CN101371838A - Novel uses of neferine and analogue thereof - Google Patents
Novel uses of neferine and analogue thereof Download PDFInfo
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- CN101371838A CN101371838A CNA2008102239030A CN200810223903A CN101371838A CN 101371838 A CN101371838 A CN 101371838A CN A2008102239030 A CNA2008102239030 A CN A2008102239030A CN 200810223903 A CN200810223903 A CN 200810223903A CN 101371838 A CN101371838 A CN 101371838A
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Abstract
The invention discloses the new application of neferine and a neferine analogue. The invention refers to the application of the neferine, as shown in a formula (I), and the neferine analogue or a pharmaceutically acceptable salt of the neferine in the preparation of a medicament for inhibiting the proliferation of eukaryotic tumor cells and a medicament for preventing and/or curing a tumor. The neferine and the neferine analogue or the pharmaceutically acceptable salt shown in the formula (I) can combine with G-quadruplex DNA to increase the stability of the G-quadruplex DNA, thereby competitively inhibiting the combination of telomerase and telomere and the activity of the telomerase, weakening the proliferation ability of a cell, controlling the extension of the telomere and accelerating the apoptosis of the cell. That the neferine and the neferine analogue or the pharmaceutically acceptable salt shown in the formula (I) is used for preparing the medicament for preventing and/or curing the tumor has great meaning.
Description
Technical field
The present invention relates to the new purposes of (-)-Neferine and analog thereof.
Background technology
Telomere is meant the noncoding DNA zone of eukaryote linear chromosomal end, and its function is: assist chromosome to arrange in regrouping process; Stablize the end of chromosome structure, prevent the terminal connection of interchromosomal; Can compensate hysteresis chain 5 ' the terminal vacancy that behind elimination RNA primer, causes.Telomeric DNA sequence can form four chain body structures (Wang, Y.and Patel, D.J., Structure, 2,1141-1156 (1994) .) external.
The cell of tissue culture proves that telomere plays an important role in the life-span of decision cell, the aged cells telomere through too much being commissioned to train foster shortens, and it is unstable that chromosome also becomes.In the time of fissional, because 3 ' end is the hysteresis chain in reproduction process, archaeal dna polymerase can not duplicated chromosome 3 ' chain least significant end, this " end duplicates problem " causes telomere of the every multiplication of cell just to shorten about 30-200 base, after approximately duplicating through 60-70 time, telomere reaches a critical length, this moment, cell just entered non-splitting status, be called period of decline, this will cause apoptosis until dead (Harley, C.B., et al., Nature, 345,458-460 (1990) .).
Telomerase is basic nucleoprotein reverse transcriptase, telomeric dna can be added to the eukaryotic cell end of chromosome.Telomerase for keeping chromosome stability and cytoactive to play an important role, can prolong the telomere that shortens in the different plant species cell, thereby strengthens the multiplication capacity of cell in vitro.Telomerase is activity inhibited in normal human tissue, is activated again in tumor, may participate in vicious transformation.Telomerase is stable at the maintenance telomere, genome is complete, the aspects such as active and potential continuation multiplication capacity of cell long-period play an important role.Discoveries such as Kim, in the cancerous cell of 85-90%, a kind of reverse transcriptase-telomerase is activated (Kim, N.W., et al., Science, 266,2011-2015 (1994) .), and this provides a kind of special target that is used for the treatment of cancer.
Telomeric sequence is different with the difference of organism.In human and other vertebratess, telomere contains the repetitive sequence of TTAGGG.In human body, telomerase joins the telomere end with the TTAGGG repetitive sequence, and the telomere that is brought with statocyte division shortens, and the length of telomere is held as a result, makes the cancerous cell immortalization.Human telomere has the double-stranded region of one section 5-15kb, and a chain is rich in purine (A chain), and a chain is rich in pyrimidine (B chain).At 3 ' end, the A chain exists the strand of 200 base length outstanding, and this strand can be used as the primer of telomerase.Discoveries such as Zahler, the formation of G-four serobilas can stop combining of telomerase and telomere, thereby suppress the activity (Zahler, A.M., et al., Nature, 350 718-720 (1991) .) of telomerase.G-four serobila DNA are a kind of four chain DNA structures (Cech, T.R., Nature, 332,777-778 (1988) .) that formed by the DNA that contains a succession of continuous guanine residue.Therefore, about the micromolecular research of stablizing telomere G-four serobila DNA be a hot fields of present cancer therapy drug design.
(neferine Nef) is a kind of alkaloid (the molecular formula C that extracts to (-)-Neferine from the green plumule of nymphaeaceae plant lotus Nelumbo nucifera Gaertn mature seed
38H
44N
2O
6).The discovered in recent years (-)-Neferine has pharmacological action such as cardiovascular widely such as arrhythmia, blood pressure lowering, protection Myocardial Ischemia Reperfusion Injury, antiplatelet aggregation.
Summary of the invention
The new purposes that the purpose of this invention is to provide (-)-Neferine and analog thereof.
The purposes of (-)-Neferine provided by the present invention and analog thereof is: the application of acceptable salt in preparation inhibition eukaryote tumor cell proliferation medicine on the chemical compound shown in the formula (I) or its materia medica;
R in the formula (I)
1, R
2, R
3Be in following four kinds of groups any one: hydrogen, substituted acyl, the straight or branched alkyl, wherein alkyl can be selected from O, N, the hetero atom of S is interrupted; With R
1The carbon that links to each other is the R configuration, with R
2The carbon that links to each other is the S configuration.
Formula (I)
Described eukaryote is a mammal.
Described tumor cell is a cancerous cell; Described cancerous cell specifically can be breast cancer cell, prostate gland 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, leukaemia, head and neck cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, retina cancerous cell, transitional cell bladder carcinoma cell line, anus cancer cell or rectum cancer cell; Be preferably leukaemia, stomach cancer cell, hepatoma carcinoma cell or nasopharyngeal carcinoma cell.
The present invention also protects a kind of medicine that suppresses the eukaryote tumor cell proliferation, and its effective ingredient is an acceptable salt on the (-)-Neferine shown in the formula (I) and analog or their materia medicas.
Described eukaryote is a mammal.
Described tumor cell is a cancerous cell; Described cancerous cell specifically can be breast cancer cell, prostate gland 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, leukaemia, head and neck cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, retina cancerous cell, transitional cell bladder carcinoma cell line, anus cancer cell or rectum cancer cell; Be preferably leukaemia, stomach cancer cell, hepatoma carcinoma cell or nasopharyngeal carcinoma cell.
The new purposes of (-)-Neferine provided by the invention and analog thereof also is: acceptable salt prevents and/or treats application in the tumour medicine in preparation on the chemical compound shown in the formula (I) or its materia medica.
Described tumor can be cancer, as breast carcinoma, carcinoma of prostate, hepatocarcinoma, cancer of pancreas, pulmonary carcinoma, the brain cancer, ovarian cancer, uterus carcinoma, carcinoma of testis, skin carcinoma, leukemia, head and neck cancer, gastric cancer, nasopharyngeal carcinoma, colon cancer, retina cancer, bladder cancer, anus cancer or rectal cancer; Be particularly suitable for preparing the medicine that prevents and/or treats human leukemia, people's gastric cancer, people's hepatocarcinoma and human nasopharyngeal carcinoma.
Effective ingredient is the medicine that prevents and/or treats tumor of the (-)-Neferine shown in the formula (I) and analog or their pharmaceutically acceptable salts, 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 (-)-Neferine and analog thereof or their pharmaceutically acceptable salts 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 (-)-Neferine and analog thereof or the preparation of their pharmaceutically acceptable salts.The medicine of above-mentioned various dosage forms all can be according to the conventional method preparation of pharmaceutical field.
Evidence, (-)-Neferine shown in the formula (I) and analog thereof or their pharmaceutically acceptable salts can combine with G-four serobila DNA (abbreviating Telo7 as), increase the stability of G-four serobilas, thereby the competitive inhibition telomerase combines with telomere, the activity that suppresses telomerase, suppress telomere and extend, weaken the multiplication capacity of cell, promote apoptosis.
(-)-Neferine is external anticancer cell proliferation experiment result show, (-)-Neferine is that KB all has reasonable inhibition effect for human leukemia cell line HL-60, SGC-7901 BGC-823, Bel7402 Bel-7402 and KB cell, wherein, when being 50 μ M, the drug level of (-)-Neferine surpassed 90% for the suppression ratio of HL-60, BGC-823.
Description of drawings
Fig. 1 is the fluorescence titration figure of (-)-Neferine and Telo7, the curve among the figure from top to bottom, the mol ratio of Telo7 and (-)-Neferine is respectively 0:1,0.05:1,0.1:1,0.25:1,0.5:1,1:1,2:1,4:1.
Melting point curve figure when Fig. 2 is the Telo7 individualism and the melting point curve figure that has added the Telo7 of (-)-Neferine; Wherein 1 is the melting point curve figure of independent Telo7, and 2 is the blended melting point curve figure of (-)-Neferine and Telo7.
The specific embodiment
Experimental technique among the following embodiment if no special instructions, is conventional method.
(1) (-)-Neferine and G-four serobilas combines
At K
+Under the condition that ion exists, [d (the TTAGGGT)] sequence in the solution exists with parallel construction four serobila states [d (TTAGGGT)] 4.As Telo7 (G-four serobila DNA) and (-)-Neferine (R in the formula (I)
1, R
2, R
3Being hydrogen) when contacting, (-)-Neferine promptly combines with Telo7.In the fluorescence spectrum, can observe, the adding of Telo7 (G-four serobila DNA) makes the fluorescence signal generation cancellation of (-)-Neferine, and promptly Telo7 makes it that fluorescent quenching take place with combining of (-)-Neferine.Thereby can prove combining of Telo7 and (-)-Neferine.
Concrete grammar is as follows:
1, preparation buffer
Buffer is an aqueous solution, contains the various materials of following final concentration: 17.2mM K
+(K
2HPO
4/ KH
2PO
4); PH7.4.
2, with 400 OD[d (TTAGGGT)] shown in strand Telo7 (Bioisystech Co., Ltd of section is held up in Beijing) be dissolved in the buffer, obtaining concentration is the Telo7 mother solution of 200uM.
3,3.0mg (-)-Neferine (Nat'l Pharmaceutical ﹠ Biological Products Control Institute) is dissolved in the buffer, obtaining concentration is the (-)-Neferine mother solution of 10mM.
4, the Telo7 of a series of different mol ratios of preparation and the mixed solution of (-)-Neferine, the concentration of (-)-Neferine is that 20uM is constant in the mixed solution, and the mol ratio of Telo7 and (-)-Neferine is respectively 0:1,0.05:1,0.1:1,0.25:1,0.5:1,1:1,2:1,4:1.
5, above-mentioned mixed solution is hatched 12h for 25 ℃, the variation of (-)-Neferine fluorescence intensity is observed in fluoremetry.
As seen from Figure 1, behind the adding Telo7, Telo7 weakens the fluorescence intensity of (-)-Neferine, and fluorescent quenching has taken place in the solution of (-)-Neferine, determines that therefore Telo7 four serobilas have taken place to combine with (-)-Neferine.
(2) combine the heat stability of Telo7 afterwards with (-)-Neferine
Temperature when the fusing point of Telo7 four serobilas is meant G4 STRUCTURE DECOMPOSITION 50%.The fusing point of DNA (Tm) has reacted its heat stability, and this G4 structure of the high more explanation of fusing point is stable more, otherwise this G4 structure of the low more explanation of fusing point is unstable more.The G4 structure is stable more to be shown the influence of tumor cell proliferation greatly more, and the antitumor cultivation effect is obvious more.
The fusing point of Telo7 in the mixed solution (mol ratio is 10:1) by circular dichroism spectra (CD) alternating temperature measuring (-)-Neferine and Telo7, with concentration be 200uM Telo7 solution in contrast.The instrument that adopts is a Jasco815 circular dichroism spectrometer, and the CD absorption cell light path that adopts in the experiment is 1cm.Before experimentizing, use high-purity N
2Deoxygenation 5 minutes, and use high-purity N in the experiment always
2To guarantee not having ozone to occur, before experimental data is gathered, carry out the baseline check and correction as protection gas with buffer.Gather CD spectrum near ultraviolet band 220nm-320nm, scanning speed is 500nm/min, and the collection number of times is 3 times.Adopt the JascoPTC-423S temperature control instrument in the alternating temperature experiment, warm speed is 2 ℃/min, carries out the Telo7 Measurement of melting point by monitoring 262nm CD signal, and the result as shown in Figure 2.Test repeats 3 times, the The data mean+SD.
The result shows that in the contrast, the fusing point of Telo7 is 43 ± 1 ℃; In the mixed solution of (-)-Neferine and Telo7, the fusing point of Telo7 is 57 ± 1 ℃, and the fusing point that improves Telo7 reaches 14 ℃.The alternating temperature result has confirmed that the existence of (-)-Neferine can improve the stability of Telo7 significantly.
Mtt assay is adopted in test.
The ultimate principle of mtt assay is: tetramethyl azo azoles salt [MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] (available from Beijing chemical reagents corporation) is 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.Can calculate growth of tumour cell suppression ratio (%)=(OD according to formula
Contrast-OD
Experiment)/OD
Contrast* 100%, and then calculate half-inhibition concentration (IC
50).
1) (-)-Neferine is to the influence of cancer cell multiplication ability
The concrete operations step is as follows:
1) selects the adherent human leukemia cell HL-60 of exponential phase for use, after 0.25% trypsinization, be mixed with the cell suspension of 5000/ml with the RPMI1640 culture fluid that contains 10% calf serum, be seeded in 96 well culture plates, 100 μ l, 37 ℃, 5% CO are inoculated in every hole
2Cultivate 24h.
2) establish the (-)-Neferine group by 3 mass concentration gradients, the 1-3 row hole that 1-3 is capable adds (-)-Neferine 100 μ l from low to high successively by concentration, makes that the (-)-Neferine final concentration is followed successively by 12.5 μ M, 25 μ M, 50 μ M in every hole; Capable the 4th row hole of 1-3 adds 200 μ l RPMI RPMI-1640s for 1 group of contrast.1-3 is capable, and the 5th row hole is blank group, and every hole is inoculating cell not, only adds 200ul RPMI RPMI-1640.37 ℃, 5% CO
2Cultivate 72h.
3) abandon supernatant, every hole adds the serum-free medium of the freshly prepared 0.5mg/ml MTT of 100 μ l, and 37 ℃ are continued to cultivate 4h.Carefully abandon supernatant, and add 100 μ l DMSO dissolving MTT formazon precipitation,, measure the optical density value in 96 each hole of orifice plate down in the 490nm wavelength with BIORAD 550 type microplate reader with miniature ultrasonic agitator mixing.Calculate the growth of tumour cell suppression ratio according to the following equation, growth of tumour cell suppression ratio (%)=(OD
Contrast-OD
Experiment)/OD
Contrast* 100% (OD wherein
Contrast, OD
ExperimentFor deducting OD
BlankEmpirical value).Experimental result is as shown in table 1.
Embodiment 3, (-)-Neferine are to the influence of gastric carcinoma cells, human liver cancer cell and KB cell multiplication capacity
Srb assay is adopted in test.
The ultimate principle of srb assay is: SRB is a kind of protein bound dyestuff, pink, water soluble.SRB can develop the color with amino combination of alkalescence of cell protein, is good linear relationship in its OD value of 490nm-520nm wavelength place and viable count.So can be used as the quantitative of cell number.
The concrete operations step is as follows:
1) be respectively that the KB cell inoculation is in RPMI 1640 culture medium that contain 10% hyclone with SGC-7901 BGC-823, Bel7402 Bel-7402, KB cell.Cell culture 50ml culture bottle places 37 ℃, 5%CO
2Incubator is cultivated under complete wet condition.Above-mentioned three kinds of cells propagation is good and that be in exponential phase are mixed with the cell suspension of 5000/ml respectively with the RPMI RPMI-1640 that contains 10% calf serum, be inoculated in 96 orifice plates 100uL/ hole.The pre-cultivation 24 hours.
2) establish the (-)-Neferine group by 3 mass concentration gradients, the 1-3 row hole that 1-3 is capable adds (-)-Neferine 100 μ l from low to high successively by concentration, makes that the (-)-Neferine final concentration is followed successively by 12.5 μ M, 25 μ M, 50 μ M in every hole; Capable the 4th row hole of 1-3 adds 200 μ l RPMI RPMI-1640s for 2 groups of contrasts.1-3 is capable, and the 5th row hole is blank group, and every hole is inoculating cell not, only adds 200ul RPMI RPMI-1640.37 ℃, 5% CO
2Cultivate 72h.
3) with reference to Skehan ' s method (Skehan P, et al.J of Nat Cancer Ins, 1990,82 (13): 1107～1112) every hole adds 0.4%SRB 100uL, measures the optical density value in 96 each hole of orifice plate down in the 509nm wavelength with BIORAD 550 type microplate reader.Calculate the growth of tumour cell suppression ratio according to the following equation, growth of tumour cell suppression ratio (%)=(OD
Contrast-OD
Experiment)/OD
Contrast* 100% (OD wherein
Contrast, OD
ExperimentFor deducting OD
BlankEmpirical value).Experimental result is as shown in table 1.
Table 1 (-)-Neferine suppresses the result of the test of tumor cell proliferation
Claims (10)
1. the chemical compound shown in the formula (I) or its pharmaceutically acceptable salt application in the medicine of preparation inhibition eukaryote tumor cell proliferation;
Formula (I)
Wherein, R in the formula (I)
1, R
2, R
3Be in following four kinds of groups any one: hydrogen, substituted acyl, straight or branched alkyl, wherein alkyl can be selected from O, N, the hetero atom of S is interrupted; With R
1The carbon that links to each other is the R configuration, with R
2The carbon that links to each other is the S configuration.
2. medicine that suppresses the eukaryote tumor cell proliferation, its effective ingredient is an acceptable salt on the described formula of claim 1 (I) chemical compound or its materia medica.
3. application according to claim 1 or medicine according to claim 2 is characterized in that: described eukaryote is a mammal.
4. according to claim 1 or 3 described application or according to claim 2 or 3 described medicines, it is characterized in that: described tumor cell is a cancerous cell; Described cancerous cell is breast cancer cell, prostate gland 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, leukaemia, head and neck cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, retina cancerous cell, transitional cell bladder carcinoma cell line, anus cancer cell or rectum cancer cell; Be preferably leukaemia, stomach cancer cell, hepatoma carcinoma cell or nasopharyngeal carcinoma cell.
5. acceptable salt prevents and/or treats application in the tumour medicine in preparation on the described formula of claim 1 (I) chemical compound or its materia medica.
6. application according to claim 5 is characterized in that: described tumor is a cancer.
7. application according to claim 6 is characterized in that: described cancer is breast carcinoma, carcinoma of prostate, hepatocarcinoma, cancer of pancreas, pulmonary carcinoma, the brain cancer, ovarian cancer, uterus carcinoma, carcinoma of testis, skin carcinoma, leukemia, head and neck cancer, gastric cancer, nasopharyngeal carcinoma, colon cancer, retina cancer, bladder cancer, anus cancer or rectal cancer; Be preferably leukemia, gastric cancer, hepatocarcinoma or nasopharyngeal carcinoma.
8. medicine that prevents and/or treats tumor, its effective ingredient is an acceptable salt on the described formula of claim 1 (I) chemical compound or its materia medica.
9. medicine according to claim 8 is characterized in that: described tumor is a cancer.
10. medicine according to claim 9 is characterized in that: described cancer is breast carcinoma, carcinoma of prostate, hepatocarcinoma, cancer of pancreas, pulmonary carcinoma, the brain cancer, ovarian cancer, uterus carcinoma, carcinoma of testis, skin carcinoma, leukemia, head and neck cancer, gastric cancer, nasopharyngeal carcinoma, colon cancer, retina cancer, bladder cancer, anus cancer or rectal cancer; Be preferably leukemia, gastric cancer, hepatocarcinoma or nasopharyngeal carcinoma.
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Cited By (7)
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| WO2010118675A1 (en) * | 2009-04-14 | 2010-10-21 | 中国中医科学院中药研究所 | New use of neferine |
| CN110180033A (en) * | 2019-05-16 | 2019-08-30 | 深圳市第二人民医院 | Carry the three-dimensional porous rack and preparation method thereof of neferine |
| CN110585207A (en) * | 2019-09-25 | 2019-12-20 | 山东中医药大学 | Application of liensinine in preparation of medicine for preventing and treating brain glioma |
| CN112457246A (en) * | 2019-09-06 | 2021-03-09 | 中国科学院天津工业生物技术研究所 | Dopamine D1 receptor antagonists and uses thereof |
| CN112691105A (en) * | 2020-07-02 | 2021-04-23 | 中国人民解放军军事科学院军事医学研究院 | New use of neferine in inhibiting SARS-CoV and SARS-CoV-2 infection |
| CN114053275A (en) * | 2021-12-22 | 2022-02-18 | 中南大学湘雅医院 | Drug capable of reversing drug resistance of chronic myelogenous leukemia to imatinib drug |
| CN114796220A (en) * | 2022-05-16 | 2022-07-29 | 康珞生物科技（武汉）有限公司 | Application of neferine in preparation of anti-hepatitis B virus medicine |
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2008
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010118675A1 (en) * | 2009-04-14 | 2010-10-21 | 中国中医科学院中药研究所 | New use of neferine |
| CN101862331B (en) * | 2009-04-14 | 2013-05-22 | 中国中医科学院中药研究所 | New use of methyl liensinine |
| CN110180033A (en) * | 2019-05-16 | 2019-08-30 | 深圳市第二人民医院 | Carry the three-dimensional porous rack and preparation method thereof of neferine |
| CN112457246A (en) * | 2019-09-06 | 2021-03-09 | 中国科学院天津工业生物技术研究所 | Dopamine D1 receptor antagonists and uses thereof |
| CN110585207A (en) * | 2019-09-25 | 2019-12-20 | 山东中医药大学 | Application of liensinine in preparation of medicine for preventing and treating brain glioma |
| CN112691105A (en) * | 2020-07-02 | 2021-04-23 | 中国人民解放军军事科学院军事医学研究院 | New use of neferine in inhibiting SARS-CoV and SARS-CoV-2 infection |
| CN114053275A (en) * | 2021-12-22 | 2022-02-18 | 中南大学湘雅医院 | Drug capable of reversing drug resistance of chronic myelogenous leukemia to imatinib drug |
| CN114796220A (en) * | 2022-05-16 | 2022-07-29 | 康珞生物科技（武汉）有限公司 | Application of neferine in preparation of anti-hepatitis B virus medicine |
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