural biological product is compared chemosynthesis class medicine and is had the advantage of high-efficiency low-toxicity.
The specific embodiment
The extraction of embodiment 1 bromine phenolic compound, separation and structure are identified
Gather and air-dry marine organisms multitube algae (Polysiphonia urceolata) sample 9.6kg (dry weight), use 10L 95% ethanol extraction three times, each 72 hours; Merge lixiviating solution, the ethanol extraction 310g of 40 ℃ of following concentrating under reduced pressure of extracting solution, concentrate adopt the equal-volume ethyl acetate extraction after suspending with 10 times of weight distilled water, and concentrating under reduced pressure gets ethyl acetate phase extractum 100g.Silica gel column chromatography is carried out at the ethyl acetate extraction position, with petroleum ether-acetone gradient elution (volume ratio was from 500: 1 to 1: 1), use chloroform-methanol gradient elution (volume ratio was from 20: 1 to 1: 1) instead, use 95% ethanol elution at last, thin layer chromatography is checked, be merged into eluent like the phase-splitting, concentrating under reduced pressure gets 8 partial L
1～L
8L
4[petroleum ether: acetone volume ratio=3: 1] eluting is partly gone up silicagel column, carries out eluting with chloroform-acetone (volume ratio 9: 1), and the thin layer chromatography inspection is merged into eluent like the phase-splitting, and concentrating under reduced pressure gets 3 part F
1～F
3
Get F
2Silicagel column on the part, carry out eluting with chloroform-methanol (volume ratio 15: 1), and get The compounds of this invention 1 (52 milligrams) with gel Sephadex-LH 20 (methanol-eluted fractions) purification, through Spectrum Analysis, this chemical compound is: 3-bromo-4-[3-bromo-4,5-dihydroxyphenyl] methyl-5-(ethoxymethyl) 1,2-benPTP1Benediol (English); 3-bromo-4-[3-bromo-4, the 5-dihydroxy phenyl] methyl-5-(ethyoxyl)-1,2-biphenol (Chinese).
Get F
1Silicagel column on the part, carry out eluting with petroleum ether-acetone (volume ratio 4: 1), and get The compounds of this invention 2 (62 milligrams) with gel Sephadex-LH 20 purification, through Spectrum Analysis, this chemical compound is: 5R, 10R-2,7-dibromo-3,8-dihydroxy-5,10-dimethoxyl-5,10-dihydro-chromeno[5,4,3-cde] chromene (English), 5R, 10R-2,7-two bromo-3,8-dihydroxy-5,10-dimethoxy-5,10-dihydro-.alpha.-5:6-benzopyran also [5,4,3-cde] .alpha.-5:6-benzopyran (Chinese).
Embodiment 2 tyrosine kinase activities suppress the active property surveyed
Adopt the double-antibody sandwich elisa method.Press the explanation of C-kit test kit, compound sample is diluted to finite concentration (1 μ g/mL) to join in 96 orifice plates, except that blank well, add 100 μ L serum specimens respectively, add biotinylated antibody working solution 50 μ L again, hatch 60min in 25 ℃ behind the mixing, wash plate 4 times, respectively at the Avidin 100 μ L of each hole (comprising blank well) adding horseradish peroxidase labelling, hatch 30min in 25 ℃.Add substrate colour developing liquid (OPD) 100 μ L behind each hole lucifuge incubated at room 15min, the absorbance value that every hole adds stop buffer (1.8N sulphuric acid) 100 μ L and places detector to measure 490nm immediately detects substrate phosphorylation.Positive control: Glivic (imatinib mesylate), can be competitively in conjunction with C-kit SRCA TP in conjunction with the territory, suppress the tyrosine receptor phosphorylation.
The suppression ratio (%) of table 1 pair protein hydroxyphenylaminopropionic acid kinase activity
Figure 1 Inhibition of protein tyrosine kinase
| Sample | Suppression ratio % concentration | Estimate |
| Compound 1 | 67.3(1μg/mL) | Inhibitory action is arranged |
| Compound 2 | 87.9(1μg/mL) | Inhibitory action is arranged |
| Positive control Glivic | 80(10μM/mL) | Inhibitory action is arranged |
[experiment conclusion]: bromine phenolic compound has good inhibitory effect to protein tyrosine kinase, can be used for the control of the malignant tumor of high expressed C-kit receptor.
Animal experiment in embodiment 3 bodies
1, experiment material
(1) tumor strain
B
16Melanoma cell, institute of materia medica, the Academy of Medical Sciences, Shandong pharmacological room provides.
(2) laboratory animal
Qingdao City's Experimental Animal Center provides C57BL/6 mice, male and female half and half, body weight 20 ± 2g, 6～8 ages in week.
2, test method
(1) mice B
16The modeling of melanoma mice with tumor
The B16 melanoma cell suspension concentration that incubation growth is vigorous is adjusted to 1 * 10
6/ mL in mice left side back subcutaneous injection B16 melanoma cell suspension 0.2mL/ only, finishes in the whole operation process 30min under the aseptic condition; Be divided into 4 groups behind the 24h at random, 10/group, male and female half and half divide cage to feed.
(2) grouping and administration
Organized by examination: 3-bromo-4-[3-bromo-4, the 5-dihydroxy phenyl] methyl-5-(ethyoxyl)-1,2-biphenol (1 group of medicine), 5R, 10R-2,7-two bromo-3,8-dihydroxy-5,10-dimethoxy-5,10-dihydro-.alpha.-5:6-benzopyran also [5,4,3-cde] .alpha.-5:6-benzopyran (2 groups of medicines) uses dimethyl sulfoxide (DMSO) dissolving of weight concentration 30% respectively, becomes corresponding administration concentration according to the 150mg/Kg dose dilution; Blank group (30% dimethyl sulfoxide); Positive controls (dacarbazine of 60mg/Kg).
From inoculating the 5th day, once a day, lumbar injection (i.p) administration is 14 days continuously, observes the mice growing state.Behind the last administration 24h, mice is put to death in the cervical vertebra dislocation, gets the tumor piece and weighs, and calculates the suppression ratio (tumour inhibiting rate) of tumor growth.
(3) index detects
Tumour inhibiting rate (%)=(the average tumor of the average tumor weight-experimental group of blank group is heavy)/average tumor of blank group heavy * 100%
See Table 2.The result shows that the average tumor weight average that medicine is 1 group, 2 groups is lower than the blank group, and the tumor that its Chinese medicine is 2 groups tumor heavy and positive controls is heavy all to have significance with blank group comparing difference.* represents with the blank group significant difference (P＜0.05) is arranged relatively in the table.
Table 2 mouse tumor heavily reach tumour inhibiting rate (± s, n=10)
Table 2 Weight of Tumor and Inhibition Ratios(±s，n＝10)
| Group | Tumor heavy (g) | Tumour inhibiting rate (%) |
| The blank group | 0.2842±0.0320 | -- |
| 1 group of medicine | 0.0785±0.0216 | 72.4 |
| 2 groups of medicines | 0.0366±0.0102 * | 87.1 |
| Positive controls | 0.0358±0.0121 * | 87.4 |
Claims (2)
1. two kinds of bromine phenolic compound application in preparation treatment malignant tumor medicine, it is characterized in that: described bromine phenolic compound is a 3-bromo-4-[3-bromo-4, the 5-dihydroxy phenyl] methyl-5-(ethyoxyl)-1,2-biphenol and/or 5R, 10R-2,7-two bromo-3,8-dihydroxy-5,10-dimethoxy-5,10-dihydro-.alpha.-5:6-benzopyran also [5,4,3-cde] acceptable salt, ester or ether on .alpha.-5:6-benzopyran and the materia medica thereof.
2. according to the described application of claim 1, it is characterized in that: described preparation treatment malignant tumor medicine is meant the malignant tumor medicine of the various high expressed C-kit receptors of preparation treatment.
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| CN101987813A (en) * | 2009-08-07 | 2011-03-23 | 中国科学院海洋研究所 | Chemical total synthesis method for type II anti-diabetic medicament hypnopyrine |
| CN102199157A (en) * | 2011-03-17 | 2011-09-28 | 鲁东大学 | Bromine-containing benzopyran compound and preparation and application thereof |
| CN102372609A (en) * | 2010-08-20 | 2012-03-14 | 中国科学院海洋研究所 | Method for preparing compound 2,3-dibromo-4,5-dyhydroxyl benzyl methyl ether |
| CN102911182A (en) * | 2012-10-12 | 2013-02-06 | 鲁东大学 | Bromophenol compound and application thereof |
| CN110183460A (en) * | 2019-04-30 | 2019-08-30 | 四川轻化工大学 | Dioscoreae septemlobae,rhizoma phenanthrene class compound and application and extracting method |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101987813A (en) * | 2009-08-07 | 2011-03-23 | 中国科学院海洋研究所 | Chemical total synthesis method for type II anti-diabetic medicament hypnopyrine |
| CN101987813B (en) * | 2009-08-07 | 2013-04-17 | 中国科学院海洋研究所 | Chemical total synthesis method for diabetes type II resistant medicament hypnopyrine |
| CN102372609A (en) * | 2010-08-20 | 2012-03-14 | 中国科学院海洋研究所 | Method for preparing compound 2,3-dibromo-4,5-dyhydroxyl benzyl methyl ether |
| CN102199157A (en) * | 2011-03-17 | 2011-09-28 | 鲁东大学 | Bromine-containing benzopyran compound and preparation and application thereof |
| CN102199157B (en) * | 2011-03-17 | 2013-04-17 | 鲁东大学 | Bromine-containing benzopyran compound and preparation and application thereof |
| CN102911182A (en) * | 2012-10-12 | 2013-02-06 | 鲁东大学 | Bromophenol compound and application thereof |
| CN102911182B (en) * | 2012-10-12 | 2014-12-10 | 鲁东大学 | Bromophenol compound and application thereof |
| CN110183460A (en) * | 2019-04-30 | 2019-08-30 | 四川轻化工大学 | Dioscoreae septemlobae,rhizoma phenanthrene class compound and application and extracting method |
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