CN102532084B - One class coumarin kind compound, Preparation Method And The Use - Google Patents
One class coumarin kind compound, Preparation Method And The Use Download PDFInfo
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Abstract
The present invention relates to compound, Preparation Method And The Use that a class obtains from Chinese medicine is pointed at both ends, described compound is coumarin kind compound and pharmacy acceptable salt thereof; Relate to preparation method and the pharmaceutical composition thereof of this compounds, and described compound is for the preparation of the purposes of cancer therapy drug, especially for the treatment of the cancers such as leukemia, lung cancer, colorectal carcinoma, liver cancer, sarcoma.
Description
Technical field
The present invention relates to compound, Preparation Method And The Use that a class obtains from Chinese medicine is pointed at both ends, described compound is coumarin kind compound and pharmacy acceptable salt thereof; Relate to preparation method and the pharmaceutical composition thereof of this compounds, and described compound is for the preparation of the purposes of cancer therapy drug, especially for the treatment of the cancers such as leukemia, lung cancer, colorectal carcinoma, liver cancer, sarcoma.
Background technology
Chinese medicine is pointed at both ends is the rhizome of ranunculaceae plant anemone raddeana Regel (Anemone raddeana Regel.), begin to be loaded in Ming Dynasty Liu Wen safe show " Bencao Pinhui Jingyao ".There is the effect of wind-damp dispelling, subduing inflammation clinically, be used for the treatment of rheumatism and arthritis, spasm of the limbs, the diseases such as carbuncle turgescence canker.Compound involved in the present invention is coumarin kind compound.
Tonka bean camphor is the general name of a class natural compounds with benzene a pair of horses going side by side α-pyrone parent nucleus, structurally can regard the lactone along coumarinic acid dehydration as.This compounds is the derivative of shikimic acid biosynthetic pathway meta-bolites; extensively be distributed in vegitabilia; particularly in higher plant; as umbelliferae (Umbelliferae), Rutaceae (Rutaceae) etc.; there is many-sided biologic activity; as antibacterial, anticancer, anticoagulation, stop blooding, relieving asthma, eliminate the phlegm, protect blood vessel, treatment stenocardia and anti-oxidant [YangXW; HattoriM; Namba T.J.Chin.Pharm.Sci.; 1996,5 (3): 132-140] etc.McCulloch etc. [McCulloch P, GeorgeWD.Br.J.Cancer, 1989,59:179-183.] report that coumarin kind compound warfarin (warfarin) can suppress the Lung metastases of the Mtln3 cancer cells of female F344 mouse; Fuskova etc. [Fuskova A, Proksa B, Fuska J.Pharmazie, 1977,32:291-293] report that coumarin kind compound reaches the effect of killing tumour cell by the synthesis of arrestin matter and nucleic acid.
Summary of the invention
The present invention through botanical anticancer screening active ingredients widely, the antitumour activity of the class coumarins composition contained during Late Cambrian Chinese medicine is pointed at both ends.
First aspect, the present invention relates to a class as shown in the formula the compound of (I) or its pharmacy acceptable salt
Wherein, R=-CH
3or-CHO.
Second aspect, the present invention relates to the preparation method of above-claimed cpd or its pharmacy acceptable salt, comprises the following steps:
1) pointed at both ends or after pulverizing the ethanol that adds pointed at both ends is extracted, obtain extracting solution;
2) by extracting liquid filtering, be concentrated into without alcohol, obtain concentrated solution;
3) concentrated solution is used sherwood oil, extraction into ethyl acetate successively, obtain extraction liquid;
4), after extraction liquid is concentrated, through column chromatography, high-pressure liquid phase is prepared and be get final product.
Wherein the volume percent range of alcohol concn is 40%-95%, and column chromatography used medium can be silica gel, aluminum oxide.
3rd aspect, the present invention relates to a kind of pharmaceutical composition, the compound containing arbitrary formula (I) or its pharmacy acceptable salt, and one or more pharmaceutically acceptable carrier or vehicle.Physico-chemical property and the spectral data of described formula (I) compound are as follows:
Compd A (R=-CH
3): faint yellow needle, molecular formula C
12h
12o
5, ESI-MS molecular weight 236, according to
1hNMR,
13cNMR,
1h-
1h COSY, DEPT, HSQC, HMBC, ESI-MS etc., confirm that this compound is: 4,7-dimethoxy-5-methyl-6-Hydroxycoumarins.
The spectral data (DMSO) of table 1 compd A
Compd B (R=-CHO): white needles, molecular formula C
12h
10o
6, ESI-MS molecular weight 250, comprehensively analyzes
1hNMR,
13cNMR,
1h-
1h COSY, HSQC, HMBC etc., confirm that this compound is: 4,7-dimethoxy-5-aldehyde radical-6-Hydroxycoumarins.
Spectral data (the CDCl of table 2 compd B
3)
4th aspect, the present invention relates to pharmaceutical composition described in described compound or its pharmacy acceptable salt and the third aspect and is preparing the purposes in cancer therapy drug.Cancer is wherein leukemia, lung cancer, colorectal carcinoma, liver cancer, sarcoma.
Human leukocyte elastase (human leukocyte elastase HLE) is a kind of main proteolytic enzyme in human body, and its direct effect substrate is the extracellular matrix such as elastin, collagen protein, protein-polysaccharide in the reticular tissue such as lung, liver, kidney.In body, the too much or hyperactivity of elastoser expression of enzymes all can cause serious tissue injury, and causes or increase the weight of the diseases such as multiple pulmonary emphysema, chronic bronchitis, pyemia, ephritis, rheumatoid arthritis and some skin disease.In addition because elastoser can destroy collegen filament and Tissue Base rete, play a crucial role in the formation and metastases of tumour, so elastoser becomes action target spot [the Dona M of PTS, Dell Aica I, Pezzato E, et al.Hyperforin inhibits cancer invasion and metastasis.Cancer Res, 2004, 64 (17): 6225.Sun Z, Yang P.Role of imbalance between neutrophil elastase and alpha 1-antitrypsin in cancer development and progression.Lancet Oncol, 2004, 5 (3): 182].
Confirm through experiment, compd A of the present invention and B have obvious restraining effect to HLE, and present good concentration dependant sexual intercourse.
Retinoid receptor (RAR) is present in nucleus, it can mediate the effect of vitamin A acid (vitamin A oxidation metabolites in vivo), regulate the expression of target gene, thus play a significant role in the growth, atomization of the maintenance of animal life and body.RAR albumen is made up of six functional domains such as A, B, C, D, E, F.Wherein A, B are genetic transcription regulatory region; C district is DNA land; E is vitamin A acid land, forms dimer after E district binding partner, and then C district is combined with DNA and then regulatory gene is expressed.Now determine the RAR of three types: i.e. RAR α, RAR β and RAR γ.The generation of acute promyelocytic leukemia (APL) is due to t (15 mostly; 17) chromosome translocation, and t (15; 17) chromosome translocation be by Retinoic Acid Receptor Alpha 1 gene (RARA) on the PML gene on No. 15 karyomit(e)s and No. 17 karyomit(e)s between rearrangement caused by.So become the key for the treatment of acute promyelocytic leukemia for the research of Retinoic Acid Receptor Alpha, this model is the high flux screening model based on Mammalian one-hybrid system built for retinoid receptor, for screening lead compound [the AlBahar S for the treatment of acute promyelocytic leukemia, Pandita R, Bavishi K, et al.All trans-retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia.Indian J Cancer, 2004, 41 (3): 125-128].
Confirm through experiment, compd A of the present invention and B have obvious agonist activity to retinoid receptor.
In addition, confirm through experimentation on animals, the compd A that the present invention relates to, B have obvious therapeutic action to cancer mouse.
And compd A of the present invention, B do not have cytotoxicity to normal cell.
Formula (I) compound that the present invention relates to or its pharmacy acceptable salt, all can use separately or with other anti-cancer agent in combination.
Pharmaceutical composition of the present invention contains arbitrary formula (I) compound or its pharmacy acceptable salt, and one or more pharmaceutically acceptable carriers or vehicle, described carrier or vehicle comprise carrier and the vehicle of the application of pharmaceutics routine, as weighting agent, tamanori, sanitas, correctives, thinner, tinting material etc.According to the ordinary method of art of pharmacy, formula of the present invention (I) compound or its pharmacy acceptable salt, all can make the formulation of the administering modes such as applicable oral, injection, as: tablet, capsule, injection etc.
According to the understanding of those of ordinary skill in the art, the dosage of compd A, B should be determined according to factors such as the age for the treatment of target, body weight and disease severities, can be generally 30mg/d.
Accompanying drawing explanation
Accompanying drawing 1: compd A
1h-NMR collection of illustrative plates
Accompanying drawing 2: compd A
13c-NMR collection of illustrative plates
Accompanying drawing 3: the DEPT spectrum of compd A
Accompanying drawing 4: the ESI-MS collection of illustrative plates of compd A
Accompanying drawing 5: compd A
1h-
1h COSY collection of illustrative plates
Accompanying drawing 6: the HSQC collection of illustrative plates of compd A
Accompanying drawing 7: the HMBC collection of illustrative plates of compd A
Accompanying drawing 8: compd B
1h-NMR collection of illustrative plates
Accompanying drawing 9: compd B
13c-NMR collection of illustrative plates
Accompanying drawing 10: the ESI-MS collection of illustrative plates of compd B
Accompanying drawing 11: compd B
1h-
1h COSY collection of illustrative plates
Accompanying drawing 12: the HSQC collection of illustrative plates of compd B
Accompanying drawing 13: the HMBC collection of illustrative plates of compd B
Embodiment
The following examples, experimental example will do more detailed description to the present invention, and they are not construed as limiting the invention.Except non-specifically is explained, in the present invention, all per-cent is volume percent.
Chinese medicine (Chinese Pharmacopoeia) pointed at both ends: Shijiazhuang Le Rentang company limited
Column chromatography silica gel (300-400 order): Haiyang Chemical Plant, Qingdao
Thin-layer chromatography silica-gel plate and trifluoroacetic acid aqueous solution: Merck & Co., Inc.
HPLC：Waters 996
HPLC chromatographic column: Phenomenex 250 × 21.2mm, 10um
INVOA 500 type nuclear magnetic resonance spectrometer (Volian company), TMS is interior mark
ZMD Micromass type mass spectrograph: Micromass company of Britain
CO
2constant temperature cell culture incubator: SHELLAN company of the U.S.
PMI1640 nutrient solution: GIBCO company
MTT:Sigma company
Leukemia K562 cell: American Type Culture Collecti
Human lung cancer cell A549: American Type Culture Collecti
Human colon cancer cell HCT-15: American Type Culture Collecti
Fetal hepatocyte strain L02: Shanghai Inst. of Cytobiology, Chinese Academy of Sciences
Human leukocyte elastase (Human Leukocyte Elastase HLE): Sigma company
Peptide substrate (N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide): Sigma company
Lipofectamine 2000Reagent:invitrogen company
Victor more than 21420 marks calculating instrument: PE company of the U.S.
Embodiment: the preparation of formula (I) compound
By 2.5 kilograms pointed at both ends for Chinese medicine, after pulverizing, extract with 4 times of 80% alcohol heating reflux, extract 2 times, each 2 hours, united extraction liquid, is evaporated to without alcohol, uses equal-volume sherwood oil, ethyl acetate, n-butanol extraction 2 times successively, concentrated acetic acid ethyl acetate extract is through silica gel column chromatography, petroleum ether-ethyl acetate (1: 1 volume ratio) wash-out, collects 3-4 times of column volume elutriant, concentrates to obtain 10 grams of medicinal extract; Again through silica gel column chromatography, sherwood oil-acetone gradient elution (3: 1,2: 1,1: 1), collects 2: 1 elution fraction and concentrates, obtain compd A (R through HPLC preparation (25% acetonitrile-water)
t=12.6min, 73mg), compd B (R
t=11.5min, 21mg).
Experimental example
The outer inhibiting tumor assay of experimental example 1:MTT body of laws
Experiment material: K562, A549, HCT-15.
Adopt conventional mtt assay.Collect and be in above-mentioned each tumour cell of logarithmic phase, with the trypsin digestion and cell of 0.25%, then with 10% RPMI1640 nutrient solution to adjust cell concn be 1.0 × 10
5/ ml, is inoculated in 96 porocyte culture plates, and every hole 100ul adds the compd A-D of different concns respectively, and negative control medicine is phosphate buffered saline buffer.Often organize and all establish 3 multiple holes.Be placed in 37 DEG C, 5%CO
272h is cultivated in incubator, terminate front 4h in cultivation, each culture hole adds 10ul MTT (5mg/ml), cultivates after terminating, suck culture supernatant, every hole adds the SDS 100ul of 10%, and concussion 10min, makes crystallisate fully dissolve, placement is spent the night, finally measure each hole OD value by microplate reader in 490nm wavelength place, carry out analysis of cell proliferation, statistic data also carries out t inspection.
Experimental result shows, and shown in extract of the present invention and formula (I), compd A, B have obvious restraining effect to K562, A549, HCT-15 Growth of Cells.They are to the IC of tumour cell
50value sees the following form:
Extract of the present invention and compd A, B are to the IC of tumour cell
50value (IC
50: ug/ml)
Experimental example 2: compd A and B are to the inhibit activities of HLE
In the sample well of 96 orifice plates, add the DMSO solution of test sample, add HLE enzyme liquid and damping fluid totally 100 μ l; Control wells DMSO replaces sample solution; Blank well replaces sample solution with DMSO and replaces enzyme liquid with damping fluid.Use 1420Victor
2many marks calculating instrument, under 410nm wavelength, reads every hole OD value (at the bottom of sample copy A1); Add substrate 100 μ l, 37 DEG C of insulation reaction read the OD value (A2) in every hole again after 120 minutes, and the inhibiting rate of calculation sample.
The compd A and the B that get concentration gradient carry out determination of activity to HLE.Two compd As and the restraining effect of B to HLE present the relation of good concentration dependent, its IC
50be respectively 27.6 μ g/mL and 59.6 μ g/mL.
Experimental example 3: compd A and B are to the agonist activity of retinoid receptor
By cell strain CHO-K1 with 3 × 10
5individual/mL cell count is inoculated in 96 orifice plates, after 24h, nutrient solution is changed into containing 10% foetal calf serum without dual anti-PRMI 1640 substratum, with Lipofectamine TM 2000Reagent, recombinant plasmid pBIND-RAR α and the pGL3-GAL4 plasmid co-transfection containing 5 GAL4 respective element and luciferase reporter gene are entered cell.The positive drug induction adding different concns after 6h stimulates, and DMSO is as blank.Cell pyrolysis liquid (EDTA is added after administration 24h, TritonX-100, Tris), after lysing cell 5min, add reaction solution (EDTA, TritonX-100, Tris, ATP, ConA, Luciferase etc.) and detect luciferase expression activity with 1420Multilabel Counter rapidly.The induced expression multiplication number of luciferase is the activity of dosing group luciferase and the ratio of blank (DMSO).The induction multiplication activity being greater than 2 times in the screening of routine is defined as positive compound.
Under different concns, compd A and B are to the multiplication number of retinoid receptor
Experimental example 4 liver cancer mouse tumor inhibition
Experiment material: BALb/c mouse inbred lines, male 8-12 age in week, body weight 20-22g, purchased from Hebei Medical University's Experimental Animal Center.H-22 liver cancer mouse, purchased from Hebei Medical University's Experimental Animal Center.
Experimental technique: aseptic aspiration lotus H-22 liver cancer mouse the 7th day ascites, with normal saline dilution 10 times, in test mice right fore armpit subcutaneous injection 0.2ml.Be divided into 5 groups at random, every treated animal 10, records simultaneously and often organizes Mouse Weight.If physiological saline group and cis-platinum positive controls, compd A, B dosage are 5.0mg/Kg, after inoculation next day continuous intraperitoneal injection 8 days, within 9th day, de-cervical vertebra puts to death animal, and record Mouse Weight, dissects and take out knurl block, weigh, calculate tumour inhibiting rate according to following formula.
Experimental result: shown in extract of the present invention and formula (I), compd A, the tumor growth of B to H-22 liver cancer mouse have certain restraining effect, and have no significant effect the body weight of mouse.
The compounds of this invention is to the tumour inhibiting rate of H-22 liver cancer mouse (BALb/c mouse)
Body weight (g) tumour inhibiting rate (%) after body weight (g) medication before group dosage (mg/kg) medication
Physiological saline--18.6 ± 1.1 20.7 ± 1.2--
Cis-platinum 2.0 19.7 ± 1.4 16.7 ± 1.8 78.8
*
Compd A 5.0 18.9 ± 1.3 19.7 ± 1.1 48.9
*
Compd B 5.0 20.1 ± 0.9 21.2 ± 0.9 40.8
*
*: P < 0.01 compared with blank group; *: P < 0.05 compared with blank group
Experimental example 5:S180 sarcoma mouse tumor inhibition
Experiment material: mouse S180, Hebei Medical University.Cleaning grade Kunming mouse, male, body weight 18-22g, purchased from Hebei province's Experimental Animal Center.Cis-platinum, Dezhou, Shandong Province pharmaceutical factory produces.
Experimental technique: adopt Kunming mouse subcutaneous vaccination S-180 sarcoma model.Knurl kind vitro culture is to logarithmic phase, and numeration, regulates cell count to be 6 × 10
6individual/ml, is inoculated in mouse right fore oxter, every 0.2ml, is divided into 5 groups at random, and every treated animal 10, records simultaneously and often organize Mouse Weight.If physiological saline group and cis-platinum blank group and attached property control group, shown in formula (I), compd A, B establish 5.0mg/Kg dosage group, after inoculation next day continuous intraperitoneal injection 8 days, within 9th day, de-cervical vertebra puts to death animal, record Mouse Weight, dissect and take out knurl block, weigh, calculate tumour inhibiting rate according to following formula.
Experimental result: formula of the present invention (I) compd A, the growth of B to S180 murine sarcoma have obvious restraining effect, and have no significant effect Mouse Weight.
Compd A, B are to the tumour inhibiting rate of Kunming kind S180 sarcoma mouse
Body weight (g) tumour inhibiting rate (%) after body weight (g) medication before group dosage (mg/kg) medication
Physiological saline--18.8 ± 1.1 20.1 ± 0.8---
Cis-platinum 2.0 19.5 ± 1.2 16.4 ± 0.7 55.8
*
Compd A 5.0 20.6 ± 0.9 21.5 ± 1.2 33.8
*
Compd B 5.0 20.4 ± 1.4 21.2 ± 1.1 29.7
*
*: P < 0.01 compared with blank group; *: P < 0.05 compared with blank group
Experimental example 6:LDH method cytotoxic assay
LDH method cytotoxicity Cleaning Principle: LDH (serum lactic dehydrogenase) is a kind of stable protein, is present in Normocellular kytoplasm, once damaged membrane, namely LDH is released to extracellular; By detecting the enzymic activity of LDH in cells and supernatant, detect cytotoxicity.
Concrete mensuration process: cell L02 is adjusted to 5 × 10 with the RPMI-1640 nutrient solution containing 5% calf serum
4~ 2 × 10
5/ ml; In 96 hole circle floor cells culture plates, add L02 cell, every hole adds 100 μ l, puts 37 DEG C of 5%CO
2cO2gas incubator in cultivate 4 ~ 6 hours; Then add test compound, be incubated 24 hours, the multiple hole of each Setup Experiments three; Get supernatant, use LDH kit measurement, enzyme connection detector measures the optical density(OD) (OD value) in each hole, determined wavelength 492nm, reference wavelength 650nm.
Measurement result shows: compd A, B do not have cytotoxicity to normal cell L02 under 0.04-100ug/ml concentration.
Claims (7)
1. a class is as shown in the formula the compound of (I) or its pharmacy acceptable salt
Wherein, R=-CH
3or-CHO.
2. a preparation method for claim 1 compound, comprises the following steps:
1) pointed at both ends or after pulverizing the ethanol that adds pointed at both ends is extracted, obtain extracting solution;
2) by extracting liquid filtering, be concentrated into without alcohol, obtain concentrated solution;
3) concentrated solution is used sherwood oil, extraction into ethyl acetate successively, obtain extraction liquid;
4), after extraction liquid is concentrated, through column chromatography, high-pressure liquid phase is prepared and be get final product.
3. preparation method according to claim 2, wherein the volume percent range of alcohol concn is 40%-95%.
4. preparation method according to claim 2, wherein column chromatography used medium is silica gel, aluminum oxide.
5. a pharmaceutical composition, containing arbitrary compound according to claim 1 or its pharmacy acceptable salt, and one or more pharmaceutically acceptable carrier or vehicle.
6. pharmaceutical composition described in compound described in claim 1 or its pharmacy acceptable salt and claim 5 is preparing the purposes in cancer therapy drug.
7. purposes according to claim 6, cancer is wherein leukemia, lung cancer, colorectal carcinoma, liver cancer, sarcoma.
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| CN103408530B (en) * | 2013-08-26 | 2015-05-27 | 中国人民解放军第三军医大学 | Coumarin skeleton polycyclic compound with biological activity as well as preparation method and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1207392A (en) * | 1997-07-31 | 1999-02-10 | 中国医学科学院药物研究所 | Viformyl cumarins compound, process for preparing same and pharmaceutical composition contg. same |
| WO2008067410A2 (en) * | 2006-11-28 | 2008-06-05 | Tahitian Noni International, Inc. | Lipoxygenase and cyclooxygenase inhibition |
| CN101384577A (en) * | 2006-02-09 | 2009-03-11 | 中外制药株式会社 | Novel coumarin derivative having antitumor activity |
-
2010
- 2010-12-29 CN CN201010611115.6A patent/CN102532084B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1207392A (en) * | 1997-07-31 | 1999-02-10 | 中国医学科学院药物研究所 | Viformyl cumarins compound, process for preparing same and pharmaceutical composition contg. same |
| CN101384577A (en) * | 2006-02-09 | 2009-03-11 | 中外制药株式会社 | Novel coumarin derivative having antitumor activity |
| WO2008067410A2 (en) * | 2006-11-28 | 2008-06-05 | Tahitian Noni International, Inc. | Lipoxygenase and cyclooxygenase inhibition |
Non-Patent Citations (2)
| Title |
|---|
| TCCM对维甲酸诱导大鼠骨质疏松的影响;王萍 等;《江苏中医药》;20040430;第25卷(第4期);全文 * |
| 冷蒿地上部分化学成分的研究;李存芳;《中国优秀硕士学位论文全文数据库医药卫生科技辑》;20091015(第10期);第24页Fig.1，第82页第1-2段 * |
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