CN101926797A - New application of tetrahydropalmatine derivatives - Google Patents
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Abstract
The invention discloses new application of methyl-substituted tetrahydropalmatine derivatives. The new application is the application of the tetrahydropalmatine derivatives shown as a formula II or pharmaceutically-acceptable salts thereof to the preparation of medicaments for inhibiting eukaryotic tumor cell proliferation and the application to the preparation of medicaments for preventing and/or treating tumors. In-vivo anticancer activity test results indicate that the tetrahydropalmatine derivatives have the inhibiting effect on non-small cell lung cancer A-549 and small cell lung cancer H446 of humans, and the tumor volume of an administration group is smaller than that of negative control obviously. The results indicate that the tetrahydropalmatine derivatives shown as the formula II can be used for preparing medicaments for treating lung tumors, so that the medicinal application of the tetrahydropalmatine derivatives is widened.
Description
Technical field
The present invention relates to the new purposes of tetrahydropalmatine derivatives.
Background technology
Traditional Chinese medicine corydalis tuber is the dry tuber of Papaveraceae Corydalis plant Rhizoma Corydalis (Corydalis yanhusuo W.T.Wang), grows in low meadow, height above sea level wilderness, hills, border area.Mainly be distributed in Shaanxi, Jiangsu, Anhui, zhejiang and other places.Its nature and flavor suffering, hardship, temperature are returned liver, spleen channel.Have invigorate blood circulation, promoting the circulation of QI, analgesic effect, be mainly used in the breast side of body, pain, dysmenorrhea, puerperal become silted up resistance, tumbling and swelling etc.The Rhizoma Corydalis The Chemical Constituents is originated from the twenties in 20th century, its main component be corydalis A,B,C,D, penta element, Xin Su, the ninth of the ten Heavenly Stems element, the last of the ten Heavenly stems element, sub-element, ugly element, the third of the twelve Earthly Branches element, homochelidonie, coptisine, Rhizoma Corydalis amine alkali etc.Wherein with tetrahydropalmatine (tetrahydropalmatine, analgesic activity THP) the strongest (Wang Wenshu, Xiao Wei, analogy Rong, Zhou Yawei, traditional Chinese medicine corydalis tuber chemical constitution study, Central University for Nationalities's journal, 2007,16 (1): 80-82).Its structural formula is shown in formula I.
(formula I)
Since tetrahydropalmatine is founding of New,, state-promulgated pharmacopoeia and the pharmacology of university textbook have been listed in first nervous system medicine that modern science and technology research Chinese medicine is succeedd.In recent years, along with to the deepening continuously of its research, found also that it had pharmacological action (Xu Ting such as blood pressure lowering, anti-arrhythmia, antithrombotic, gastric acid inhibitory secretion, gold former times land, Cao Huiming, tetrahydropalmatine Pharmacological action study progress, China's clinical pharmacy magazine, 2001,10 (1): 58-60).Just because of above-mentioned many effects of tetrahydropalmatine, be that guide's thing carries out structure of modification with it, seeking the chemical compound with new drug effect is one of research direction of a significant.Wherein methyl-substituted tetrahydropalmatine derivatives (as formula II) has had more sophisticated synthesis technique, and anti-arrhythmia, antiulcer effect (Kunitomo J. are arranged, Nagai Y., Yuge E., Studies on the alkaloids of menispermaceousplants.CCXXXIV.:Alkaloids of Stephania sasakii Hayata.Isolation of water soluble quaternary base, steponine, Yakugaku Zasshi, 1967,87 (8): 1010-1011; Yellow pillow is inferior, Feng Meihua, and Peng Sixun, Shi Yiqiang, the mensuration of synthetic and some parameter of the former little thumb alkali type quaternary ammonium compound of tetrahydrochysene, China Medicine University's journal, 1988,19 (4): 249-252), but this derivant does not have the antineoplastic report up to now.
Cancer is human one of the most difficult pertinacious disease of defeating at present, also is a great problem of world medicine.Pulmonary carcinoma is considered according to clinical angle, can be divided into small cell lung cancer (SCLC) and nonsmall-cell lung cancer (NSCLC) two big classes.Nonsmall-cell lung cancer is the most general, accounts for 80% of lung cancer morbidity sum.National resident's cause of death survey result according to health ministry announcement in 2008 shows that pulmonary carcinoma has become the cause of death of Chinese the first malignant tumor.But contrast is higher lung cancer morbidity rate at present, still lacks a kind of safe and effective treatment lung cancer drugs clinically.Shortcomings such as most anti-pulmonary carcinoma one line medicine all exists for the tumor cell selectivity not strong, and toxicity is big.
Summary of the invention
The new purposes that the purpose of this invention is to provide the methyl-substituted tetrahydropalmatine derivatives shown in the formula II.
(formula II)
The purposes of tetrahydropalmatine derivatives provided by the present invention is: the application in preparation inhibition eukaryote tumor cell proliferation medicine of methyl-substituted tetrahydropalmatine derivatives shown in the formula II and pharmaceutically acceptable salt thereof.
Described tetrahydropalmatine derivatives can be levo form, d-isomer or raceme, is preferably the rotundine derivant structure shown in the formula III.Described tetrahydropalmatine derivatives pharmaceutically acceptable salt specifically can be bromine salt or iodine salt.
The present invention also protects a kind of medicine that suppresses the eukaryote tumor cell proliferation, and its effective ingredient is the tetrahydropalmatine derivative shown in the formula II or its pharmaceutically acceptable salt.
Eukaryote described in the present invention is a mammal.
Described tumor cell is a cancerous cell; Described cancerous cell specifically can be lung carcinoma cell, breast cancer cell, hepatoma carcinoma cell, pancreatic cancer cell, brain cancer cell, ovarian cancer cell, uterus carcinoma cell, testicular cancer cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, transitional cell bladder carcinoma cell line, anus cancer cell or rectum cancer cell; Be preferably lung carcinoma cell.
The new purposes of tetrahydropalmatine derivatives provided by the invention also is: acceptable salt prevents and/or treats application in the tumour medicine in preparation on the tetrahydropalmatine derivatives shown in the formula II or its materia medica.
Described tumor cell is a cancerous cell; Described cancerous cell specifically can be breast cancer cell, hepatoma carcinoma cell, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterus carcinoma cell, testicular cancer cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, transitional cell bladder carcinoma cell line, anus cancer cell or rectum cancer cell; Be preferably lung carcinoma cell.
With the tetrahydropalmatine derivatives shown in the formula II or its pharmaceutically acceptable salt is the medicine that prevents and/or treats tumor of effective ingredient preparation, also belongs to protection scope of the present invention.
The described tumour medicine that prevents and/or treats can import body such as muscle, Intradermal, subcutaneous, vein, mucosal tissue by the method for injection, injection, collunarium, eye drip, infiltration, absorption, physics or chemistry mediation; Or mixed by other materials or wrap up the back and import body.
With tetrahydropalmatine derivatives or its pharmaceutically acceptable salt is the antitumor drug of active component, when needing, can also add one or more pharmaceutically acceptable carriers in said medicine.Described carrier comprises diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant of pharmaceutical field routine etc.
Preventing and/or treating tumour medicine and can make various ways such as injection, tablet, powder, granule, capsule, oral liquid, unguentum, cream with the preparation of tetrahydropalmatine derivatives or its pharmaceutically acceptable salt.The medicine of above-mentioned various dosage forms all can be according to the conventional method preparation of pharmaceutical field.
The outer/inner active anticancer result of the test of the body of above-mentioned tetrahydropalmatine derivatives shows that the growth that it can effectively suppress tumor cell has tangible anti-tumor activity.The medicinal scope of this tetrahydropalmatine derivatives has not only been widened in this discovery, and is hopeful very much to develop the antitumor drug that becomes a kind of new and effective, low toxicity, especially anti-lung cancer drugs.
The specific embodiment
Embodiment 1, MTT reducing process detect the external active anticancer test of methyl-substituted tetrahydropalmatine derivatives (THP-1)
The ultimate principle of mtt assay is: tetrazole [MTT, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] be a kind of dyestuff that can accept hydrogen atom.Dehydrogenase relevant with NADP in the living cells mitochondrion can change into xanchromatic MTT insoluble hepatic formazon in cell, dead cell does not then have this function.Behind DMSO dissolving formazon, under certain wavelength, measure optical density value with microplate reader, can quantitatively measure the survival rate of cell.
1, material:
Tetrazolium salts (MTT): phosphate buffer (PBS) the dissolving MTT final concentration with 0.01M is 5mg/ml, filtration sterilization, and 4 ℃ keep in Dark Place after the packing.
Tumor cell line: people's non-small cell lung cancer cell strain A549 (Shanghai Inst. of Cytobiology, Chinese Academy of Sciences);
THP-1 makes by synthetic route described in the following list of references: Kunitomo J., Nagai Y., Yuge E., Studies on the alkaloids of menispermaceous plants.CCXXXIV.:Alkaloids of Stephania sasakii Hayata.Isolation of water soluble quaternary base, steponine, Yakugaku Zasshi, 1967,87 (8): 1010-1011.
The mensuration of TPH-1 specific rotatory power:
1) instrument: the Model 343Polarimeter of PerkinElmer company
2) experiment parameter: wavelength is the 589nm sodium lamp; Temperature is 20 ℃; Polarization tube length: d=10cm
Sample concentration: 10mg/mL
3) sample specific optical rotation [α] computing formula:
[α]＝α/L×C
In the formula: α is measured optical rotation; L is polarization tube length (dm); C is the concentration (g/mL) of solution
4) measurement result:
Utilize 343 type polariscopes, under above-mentioned experiment parameter, the optical rotation of working sample is-0.890 °.The specific rotatory power that can get the TPH-1 sample as calculated is-89 °, is confirmed that it is left-handed structure.
2, concrete operations step is as follows:
1) with people's non-small cell lung cancer cell A-549 of exponential phase with 0.25% trypsinization, make cell suspension with the DMEM complete culture solution that contains 10% (volumn concentration) hyclone then, respectively tumor cell is diluted to 1.0 * 10
5Individual/mL, be seeded to respectively in 96 well culture plates, every hole 200 μ l, in 37 ℃, 5%CO
2Incubator in cultivate 24h, each hole culture fluid then inclines.
2) tetrahydropalmatine derivatives (THP-1) is dissolved among the DMSO, being mixed with concentration with the DMEM complete culture solution is 150 μ g/mL, 100 μ g/mL, 50 μ g/mL, 25 μ g/mL, and wherein DMSO content is controlled to be 1% (volumn concentration); Tetrahydropalmatine derivatives is added in the culture hole of above-mentioned tumor cell A-549, inoculate 5 holes separately, every hole adds 200 μ l; Matched group correspond to respectively add in the culture hole of above-mentioned tumor cell contain 1% (volumn concentration) DMSO the DMEM complete culture solution to hole inner volume 200 μ l, also inoculate 5 holes; Blank group is for adding the DMEM complete culture solution of 200 μ l in the empty culture hole that does not contain tumor cell; Be placed on 37 ℃, 5%CO
2Incubator in cultivate 72h.
3) add 20 μ l freshly prepared 5mg/ml tetramethyl azo azoles salt (MTT) solution, 37 ℃, 5%CO to every hole after 3 days
2Continue to cultivate 4h.
4) carefully abandon supernatant, every hole adds 200 μ L DMSO dissolving MTT formazon precipitation, and room temperature is placed 15-20min, and every 5min vibration once.
5) optical density value (OD value) at mensuration wavelength 490nm place on microplate reader is by formula calculated the growth of tumour cell suppression ratio.
OD in this experiment
Contrast, OD
ExperimentValue is deduction and falls OD
BlankValue.
Three repetitions are established in experiment.
Methyl-substituted tetrahydropalmatine derivatives (THP-1) the results are shown in Table 1 to the inhibiting of people's non-small cell lung cancer cell A-549.
The vitro cytotoxicity result of the test of table 1 methyl-substituted tetrahydropalmatine derivatives (THP-1)
The above results shows that methyl-substituted tetrahydropalmatine derivatives has certain inhibitory action to people's non-small cell lung cancer cell A-549.
Embodiment 2, the interior influence of methyl-substituted tetrahydropalmatine derivatives (THP-1) body to people's non-small cell lung cancer cell A549 multiplication capacity
Tumor cell line: people's non-small cell lung cancer cell strain A549 (Shanghai Inst. of Cytobiology, Chinese Academy of Sciences);
Experimental animal: be the male BALB/c nude mouse (SPF level, Institute of Experimental Animals, Chinese Academy of Medical Sciences) in 4-6 week age in week, 24;
The weight of animals scope: 16-18g when administration begins, the initial body weight of animal is no more than or is lower than 20% of average weight;
Positive reference substance: cisplatin injection (FH section ancient cooking vessel medical treatment company limited, lot number: M071881);
Test drug: methyl-substituted tetrahydropalmatine derivatives (THP-1), with embodiment 1.
Negative control product: 0.9% sodium chloride injection (normal saline).
The concrete operations step is as follows:
(1) cultivation of tumor cell
With people's non-small cell lung cancer cell strain A549 suspension culture in contain 10% calf serum and RPMI 1640 culture medium (containing penicillin 100U/mL, streptomycin 100U/mL), place 37 ℃, 5%CO
2The cell incubator in cultivate.
Went down to posterity once in per 3 days.Go down to posterity cultivate 24 hours after cell enter exponential phase and can carry out next step test.
(2) foundation of transplanted tumor in nude mice model
Exponential phase A549 cell harvesting is centrifugal, be 0.4% with the quality percentage composition and count after expecting blue solution-dyed.
Adjusting cell concentration with above-mentioned RPMI 1640 culture medium is 1 * 10
7Individual/ml, it is subcutaneous only to be inoculated in nude mice right side axillary fossa with 0.2ml/, preparation lotus tumor kind Mus.
Treat tumor growth to the 1g, the inoculation mice, F1 is for lotus tumor kind Mus in preparation.
The selection tumor growth is vigorous and do not have diabrosis, gets tumor under the tumor animal that health condition is good, aseptic condition, is prepared into 3mm
3, it is subcutaneous to be inoculated in each animal right side axillary fossa.
Observe the tumor growth situation behind the nude inoculation, treat that gross tumor volume is 100-300mm
3The time, to screen by tumor volume size and body weight, excessive the reaching into tumor person of tumor volume will not be selected in.
With the mice with tumor random packet: negative control group, positive controls and tetrahydropalmatine group, 8 every group, grouping gives different pharmaceutical then.
(3) dosage of test sample
Negative control group: give normal saline;
Methyl-substituted tetrahydropalmatine derivatives (THP-1) group: irritating stomach dosage is the 100mg/kg body weight;
Positive controls: give the cisplatin solution of 0.5mg/ml, intraperitoneal administration dosage is: the 0.1ml/10g body weight.
(4) medication
Route of administration and frequency: methyl-substituted tetrahydropalmatine derivatives group and negative control product gastric infusion, every day 1 time, positive reference substance intraperitoneal administration, 1 time/week.The administration time limit: 4 weeks
(5) experimental result:
In process of the test, from grouping, administration, 2 times with vernier caliper measurement and write down tumor major diameter, minor axis and body weight weekly, comprises first administration and last administration same day, calculates gross tumor volume and the difference of tumor growth curve between each group relatively.
Calculate gross tumor volume according to following formula:
V=1/2 * major diameter * minor axis
2
Carry out therapeutic evaluation according to gross tumor volume
Calculate relative tumour volume (RTV) and relative tumor proliferation rate T/C% according to following formula:
RTV＝Vt/V
0
Vt: measure the tumor volume that tumor obtains every day
V
0: initial tumor volume (before the administration)
RTV meansigma methods * 100% of the RTV meansigma methods/matched group of T/C%=administration group
Utilize the T method of inspection among the biostatistics, each group nude mice experimental result is carried out sorting-out in statistics, the results are shown in Table 1.
Table 1THP-1 is to the influence of people's nonsmall-cell lung cancer A549 relative tumour volume (RTV)
Wherein, the significant difference of " P " value for comparing with negative control group.* expression is compared with the normal control group: * P＜0.05; * P＜0.01; * * P＜0.001
Table 2THP-1 is to the influence of the relative tumor proliferation rate of people's nonsmall-cell lung cancer A549 (T/C%)
| Time/sky | 4 | 7 | 11 | 14 | 18 | 21 | 25 |
| Positive controls | 69 | 70 | 47 | 55 | 50 | 49 | 49 |
| The THP-1 group | 29 | 40 | 38 | 55 | 61 | 65 | 68 |
Embodiment 3, the interior influence of methyl-substituted tetrahydropalmatine derivatives (THP-1) body to human small cell lung carcinoma cell H446 multiplication capacity
Concrete operations step and interpretation are all identical with nonsmall-cell lung cancer A549, only with cell strain by non-small cell A549, be changed to small cell lung cancer H446 cell strain.
This experimental result is as follows:
Table 3THP-1 is to the influence of human small cell lung carcinoma H446 relative tumour volume (RTV)
| Time/sky | 5 | 8 | 12 | 15 | 19 | 22 | 28 |
| Negative control group | 1.65±0.31 | 2.24±1.12 | 3.01±1.11 | 4.12±1.31 | 4.84±1.10 | 5.28±1.51 | 6.47±1.80 |
| Positive controls | 0.98±0.26** | 1.57±1.04 | 1.27±0.31** | 2.12±1.04** | 1.75±0.77** | 1.60±0.80** | 1.34±0.65** |
| The THP-1 group | 1.44±0.41 | 1.41±0.22 | 2.05±0.54 | 2.32±0.52* | 2.14±1.64** | 3.52±1.35 | 3.66±1.39* |
Wherein, the significant difference of " P " value for comparing with negative control group.* expression is compared with the normal control group: * P＜0.05; * P＜0.01; * * P＜0.001
Table 4THP-1 is to the influence of the relative tumor proliferation rate of human small cell lung carcinoma H446 (T/C%)
| Time/sky | 5 | 8 | 12 | 15 | 19 | 22 | 26 | 28 |
| Positive controls | 59 | 70 | 42 | 52 | 36 | 30 | 21 | 21 |
| The THP-1 group | 87 | 63 | 68 | 56 | 44 | 36 | 37 | 48 |
The above results shows that methyl-substituted tetrahydropalmatine derivatives has the good restraining effect in vivo to people's pulmonary carcinoma (comprising nonsmall-cell lung cancer and small cell lung cancer).Experimental result shows that methyl-substituted tetrahydropalmatine derivatives can effectively suppress growth of tumor in external MTT and the nude mouse, and gross tumor volume is significantly less than negative control.This result shows that above-mentioned tetrahydropalmatine derivatives can be used for preparation treatment lung tumors medicine, has widened the medical applications of tetrahydropalmatine derivatives.
Claims (10)
1. the tetrahydropalmatine derivatives shown in the formula II or its pharmaceutically acceptable salt application in preparation inhibition eukaryote tumor cell proliferation medicine;
(formula II).
2. application according to claim 1 is characterized in that: the tetrahydropalmatine derivatives shown in the described formula II is a levo form, and its structural formula is shown in formula III:
3. application according to claim 1 and 2 is characterized in that: described eukaryote is a mammal; Described tumor cell is a cancerous cell; Described cancerous cell is lung carcinoma cell, breast cancer cell, hepatoma carcinoma cell, pancreatic cancer cell, brain cancer cell, ovarian cancer cell, uterus carcinoma cell, testicular cancer cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, transitional cell bladder carcinoma cell line, anus cancer cell or rectum cancer cell; Be preferably lung carcinoma cell.
4. medicine that suppresses the eukaryote tumor cell proliferation, its effective ingredient is the tetrahydropalmatine derivatives shown in formula II or the formula III or its pharmaceutically acceptable salt.
5. medicine according to claim 4 is characterized in that: described tetrahydropalmatine derivatives pharmaceutically acceptable salt is iodine salt or bromine salt; Described eukaryote is a mammal; Described tumor cell is a cancerous cell; Described cancerous cell is breast cancer cell, hepatoma carcinoma cell, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterus carcinoma cell, testicular cancer cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, transitional cell bladder carcinoma cell line, anus cancer cell or rectum cancer cell; Be preferably lung carcinoma cell.
6. acceptable salt prevents and/or treats application in the tumour medicine in preparation on the tetrahydropalmatine derivatives shown in the formula II or its materia medica.
7. application according to claim 6 is characterized in that: the tetrahydropalmatine derivatives shown in the described formula II is a levo form, and its structural formula is shown in formula III:
8. according to claim 6 or 7 described application, it is characterized in that: described tetrahydropalmatine derivatives pharmaceutically acceptable salt is iodine salt or bromine salt; Described tumor is a cancer; Described cancer is breast carcinoma, hepatocarcinoma, cancer of pancreas, pulmonary carcinoma, the brain cancer, ovarian cancer, uterus carcinoma, carcinoma of testis, skin carcinoma, gastric cancer, nasopharyngeal carcinoma, colon cancer, bladder cancer, anus cancer or rectal cancer; Be preferably pulmonary carcinoma.
9. medicine that prevents and/or treats tumor, its effective ingredient is the tetrahydropalmatine derivatives shown in formula II or the formula III or its pharmaceutically acceptable salt.
10. medicine according to claim 9 is characterized in that: described tetrahydropalmatine derivatives pharmaceutically acceptable salt is an iodine salt; Described tumor is a cancer; Described cancer is breast carcinoma, hepatocarcinoma, cancer of pancreas, pulmonary carcinoma, the brain cancer, ovarian cancer, uterus carcinoma, carcinoma of testis, skin carcinoma, gastric cancer, nasopharyngeal carcinoma, colon cancer, bladder cancer, anus cancer or rectal cancer; Be preferably pulmonary carcinoma.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017054640A1 (en) * | 2015-09-29 | 2017-04-06 | 浙江大学 | Use of tetrahydropalmatine in preparing anti-cisplatin toxicity medicament |
| WO2017080313A1 (en) * | 2015-11-13 | 2017-05-18 | Institute Of Chemistry, Chinese Academy Of Sciences | Tetrahydropalmatine derivative, its preparation method and use |
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| CN101327214A (en) * | 2008-07-18 | 2008-12-24 | 中国药科大学 | Medicine use of isoquinoline alkaloids as tissue factor inhibitor |
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| CN101327214A (en) * | 2008-07-18 | 2008-12-24 | 中国药科大学 | Medicine use of isoquinoline alkaloids as tissue factor inhibitor |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017054640A1 (en) * | 2015-09-29 | 2017-04-06 | 浙江大学 | Use of tetrahydropalmatine in preparing anti-cisplatin toxicity medicament |
| WO2017080313A1 (en) * | 2015-11-13 | 2017-05-18 | Institute Of Chemistry, Chinese Academy Of Sciences | Tetrahydropalmatine derivative, its preparation method and use |
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Application publication date: 20101229 |