CN103113335B - Benzoquinone compound and use thereof for preparing anti-tumour drug - Google Patents
Benzoquinone compound and use thereof for preparing anti-tumour drug Download PDFInfo
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- CN103113335B CN103113335B CN201110366276.8A CN201110366276A CN103113335B CN 103113335 B CN103113335 B CN 103113335B CN 201110366276 A CN201110366276 A CN 201110366276A CN 103113335 B CN103113335 B CN 103113335B
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- arnebinone
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Abstract
The invention belongs to the field of pharmacy and relates to a benzoquinone compound and use thereof for preparing an anti-tumour drug, in particular to preparation of Arnebinone B and use thereof for resisting lung cancer, prostatic cancer and nasopharynx cancer. The benzoquinone compound provided by the invention is Arnebinone B, which is separated from arnebiae. In-vitro anti-tumour activity experimental results show that the median inhibitory concentration of Arnebinone B on lung carcinoma cell A549 is 4.86 mu g/ml, the median inhibitory concentration of Arnebinone B on prostate cancer cell DU145 is 5.16 mu g/ml, the median inhibitory concentration of Arnebinone B on nasopharyngeal carcinoma cell KB is 5.2 mu g/ml, and the median inhibitory concentration of Arnebinone B on KB drug-resistant strain KB-VIN is 4.98 mu g/ml. The result shows that Arnebinone B can be used for preparing the anti-tumour drug, in particular drugs for treating lung cancer, prostatic cancer and nasopharynx cancer.
Description
Technical field
The invention belongs to pharmacy field, relate to benzoquinone compound and preparing the purposes in antitumor drug, particularly relate to the preparation of the Tokyo Violet B prime in benzoquinone compound and the purposes in anti-lung cancer, prostate cancer, nasopharyngeal carcinoma thereof.
Background technology
Show according to the World Health Organization (WH0) statistical information, whole world cancer is fallen ill about 1,000 ten thousand people every year, and death about 7,000,000 people, become the mankind No. second killer being only second to cardiovascular diseases, finding effective cancer therapy drug becomes the task of top priority.At present, in cancer therapy drug research, the studies and clinical application of chemotherapeutics obtains remarkable progress; Wherein, the anticarcinogen of chemosynthesis has the features such as strong, the anti-knurl wide spectrum of cancer resistance as metal complexes platinum complex, Gallium salt, organic germanium compounds, tin title complex etc., but also there is the weak points such as toxic side effect is large, cost is high, poorly water-soluble, therefore, investigators turn one's attention to the herbal medicine of aboundresources, pure natural.In recent years, from herbal medicine, find new cancer therapy drug be proved to be a up-and-coming direction, the screening of natural anti-cancer drugs had just become a study hotspot now naturally.Current there are some researches show that the natural product taxol, camptothecine, vincristine(VCR), podophyllotoxin etc. comprised in herbal medicine has good antitumour activity and be widely used clinically.
Chinese Drug Zicao (Radix Arnebiae) is the dry root of comfrey lithospermum euchromum Royle Arnebia euchroma (Royle) Johnst or arnebia guttata Bunge A.guttata Bunge; Chemical composition and pharmacology activity research show, Asian puccoon contains and multiplely comprises the physiologically active ingredient such as naphthoquinones class, benzoquinones class, mentioned component have antibacterial, anti-inflammatory, anticancer, antifertility, strengthening immunity, hypoglycemic, protect the multiple effects such as liver, be generally used for warm macula, jaundice due to damp-heat, purpura clinically, tell nosebleed, hematuria, stranguria with turbid discharge, bloody flux, constipation with heat retention, burn, eczema, erysipelas, large carbuncle, burn due to hot liquid or fire etc.According to the literature, Naphthoquinone in Zicao class Shikonin and derivative thereof to kinds of tumor cells, as Glioma of Mice cell C6, Human tongue cancer cell line Tca-8113, human cervical carcinoma cell HeLa, human melanoma cell A375-S2, human gastric cancer cells BGC-823, human esophagus cancer cell ECa-109 etc. have stronger restraining effect; Described Shikonin can Inhibition test rat by tumor necrosis factor alpha and melanoma B
16caused vasculogenesis, thus the growth of Tumor suppression.Studies have found that, the antitumor effective dose of Shikonin is 5-l0mg/kg/day, demonstrates toxicity when being greater than 15mg/kg/day, and lower than invalid during 1mg/kg/day.According to another report, the mechanism of action that Antioxidant Activity of Natural ShiKoniu compounds and derivative thereof have cell toxicant and anti-tumor activity is mainly: Shikonin is by activating caspase proteolytic enzyme inducing apoptosis of tumour cell, activating the activity of mitogen activated protein kinase (mitogen-activated protein kinase), arrestin Tyrosylprotein kinase and DNA topoisomerase I, thus affect the process such as metabolism, propagation, differentiation, signal transmission, genetic expression of tumour cell, thus hinder the growth of tumour cell.
Have report, the benzoquinones phenol compound in Asian puccoon has the biosynthesizing effect of vitro inhibition prostaglandin(PG); Take a broad view of report both domestic and external, the antitumor drug effect being showed no benzoquinone compound in lithospermum and the antitumor drug prepared with it.
Summary of the invention
The object of this invention is to provide benzoquinone compound and preparing the purposes in antitumor drug, particularly relating to the preparation of the Tokyo Violet B prime in benzoquinone compound and the purposes in anti-lung cancer, prostate cancer, nasopharyngeal carcinoma thereof.
The present invention is separated and obtains new benzoquinone compound and confirm its tumor cell in vitro cytotoxic activity from Chinese medicinal materials lithospermum euchromum Royle; Wherein, described benzoquinone compound is monomeric compound.
In the present invention, described benzoquinone compound has the chemical structure of following formula:
In the present invention, described benzoquinone compound is Tokyo Violet B prime (Arnebinone B).
Benzoquinone compound of the present invention is prepared by following method:
Get Radix Arnebiae (Radix Lithospermi) meal 20kg, room temperature 95% ethanol repeatedly cold soaking, seepage pressure effects for several times after, decompression and solvent recovery, obtain medicinal extract 820g, medicinal extract suspends in water, and with sherwood oil, ethyl acetate and n-butanol extraction, obtains sherwood oil, ethyl acetate and n-butyl alcohol extract respectively; Get acetic acid ethyl ester extract 200g and carry out silica gel column chromatography, carry out repeatedly silica gel column chromatography and recrystallization with sherwood oil, sherwood oil-acetone, acetone successively, obtained new compound Tokyo Violet B prime (Arnebinone B, 10mg);
Described Tokyo Violet B prime (Arnebinone B) is faint yellow needle, mp.172-174 DEG C; Molecular formula: C
17h
18o
4; Molecular weight: 286;
(c=0.08, MeOH); UV λ maxnm (lg ε): 205.6 (4.36); 273.0 (3.23); 358.8 (0.12); IR (KBr) υ max (cm
-1): 2959,2924,2844,2351,1669,1639,1598,1446,1212,1058,964,838;
1h-NMR (400MHz): δ 1.48 (3H, s, Me-17); 1.94,2.12 (2H, dm ,-CH
2-11), 2.02,2.31 (2H, dm ,-CH
2-10), 2.74 (1H, d, J=12.9Hz, H-7), 3.38 (1H, d, J=12.9Hz, H-7), 3.82, (3H, s, OMe-16), 4.75 (2H, m ,-CH
2-13), 5.07 (1H, m, H-9), 5.10 (1H, m, H-15), 6.0 (1H, s, H-3), 6.38 (1H, m, H-14);
13c-NMR (100MHz): δ 181.9 (C-1), 157.9 (C-2), 107.3 (C-3), 187.6 (C-4), 147.4 (C-5), 141.4 (C-6), 23.2 (C-7), 139.5 (C-8), 121.9 (C-9), 24 (C-10), 26.8 (C-11), 136.1 (C-12), 77.4 (C-13), 79.3 (C-14), 123.8 (C-15), 56.2 (C-16), 26.2 (C-17); EI-MS m/z:44 (100), 69 (83), 53 (44), 91 (39), 219 (38), 77 (37), 41 (34), 115 (31), 286 (7).HR-EI-MS m/z：286.1214([M]
+,C
17H
18O
4 +；calc.286.1205)。
In the present invention, described Asian puccoon is the dry root of comfrey lithospermum euchromum Royle Arnebia euchroma (Royle) Johnst; Bitter, cold in nature, there is heat clearing and blood cooling, invigorate blood circulation, effect of promoting eruption of detoxifying.
Invention has been experiment in vitro, result shows, and described Tokyo Violet B prime has significant in vitro cytotoxic effect to human tumor cell line A549 (lung cancer), DU145 (prostate cancer), KB (nasopharyngeal carcinoma) and persister KB-VIN thereof; Above-mentioned experiment is with ED
50≤ 20 μ g/ml are effective standard; Result confirms, described Tokyo Violet B prime all has stronger inhibit activities to each tumor cell line, to the ED of lung cell A549
50be 4.86 μ g/ml, to the ED of prostate cancer cell DU145
50be 5.16 μ g/ml, to the ED of nasopharyngeal carcinoma cell KB
50be 5.2 μ g/ml, to the ED of KB persister KB-VIN
50be 4.98 μ g/ml.Tokyo Violet B prime of the present invention can be used for preparing anti-tumor drug, especially the medicine of preparation treatment lung cancer, prostate cancer or nasopharyngeal carcinoma.
Embodiment
Embodiment 1 prepares Tokyo Violet B prime
Radix Arnebiae (Radix Lithospermi) meal 20kg, with after 95% ethanol repeatedly cold soaking, seepage pressure effects several under room temperature, decompression and solvent recovery, obtain medicinal extract 820g, medicinal extract is suspended in distilled water, with sherwood oil, ethyl acetate and n-butanol extraction, obtain petroleum ether extract 220g, acetic acid ethyl ester extract 420g and n-butyl alcohol extract 180g; Acetic acid ethyl ester extract 200g, after silica gel mixed sample, oven dry, carries out silica gel column chromatography, carries out gradient elution successively with sherwood oil, sherwood oil-acetone, acetone, obtains 9 stream part Fr.1 ~ Fr.9; Gained stream part Fr.6 is through sherwood oil-acetone (8:1,5:1,5:2,2:1) silica gel column chromatography obtains Fr.6A ~ Fr.6D 4 wash-out stream parts, wherein Fr.6C obtains compound Tokyo Violet B prime (Arnebinone B through sherwood oil-acetone recrystallization, 10mg), its chemical structure, through Wave Spectrum and X-single crystal diffraction experimental identification, is new compound.
The test of embodiment 2 cell in vitro poison
4 kinds of tumor cell lines A549, DU145, KB and persister KB-VIN thereof in the T-25 flask of the 10% calf serum RPMI1640 nutrient solution 4ml containing 25mM HEPES, 0.2% (w/v) sodium bicarbonate and 100 μ g/ml kantlex, 37 DEG C, 5%CO
2condition under cultivate.Cell suspending liquid after tryptic digestion adds in 96 orifice plates, and cell concn is 0.25-1 × 10
4/ hole.The test compound sample that tumour cell adds different concns after 72 hours 37 DEG C of cultivations, is fixed with 50% ice-cold trichoroacetic acid(TCA) and uses the SRB of 0.4% to dye, and after dyestuff dissolves, measures absorption value under 562nm.ED
50drug level during cell half growth-inhibiting converts according to dose-effect data.In triplicate, absorption value difference is less than 5%, ED in each experiment
50difference is less than 30%.With ED
50≤ 20 μ g/ml are effective standard, and result shows, and Tokyo Violet B prime all has stronger inhibit activities to each tumor cell line, to the ED of lung cell A549
50be 4.86 μ g/ml, to the ED of prostate cancer cell DU145
50be 5.16 μ g/ml, to the ED of nasopharyngeal carcinoma cell KB
50be 5.2 μ g/ml, to the ED of KB persister KB-VIN
50be 4.98 μ g/ml.
Experimental result shows, described Tokyo Violet B prime has significant cytotoxic activity, can be used for preparing antitumor drug.
Claims (3)
1. there is the benzoquinone compound of following structural formula,
Described benzoquinone compound is Tokyo Violet B prime.
2. benzoquinone compound according to claim 1 is preparing the purposes in antitumor drug.
3., by purposes according to claim 2, it is characterized in that, described tumour is lung cancer, prostate cancer or nasopharyngeal carcinoma.
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| CN107412311A (en) * | 2017-07-19 | 2017-12-01 | 深圳弘汇生物医药有限公司 | The medical usage and preparation method of Asian puccoon α glucoside inhibiting activity extracts and combinations thereof |
| CN109867644B (en) * | 2018-01-31 | 2022-08-23 | 深圳市人民医院 | Benzoquinone compound, preparation method thereof and application thereof in preparation of antitumor drugs |
| CN110302232A (en) * | 2019-08-07 | 2019-10-08 | 中美（河南）荷美尔肿瘤研究院 | A kind of application extracting the method for separating alkanet effective component and its extract and inhibiting in Growth of Colon Cancer Cells drug in preparation |
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| US6025400A (en) * | 1998-08-24 | 2000-02-15 | Marco Polo Technologies | Compositions for treatment of antibiotic-resistant gram-positive bacterial infections and methods for using and preparing the same |
| CN1374288A (en) * | 2002-03-19 | 2002-10-16 | 中山大学 | Gronwell naphthaquinone derivative and its application in preparing anticancer medicine |
| CN1399957A (en) * | 2001-08-03 | 2003-03-05 | 北京金本草中药科技发展有限公司 | Application of shikonin and its derivative in pharmaceutical industry |
| CN102020598A (en) * | 2010-11-11 | 2011-04-20 | 中山大学 | Gronwell naphthaquinone derivative, preparation method of gronwell naphthaquinone derivative and application of gronwell naphthaquinone derivative serving as anticarcinoma drug |
| CN102198120A (en) * | 2010-03-26 | 2011-09-28 | 山东靶点药物研究有限公司 | Medicinal use of lithospermi naphthoquinone compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59128348A (en) * | 1983-01-11 | 1984-07-24 | Eisai Co Ltd | Monoterpenylbenzoquinone and its preparation |
| JPS59128381A (en) * | 1983-01-11 | 1984-07-24 | Eisai Co Ltd | Monoterpenylbenzohydroquinone and its preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6025400A (en) * | 1998-08-24 | 2000-02-15 | Marco Polo Technologies | Compositions for treatment of antibiotic-resistant gram-positive bacterial infections and methods for using and preparing the same |
| CN1399957A (en) * | 2001-08-03 | 2003-03-05 | 北京金本草中药科技发展有限公司 | Application of shikonin and its derivative in pharmaceutical industry |
| CN1374288A (en) * | 2002-03-19 | 2002-10-16 | 中山大学 | Gronwell naphthaquinone derivative and its application in preparing anticancer medicine |
| CN102198120A (en) * | 2010-03-26 | 2011-09-28 | 山东靶点药物研究有限公司 | Medicinal use of lithospermi naphthoquinone compounds |
| CN102020598A (en) * | 2010-11-11 | 2011-04-20 | 中山大学 | Gronwell naphthaquinone derivative, preparation method of gronwell naphthaquinone derivative and application of gronwell naphthaquinone derivative serving as anticarcinoma drug |
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