CN102093431B - Organotin-oxygen cluster containing ferrocene pyrazole and application of cluster - Google Patents
Organotin-oxygen cluster containing ferrocene pyrazole and application of cluster Download PDFInfo
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- CN102093431B CN102093431B CN 201110025890 CN201110025890A CN102093431B CN 102093431 B CN102093431 B CN 102093431B CN 201110025890 CN201110025890 CN 201110025890 CN 201110025890 A CN201110025890 A CN 201110025890A CN 102093431 B CN102093431 B CN 102093431B
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Abstract
The invention provides an organotin-oxygen cluster containing ferrocene pyrazole. The cluster is characterized in that the complexes with the following chemical formulas are prepared from a ligand 3-trifluoromethyl-5-ferrocene pyrazole acetic acid (LCOOH) and monobutyltin oxide, dibutyltin oxide and triphenyltin hydroxide respectively: [BuSnO(OOCL)]6, [Ph4Sn2O(OCH3)(OOCL)]2 and [Bu4Sn2O(OOCL)2]2. The cluster has inhibiting effects on human lung cancer cells (A549), hepatoma cells (HepG2) and mouse melanoma (B16-F10) and the inhibiting effects are obviously superior to the inhibiting effects of the control drugs 5-fluorouracil and cisplatin, so the cluster can be applied to preparing the anti-tumor drugs.
Description
One, technical field
The present invention relates to a class and have the anti-tumor activity a metal-organic complex, is exactly organotin oxygen duster compound and the application in the preparation antitumor drug thereof that a class contains the ferrocene pyrazolyl.
Two, background technology
Since nineteen sixty-five U.S. Rosenbe chanced on cis-platinum and has antitumour activity, the medical of metal complexes had caused people's extensive concern, had opened up the frontier of metal complexes cancer therapy drug research.Platinum compound is being obtained some effects aspect some cancer for the treatment of really, but severe side effect also shows, and this replaces with regard to impelling us to seek some new medicines.Along with people to the pharmacological action of metal complexes understanding further deeply, new efficient, low toxicity, the metallic compound with antitumour activity constantly are synthesized out.Brown found Ph first in 1972
3SnO
2CCH
3Since having the growth that suppresses mouse tumor, people are more and more to synthetic, molecular structure and the bioactivity research of organotin, and obtained a lot of significant results.The anticancer test center of the U.S. (NCI) has screened more than 2000 kind of organo-tin compound till 1989, is much wherein organotin oxygen duster compound.What research was more now is mainly the compound of trialkylated tin and dialkyl tin.Due to the lower molecular weight organo-tin compound can grievous injury the immunity system of animal body, so the small molecular weight organo-tin compound is unsuitable for and makes carcinostatic agent.The Sherman suggestion replaces small molecular weight alkyl tin with low toxicity or nontoxic chain alkyl, cycloalkyl, aryl organo-tin compound with antitumour activity, and its anticancer effect may be better.The carboxylic acid compound of many dibutyl tins, tributyl tin and triphenyltin has shown efficient anticancer work.Many antitumour activitys are measured and are shown, radicals R in organotin is the principal element that determines the antitumour activity of whole title complex, the title complex antitumour activity of cyclohexyl, normal-butyl and phenyl is the strongest, ethyl takes second place, methyl is the most weak nearly unavailable, but the structure of part plays an important role equally to antitumour activity and the anticancer spectrum of title complex.Title complex under physiological condition by slow hydrolytic process, final formation active intermediate and the effect of cancer cells DNA molecular, and then hinder copying of DNA and bring into play antitumour activity, organic ligand R promotes that title complex enters the transmembrane movement of cancer cells, and affects therefrom the final activity of title complex.
The applicant has carried out following literature search to the application's theme:
1, http://www.google.com net result for retrieval: (2010/12/28)
2, CNKI result for retrieval:
In full-ferrocene pyrazoles organotin oxygen duster compound is without pertinent literature.
In full-anti-tumor activity ferrocene pyrazoles organotin oxygen duster compound is without pertinent literature.
Three, summary of the invention
The object of the present invention is to provide a class to have the organotin oxygen duster compound of anti-tumor activity, technical problem to be solved is the anti-tumor activity of selecting part and confirming this Organooxotin cluster.
The present invention selects to have bioactive 3-trifluoromethyl-5-ferrocene pyrazolyl acetic acid as part, respectively with Mono-n-butyltin, Dibutyltin oxide and the synthetic organotin oxygen duster compound that contains the ferrocene pyrazolyl of fentin hydroxide assembling.And it is carried out antitumor activity screening.
3-trifluoromethyl-5-ferrocene pyrazolyl acetic acid has following chemical formula:
For convenience of statement, be denoted as: LCOOH in the following description.
One of ferrocene pyrazolyl organotin oxygen duster compound that the present invention is alleged is the title complex that following chemical formula is arranged by ligand L COOH and Mono-n-butyltin preparation:
L:R ' in formula: n-Bu,
For convenience of statement, be designated as: [BuSnO (OOCL)] in the following description
6
Two of the ferrocene pyrazolyl organotin oxygen duster compound that the present invention is alleged is the title complexs that following chemical formula is arranged by ligand L COOH and Dibutyltin oxide preparation:
L:R ' in formula: n-Bu
For convenience of statement, be designated as: [Bu in the following description
4Sn
2O (OOCL)
2]
2
Three of the ferrocene pyrazolyl organotin oxygen duster compound that the present invention is alleged is the title complexs that following chemical formula is arranged by ligand L COOH and fentin hydroxide preparation:
L:R in formula:
For convenience of statement, be designated as: [Ph in the following description
4Sn
2O (OCH
3) (OOCL)]
2
The applicant has carried out anti tumor activity in vitro research to above-mentioned three kinds of title complexs, confirm that the three all has antineoplastic biological activity, the purposes that is to say above-mentioned three kinds of title complexs is exactly the application in the preparation antitumor drug, is exactly specifically the application in the anti-lung cancer of preparation or anti-liver cancer or melanoma medicine.
The present invention has following characteristics:
1, the present invention has chosen 3-trifluoromethyl-5-ferrocene pyrazolyl acetic acid as part, not only provide favourable condition for the assembling metal title complex, and it is low to have introduced toxicity, the organic group that biological activity is good, thus reach the biological activity (seeing Table 1) that improves title complex.
2, the raw material of the present invention's employing cheaply is easy to get, and cost is low.And toxicity is low, environmental friendliness.
Four, description of drawings
Fig. 1 is title complex [BuSnO (OOCL)]
6Crystalline structure figure.
Fig. 2 is title complex [Bu
4Sn
2O (OOCL)
2]
2Crystalline structure figure.
Fig. 3 is title complex [Ph
4Sn
2O (OCH
3) (OOCL)]
2Crystalline structure figure.
Five, embodiment
Further describe the present invention by following examples, but should notice that scope of the present invention is not subjected to any restriction of these embodiment.
One, part [3-trifluoromethyl-5-ferrocene pyrazolyl acetic acid (LCOOH)] is synthetic:
Take 5-ferrocenyl-3-trifluoromethyl pyrazol S (6.40g, 0.02mol) and be dissolved in acetonitrile, then take t-BuOK (3.36g, 0.03mol) and join in mentioned solution, after 60 ℃ of heating 2h, with BrCH
2COOC
2H
5(6.68g, 0.04mol) dropwise splashes in flask, drips off afterreaction and carries out 4～5h, and TLC detects principal reaction to be finished substantially.Decompression steams acetonitrile, adds the water temperature rising reflux and makes the product hydrolysis, finishes reaction after 1.5h, takes out mixture, drips the pH of rare HCl (1M) regulator solution to slightly acidic (pH=5～6) under ice bath in said mixture.Repeatedly extract with ethyl acetate, keep ethyl acetate layer, use anhydrous MgSO
4Dried overnight is filtered.Steam ethyl acetate, get yellow oil, pass through column chromatography for separation.Obtain sterling 3.40g, productive rate 45%, MS:(EI, 70eV): MS:(EI): M/z=378.02[M
+] .Anal.Calc for C
15H
13O
2N
2F
3Fe:C 47.70, H3.39, and N 7.38%; Found:C 47.62, and H 3.44, N 7.41%.
1H NMR (400MHz, CDCl
3): δ=4.293 (s, 5H), 4.490 (s, 4H), 5.086 (s, 2H), 6.512 (s, 1H)
Two, organotin oxygen duster compound is synthetic
1, [Ph
4Sn
2O (OCH
3) (OOCL)]
2Synthetic
Take Ph
3SnOH (0.1472,0.4mmol) and LCOOH (0.1512g, 0.4mmol) in the 50mL round-bottomed flask, add 25mL benzene, except a small amount of water that generates in dereaction, after backflow 12h, underpressure distillation is removed benzene and is got yellow solid with water-and-oil separator, with methylene dichloride: methyl alcohol=2: 1 (v/v) dissolving, filter, change in 50mL fine taper bottle standingly, have yellow crystals to separate out after the week.Anal.Calcd.for?C
82H
70N
4O
8F
6Fe
2Sn
4：C?50.77，H?3.64，N?2.89；Found：C?50.57，H?3.655，N?2.902(％).
119Sn?NMR(CDCl
3)：δ＝-88.243ppm.
2, [BuSnO (OOCL)]
6Synthetic
Take n-BuSnO (OH) (0.0836g, 0.4mmol) and LCOOH (0.1512,0.4mmol) in the 50mL round-bottomed flask, add 25mL benzene, except a small amount of water that generates in dereaction, after backflow 12h, underpressure distillation is removed benzene and is got yellow oil, uses the acetonitrile dissolution filter with water-and-oil separator, change in 50mL fine taper bottle standingly, separate out yellow bulk crystals after three days.Anal.Calcd?forC
120H
124N
12O
18F
18Fe
6Sn
6：C?42.25，H?3.66，N?4.93；Found：C?42.18，H?3.723，N?4.648(％).
119Sn?NMR(CDCl3)：δ＝-478.1ppm.
3, [Bu
4Sn
2O (OOCL)
2]
2Synthetic
Take n-Bu
2SnO (0.0996g, 0.4mmol) and LCOOH (0.1512,0.4mmol) in the 50mL round-bottomed flask, add 25mL benzene, except a small amount of water that generates in dereaction, after backflow 12h, underpressure distillation is removed benzene and is got yellow oil, filters with dissolve with methanol with water-and-oil separator, change in 50mL fine taper bottle standingly, separate out yellow bulk crystals after the week.Anal.Calcd.forC
96H
120N
8O
10F
12Fe
4Sn
4：C?46.64；H?4.89；N?4.53；Found：C?46.48，H?4.810；N?4.312(％).
119Sn?NMR(CDCl
3)：δ＝-200.568，-204.243ppm.
Three, the anti tumor activity in vitro of ferrocene pyrazolyl organotin oxygen duster compound research
Adopt MTT[3-(4,5)-two methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method measures analog derivative to human lung carcinoma cell (A549), the minimum inhibitory concentration of human liver cancer cell (HepG2) and murine melanoma (B16-F10) (minimalinhibitory concentration, MIC).
(1) preparation of nutrient solution (every liter): 1. suspension cell: RPMI-1640 cultivates one bag, powder (10.4g), new-born calf serum 100mL, penicillin solution (200,000 U/mL) 0.5ml, Streptomycin sulphate solution (200,000 U/mL) 0.5mL, after adding the tri-distilled water dissolving, the NaHCO with 5.6%
3The solution adjust pH is settled to 1000mL at last to 7.2-7.4.Filtration sterilization.2. attached cell: the same, then add NaHCO
32.00g, HEPES 2.38g.
(2) preparation of D-Hanks damping fluid (every liter): NaCl 8.00g, KCl 0.40g, Na
2HPO
412H
2O 0.06g, KH
2PO
40.06g, NaHCO
30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing the D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of experiment liquid: specimen is made into storing solution with a small amount of tri-distilled water dissolving, general 10 times of preparation storing solutions by the experiment maximum concentration.Different according to compound dissolution, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then adds tri-distilled water and dissolve.The concentration of DMSO in nutrient solution is unsuitable excessive, and in the every porocyte suspension after dosing, the final concentration of DMSO generally is no more than 0.05%-0.1%.Storing solution is stored in-20 ℃ of refrigerators standby.
(5) cultivation of human lung carcinoma cell (A549): be the adherent growth cell, cellar culture (contains 10% calf serum, 100U/mL Streptomycin sulphate) in the RPMI-1640 nutrient solution, put 37 ℃, 5%CO
2Cultivate in incubator, went down to posterity once every 3-4 days.First discard original fluid when going down to posterity, then wash with the D-Hanks damping fluid; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium to stop digestion; Piping and druming makes attached cell split away off from the culturing bottle wall; Pipette in right amount to the fresh culture bottle, then replenish fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(6) cultivation of human liver cancer cell (HepG2): be the suspension growth cell, cellar culture (contains 10% calf serum, 100U/mL Streptomycin sulphate) in the RPMI-1640 nutrient solution, be placed in 37 ℃, 5%CO
2Cultivate in incubator, went down to posterity once every 3-4 days.When going down to posterity, nutrient solution in former bottle is transferred in centrifuge tube, the centrifugal 5min of 1000rpm discards original fluid, add the equivalent fresh medium, piping and druming evenly pipettes in right amount to the fresh culture bottle, then replenishes fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(7) cultivation of murine melanoma (B16-F10): identical with the cultural method of human liver cancer cell (HepG2).
(8) cell is hatched: 3 kinds of tumour cells in the vegetative period of taking the logarithm, the accent concentration of cell suspension is 1-1.5 * 10
5Individual mL
-1Every hole adds cell suspension 100 μ L in 96 well culture plates, puts 37 ℃, 5%CO
2Cultivate 24h in incubator.After cultivating 24h, add liquid by design respectively.
(9) dosing: will test liquid and join respectively in each hole according to the concentration gradient of ultimate density, each concentration is established 6 parallel holes.Experiment is divided into drug test group (the test medicine that adds respectively different concns), control group (only add nutrient solution and cell, do not add the test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after dosing are placed in 37 ℃, 5%CO
2Cultivate 48h in incubator.The activity of positive control medicine (5-fluorouracil, cis-platinum) is measured according to the method for specimen.
(10) mensuration of survivaling cell: in having cultivated 96 orifice plates after 48h, every hole adds MTT 40 μ L (being made into 4mg/mL with the D-Hanks damping fluid).After 37 ℃ of placement 4h, remove supernatant liquor.Every hole adds 150 μ LDMSO, and vibration 5min makes the formazan dissolving crystallized.At last, utilize automatic microplate reader to detect the optical density(OD) (OD value) in each hole at 570nm wavelength place.
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to following formula:
Growth inhibition ratio=(1-survival rate) * 100%=[1-(OD
Experiment-O
Blank)/(OD
Contrast-OD
Blank)] * 100% (OD
ExperimentThe average optical of expression testing drug group, OD
ContrastThe average optical of expression control group, OD
BlankThe average optical of expression control group).
Half-inhibition concentration (IC
50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, try to achieve its corresponding drug level on typical curve.The IC that records
50Be shown in Table 1
The listed part of table 1 the present invention contains ferrocene pyrazolyl organotin carboxylicesters to the inhibition IC of tumour cell
50Value (μ g/mL)
This shows that these three kinds of title complexs obviously are better than contrasting medicine 5-fluorouracil and cis-platinum to the restraining effect of A549, HepG2 and B16-F10, be expected to use in the preparation antitumor drug.
Claims (9)
1. organotin oxygen duster compound that contains the ferrocene pyrazolyl is characterized in that: by the title complex that following chemical formula is arranged of ligand L COOH and Mono-n-butyltin preparation:
L in formula:
R′：n-Bu。
2. the purposes of title complex as claimed in claim 1, is characterized in that: the application of this title complex in the preparation antitumor drug.
3. the purposes of title complex according to claim 2, is characterized in that: the application of this title complex in the anti-lung cancer of preparation or anti-liver cancer or melanoma medicine.
4. organotin oxygen duster compound that contains the ferrocene pyrazolyl is characterized in that: by the title complex that following chemical formula is arranged of ligand L COOH and Dibutyltin oxide preparation:
L in formula:
R′：n-Bu。
5. the purposes of title complex as claimed in claim 4, is characterized in that: the application of this title complex in the preparation antitumor drug.
6. the purposes of title complex according to claim 5, is characterized in that: the application of this title complex in the anti-lung cancer of preparation or anti-liver cancer or melanoma medicine.
7. organotin oxygen duster compound that contains the ferrocene pyrazolyl is characterized in that: by the title complex that following chemical formula is arranged of ligand L COOH and fentin hydroxide preparation:
L in formula:
8. the purposes of title complex as claimed in claim 7, is characterized in that: the application of this title complex in the preparation antitumor drug.
9. the purposes of title complex according to claim 8, is characterized in that: the application of this title complex in the anti-lung cancer of preparation or anti-liver cancer or melanoma medicine.
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| CN102424693B (en) * | 2011-10-10 | 2014-02-12 | 聊城大学 | Tetra-2,6-dipicolinic acid-di-(ferrocenedicarboxylic acid)triphenyl tin complex, and its preparation method and application |
| CN102391314B (en) * | 2011-11-29 | 2013-09-11 | 聊城大学 | 2,6-dipicolinic acid-(ferrocene monoformic acid)triphenyltin complex, preparation method and application thereof |
| CN103113420B (en) * | 2013-02-04 | 2015-12-23 | 衡阳师范学院 | A kind of dibutyl tin oxygen duster compound containing ferrocenyl and preparation method and application |
| RU2533823C1 (en) * | 2013-07-05 | 2014-11-20 | Федеральное государственное бюджетное учреждение науки Институт элементоорганических соединений им. А.Н. Несмеянова Российской академии наук (ИНЭОС РАН) | 1-(1,1,1,3,3,3-hexafluoro-2-ferrocenylprop-2-yl)-imidazole, possessing antitumour activity and methods of obtaining thereof (versions) |
| CN104031092A (en) * | 2014-05-26 | 2014-09-10 | 上海应用技术学院 | Ferrocene benzotriazole derivatives as well as preparation method and application of ferrocene benzotriazoles derivatives |
| CN106588973B (en) * | 2016-12-12 | 2019-02-22 | 吉林医药学院 | A kind of six core drum type organotin carboxylate complexs of p-methylphenyl tin and its preparation method and application |
| RU2714891C1 (en) * | 2019-10-15 | 2020-02-20 | Общество С Ограниченной Ответственностью "Научно-Исследовательская Фирма "Ультрасан" (Ооо Ниф "Ультрасан") | Ferrocenylalkyl derivatives of dipyrazolylselenides as biologically active compounds and methods for production thereof (versions) |
| CN113402567B (en) * | 2021-06-15 | 2023-06-09 | 宁德师范学院 | Two-dimensional layered germanium vanadium oxide cluster compound and synthetic method and application thereof |
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| CA2156965A1 (en) * | 1994-09-09 | 1996-03-10 | Marcel Gielen | Aromatic fluorine-containing organotin compounds and anti-tumour compositions |
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2011
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| CA2156965A1 (en) * | 1994-09-09 | 1996-03-10 | Marcel Gielen | Aromatic fluorine-containing organotin compounds and anti-tumour compositions |
Non-Patent Citations (2)
| Title |
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| 卢文贯，等.二正丁基锡邻二茂铁基苯甲酸酯配合物的合成、表征及其体外抗肿瘤活性.《化学研究与应用》.2001,第13卷(第4期),372-375. * |
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