CN1274694C - Lanthanum amino acid complex and its preparing process and application - Google Patents
Lanthanum amino acid complex and its preparing process and application Download PDFInfo
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- CN1274694C CN1274694C CN 200410020380 CN200410020380A CN1274694C CN 1274694 C CN1274694 C CN 1274694C CN 200410020380 CN200410020380 CN 200410020380 CN 200410020380 A CN200410020380 A CN 200410020380A CN 1274694 C CN1274694 C CN 1274694C
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Abstract
The present invention relates to a lanthanum amino acid complex and a preparing method and applications thereof. The chemical name of the lanthanum amino acid complex is N-(1, 10-phenanthroline-2-methylene)-alpha-phenylalamine lanthanum (III). The lanthanum amino acid complex has the following chemical structural formula (6) or (7) or (8). 1, 10-phenanthroline-2-formaldehyde is reduced by NaBH4 after reacting with alpha-phenylalamine and then is coordinated with lanthanum (III); thereby, a 1: 1 type mononuclear complex and a 1: 2 type mononuclear complex are obtained. Then, the 1: 1 type mononuclear complex reacts with benzenethiol to obtain a bridging binuclear complex. The complex has high anticancer activity and broad-spectrum performance if applied to resisting cancer.
Description
Technical field
Technical scheme of the present invention relates to the compound that contains lanthanum, specifically amino acid coordination compound of a kind of lanthanum and its production and application.
Background technology
Cancer is one of principal disease of harm humans health.In order to cure cancer, scientists has been carried out number of research projects in the last hundred years.1969, Rosenberg finds that cis-Platinum compound has anti-tumor activity, this field has caused various countries scientists' very big interest, synthesize many cis-platinum title complexs in succession with anti-tumor activity, for example, CN 92102045.7, CN 97120205.2, CN 01127213.9, CN 03131925.4 all are these compounds.Find that through the clinical application of long period the antitumour activity of cis-Platinum compound is still waiting to improve, and they have kidney poison, stomach toxicity and emetic property class toxic side effect to human body, life-time service also can produce resistance.Cis-platinum class medicine has developed into the stage of comparative maturity now, wants to design better antitumor drug, must break through the restriction of cis-platinum class medicine, seeks the antitumor drug of new class.CN 01110359.0 has disclosed the octahedra molybdenum tungsten complex of a kind of chirality, and CN 03113973.6 discloses a kind of turmeric yellow lithium, copper, calcium and zinc metal ion title complex, and the antitumour activity of these metal ion matchs is still undesirable, does not also possess broad spectrum.At present, rare earth metal complex progressively comes into one's own aspect the cancer therapy being used for.The someone studies Yb
3+Different Complex to the restraining effect of the different division stages of cancer cells, and finds that the rare earth chloride of low dosage has restraining effect to cancer cells, but human normal cell line is not damaged, but the work of this respect is done also seldom, bibliographical information also seldom.CN 200410018701.4 has introduced the synthetic and antitumour activity of diamine bridge linking ortho phenanthroline hydrous lanthanum (III) title complex, and this lanthanum title complex has good anticancer activity and broad spectrum, but also has the space of further improving.
Summary of the invention
Technical problem to be solved by this invention is: a kind of amino acid coordination compound of lanthanum is provided, and it is with 1, uses NaBH after 10-phenanthroline-2-formaldehyde and the reaction of α phenylalanine
4Reduction, again with lanthanum (III) coordination, obtain 1: 1 type monokaryon N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex and 1: 2 type monokaryon N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex, then, 1: 1 type mononuclear coordination compound and terephthaldehyde's acid-respons are obtained N-(1 to the dibenzoic acid bridged binuclear, 10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex, this compound is applied to anticancer, better antitumour activity and broad spectrum are arranged.
The present invention solves this technical problem the technical scheme that is adopted: a kind of amino acid coordination compound of lanthanum, its chemical name is N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex, is to have the compound shown in following chemical structural formula (6), (7) or (8).
The preparation method of the amino acid coordination compound of above-mentioned lanthanum, its synthetic route is as follows:
Operation steps is: with o-Nitraniline, arsenic powder and glycerine is raw material, and its mol ratio is 1: 0.6～0.9: 3～5, at 130-135 ℃ and dense H
2SO
4Reacted 7～8 hours, and obtained 8-nitroquinoline (1), react with reduced iron powder in acetum (1), (1) mol ratio with reduced iron powder is l: 3～5,70 ℃ of reactions 2～3 hours, obtain 8-quinolylamine (2), (2) in 30% hydrochloric acid soln, with anhydrous AlCl
3, the reaction of o-NP and crotonic aldehyde, (2), anhydrous AlCl
3The mol ratio of o-NP and crotonic aldehyde is 1: 0.5～1.5: 1～1.5: l～1.5, reacted 1～2 hour down at 90 ℃, obtain the 2-methyl isophthalic acid, 10-phenanthroline (3), (3) in moisture 4% dioxane, react with tin anhydride, (3) be 1: 1.5～2.5 with the tin anhydride mol ratio, refluxed 30 minutes, obtain 1,10-phenanthroline-2-formaldehyde (4), (4) react in the aqueous solution with α-phenylalanine, use sodium borohydride reduction again, (4), α-phenylalanine and sodium borohydride mol ratio are l: 1: 5～7, obtain N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine (5), (5) in methyl alcohol, react with the perchloric acid lanthanum, (5) get 1: 8～12 and 2: 1 respectively with the mol ratio of perchloric acid lanthanum, by obtaining product l respectively: 1 type monokaryon N-(1 with methanol mixed solvent recrystallization, 10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex (6) and 1: 2 type monokaryon N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex (7), again with title complex (6) and terephthaldehyde's acid-respons, (6) mol ratio with terephthalic acid is 1: 0.5～1, N-(1, the 10-phenanthroline-2-methylene radical)-α-phenylalanine that obtains product terephthalic acid bridged binuclear closes lanthanum (III) title complex (8).
The application of the amino acid coordination compound of above-mentioned lanthanum: with the broad spectrum cancer therapy drug of doing human prostata cancer, people's liver cancer, human cervical carcinoma, people's cancer of the stomach, human leukemia and human breast carcinoma.Adopt srb assay to test, tested it human prostata cancer PC-3MIE8 cell, people's liver cancer Bel-7402 cell, human cervical carcinoma Hela cell, people's cancer of the stomach GC-823 cell, human leukemia HL-60 cell and human breast carcinoma MDA-MB-435 cells in vitro anti-tumor activity.The srb assay operating process is as follows: cultivated in advance 1 day, and drug treating 2 days, trichoroacetic acid(TCA) is fixed 1 hour, washing, drying added SRB 30 minutes, washing, drying, dissolving, the 540nm inspection is read.Test result is that title complex (6) is IC to human leukemia HL60 cell antitumour activity
50=4.47 μ moldm
-3, be IC to the antitumour activity of human prostata cancer PC-3MIE8 cell
50=8.54 μ moldm
-3, be IC to the antitumour activity of people's liver cancer Bel-7402 cell
50=7.66 μ moldm
-3, to the antitumour activity of people's cancer of the stomach BGC-823 cell to IC
50=20.02 μ moldm
-3, be IC to human cervical carcinoma Hela cell's antitumour activity
50=9.26 μ moldm
-3, be IC to the antitumour activity of human breast carcinoma MDA-MB-435 cell
50=24.57 μ moldm
-3Title complex (7) is IC to human leukemia HL60 cell antitumour activity
50=3.13 μ moldm
-3, be IC to the antitumour activity of human prostata cancer PC-3MIE8 cell
50=5.81 μ moldm
-3, be IC to the antitumour activity of people's liver cancer Bel-7402 cell
50=3.15 μ moldm
-3, be IC to human cervical carcinoma Hela cell's antitumour activity
50=4.57 μ moldm
-3, be IC to the antitumour activity of people's cancer of the stomach BGC-823 cell
50=4.53 μ moldm
-3, be IC to the antitumour activity of human breast carcinoma MDA-MB-435 cell
50=13.78 μ moldm
-3Title complex (8) is IC to human leukemia HL60 cell antitumour activity
50=4.67 μ moldm
-3, be IC to the antitumour activity of human prostata cancer PC-3MIE8 cell
50=12.36 μ moldm
-3, be IC to the antitumour activity of people's liver cancer Bel-7402 cell
50=5.85 μ moldm
-3, be IC to the antitumour activity of human cervical carcinoma Hale cell
50=6.86 μ moldm
-3, be IC to the antitumour activity of people's cancer of the stomach BGC-823 cell
50=16.13 μ moldm
-3, be IC to the antitumour activity of human breast carcinoma MDA-MB-435 cell
50=21.05 μ moldm
-3
The invention has the beneficial effects as follows: amino acid is to constitute proteinic basic structural unit, is an important developing direction to the cancer therapy drug research of amino acid and derivative thereof, and this is that the cancer therapy drug of considering amino acids has lower toxicity and resistance.It is reported that some amino acid whose Schiff alkali and title complex thereof all show significantly antitumor and anti-microbial activity.Phenanthroline has bigger rigidity aromatic nucleus, the title complex of its derivative is long and with the fabulous effect of DNA etc. because of the life-span of the stability of its uniqueness, oxidation-reduction quality, fluorescence excitation, and becoming research nucleic acid secondary structure and design is the important compound of a class of the cancer therapy drug of target with nucleic acid.The difficulty that amino acid and phenanthroline will be combined is very big, N-of the present invention (1,10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) complex structure modern design, synthetic route is rationally feasible, and step is simple, mild condition, yield is higher.
(1,10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex to N-of the present invention that better antitumour activity and broad spectrum are arranged, and comparative data is seen embodiment 4 and 5 in detail, yet these data are not as the restriction of claim of the present invention.
La and Yb are rare earth metals, and lanthanum title complex of the present invention should be equally damage people's normal cell, but La is more cheap than Yb.
Embodiment
Embodiment 1
The first step, synthetic (Vogel Arthur.Textbook of practical organicchemistry, 4th ed.London:Longman Group Limited, 1978,91.) of 8-nitroquinoline (1)
69g (0.5mol) o-Nitraniline, 68.8g (0.3mol) As
2O
5And 138g (1.5mol) glycerine mixes, and is heated to 100 ℃, slowly drips the dense H of 120ml
2SO
4, adding speed makes temperature of reaction not be higher than 120 ℃, is warming up to 130～135 ℃ after adding, and continues stirring reaction 7～8 hours.After the cooling, pour in the 1500ml water, add the 15g gac,, filter, after the filtrate cooling,, leach crude product with weak ammonia neutralization in 1: 1 90 ℃ of insulated and stirred 1 hour, washing, the hot water recrystallization gets product 8-nitroquinoline 45g, productive rate 52%, m.p.89-91 ℃.
Second step, 8-quinolylamine (2) synthetic
50ml Glacial acetic acid and 53ml water mix, and stir to add 8.35g (0.048mol) 8-nitroquinoline down, 60 ℃ of control bath temperatures, add 6.83g (0.144mol) reduced iron powder, add the back bath temperature and rise to 70 ℃, constant temperature stirred 2～3 hours, after the reactant cooling, add dense NaOH, make solution transfer to strong basicity and carry out wet distillation, be condensed into white solid after the overhead product cooling, suction filtration, vacuum-drying obtains product 4.0g, productive rate 56.9%, m.p.62～63 ℃.
The 3rd step, 2-methyl isophthalic acid, synthetic (Madeja K., J.Prackt.Chem., 1962,17,97.) of 10-phenanthroline (3)
Under ice-water bath cooling, the hydrochloric acid of 1.5L 30% is dropwise added the anhydrous AlCl of 67g (0.5mol)
3In, add 144g (1mol) 8-quinolylamine and 70g (1mol) o-NP then, 90 ℃ of control bath temperatures, stir and slowly drip 70g (1mol) crotonic aldehyde down, constant temperature continues to stir 1 hour, cooling, pour in the 1L water, regulate pH value 4～5, add diatomite with NaOH solution, filter, filtrate continuation adds NaOH solution to strong basicity, uses chloroform extraction, boils off solvent, dissolve with dilute acetic acid again, add gac, diatomite is handled, and filters, and filtrate is alkalized with ammoniacal liquor, chloroform extraction, boil off solvent, use the sherwood oil recrystallization, get yellow product 124g, productive rate 64%, m.p.88 ℃.
The 4th step, 1, synthetic [MI ochowski, the Jacek of 10-phenanthroline-2-formaldehyde (4);
Wanda; Skrowaczewska, Zofia (Politechnika Wrocl awska, Wrocl awska) Pol.76345 (Cl C07D), 30 Jun 1975, Appl.146219,13Feb 1971,2pp.]
With 3.3g (0.03mol) SeO
2Be dissolved in the solution of 30ml dioxane and 1.5ml water, stir and slowly add 3.9g (0.02mol) 2-methyl isophthalic acid down, the 10ml dioxane of 10-phenanthroline and the mixing solutions of 0.5ml water refluxed 30 minutes, crossed filtering selenium, filtrate steaming is removed dioxane and water, resistates is dissolved in hot water, adds proper amount of active carbon, boils, filter, filtrate is used NaHCO
3The solution neutralization obtains product 2.2g, productive rate 52%, m.p.154 ℃.
The 5th step, N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine (5) synthetic
With 0.825g (0.005mol) phenylalanine and 0.2g (0.005mol) dissolution of sodium hydroxide in 20ml water, again with 1,10-phenanthroline-2-formaldehyde solid 1.04g (0.005mol) slowly joins under induction stirring in this solution, at room temperature continues then to stir 10 hours.Filter, remove unreacted solid, filtrate adds 0.945g (0.025mol) NaBH gradually under ice-water bath
4, system slowly rises to room temperature then, continues to stir 12 hours.In system, slowly add concentrated hydrochloric acid behind the stopped reaction and make about its pH value to 7, suction filtration, the ethanol/water mixed solvent recrystallization, vacuum-drying obtains faint yellow solid, productive rate 78%.
1H NMR (CDCl
3): 8.85 (H, s, phen), 8.21 (H, d, phen), 8.12 (H, d, phen), 7.63 (2H, m, phen), 7.58 (H, s, phen), 7.49 (H, d, phen), 7.21 (4H, s, ArH), 7.14 (H, s, ArH), 4.81 (2H, s, CH
2-phen), 3.50 (H, t, CH), 2.99 (2H, d, CH
2Ar); C
22H
19N
3O
22HClH
2O ultimate analysis (%): calculated value C, 59.05; H, 5.18; N, 9.40; Experimental value C, 59.04; H, 5.12; N, 9.45; IR:3440,1630,1590,1556,1510,1382,1330,858.
The 6th step, 1: 1 type monokaryon La (III) title complex (6) synthetic
The hydrochloride 0.89g (2mmol) of (5) is dissolved in the 20ml water, regulates about pH value to 7, filter, obtain free ligand (5) with NaOH.Take by weighing 2.176g (4mmol) La (ClO
4)
36H
2O, be dissolved in the 20ml anhydrous methanol, under the induction stirring to wherein slowly splashing into the 50ml absolute methanol solution that contains 0.187g (0.5mmol) free ligand (5), continue to stir 2 hours, filter, filtrate decompression is concentrated into about 5ml, stirs down and splash into anhydrous diethyl ether in concentrated solution, has a large amount of faint yellow solids to separate out.Filter, this solid successively washs several times with anhydrous methanol, anhydrous diethyl ether, uses methanol mixed solvent recrystallization then, and vacuum-drying gets title complex (6), productive rate 74%.[La (C
22H
18N
3O
2) (H
2O)
4] (ClO
4)
22H
2O ultimate analysis (%): calculated value C, 32.96; H, 3.77; N, 5.24; La, 17.34; Experimental value: C, 32.85; H, 3.74; N, 5.20; La, 17.21; IR (KBr) 3420,1620,1597,1400,1359,1091,860,625,489,220cm
-1FABMS, m/z 567 ([
139La (C
22H
18N
3O
2) (H
2O)
4]
2+); Λ
m(CH
3OH) 169.3Scm
2Mol
-1UV-visible (H
2O), λ
Max/ nm (log ε): 203 (6.35), 226 (6.81), 270 (6.68).
The 7th step, 1: 2 type monokaryon La (III) title complex (7) synthetic
Take by weighing 0.374g (1.0mmol) free ligand (5), be dissolved in the 50ml anhydrous methanol, contain 0.272g (0.5mmol) La (ClO to wherein adding 20ml under stirring
4)
36H
2The O absolute methanol solution continues to stir 2 hours.Filter, filtrate decompression is concentrated into about 5ml, stir down to wherein adding anhydrous diethyl ether 40ml, at this moment have a large amount of faint yellow flockss to produce, suction filtration is after anhydrous methanol, anhydrous diethyl ether washing several times, recrystallization in the methanol mixed solvent again, vacuum-drying gets title complex (7), productive rate 77%.[La (C
22H
18N
3O
2)
2] (ClO
4) 4H
2O ultimate analysis (%): calculated value C, 51.65; H, 4.34; N, 8.22; La, 13.59; Experimental value: C, 51.78; H, 4.38; N, 8.28; La, 13.65; IR (KBr) 3440,1620,1590,1400,1378,1090,856,636,475,210cm
-1FABMS, m/z851 ([
139La (C
22H
18N
3O
2)
2]
+); Λ
m(CH
3OH) 89.1Scm
2Mol
-1UV-visible (H
2O), λ
Max/ nm (log ε): 202 (6.35), 227 (6.88), 272 (6.70).
The 8th step, double-core La (III) title complex (8) synthetic
Take by weighing 0.4g (0.5mmol) title complex (6) and be dissolved in the 10ml anhydrous methanol,, stirred 2 hours to the methyl alcohol suspension liquid that wherein slowly adds 53mg (0.25mmol) para-phthalic sodium, filter, filtrate decompression is concentrated into 5ml, under agitation to wherein splashing into anhydrous diethyl ether, has faint yellow solid to separate out, filter, successively, use methanol mixed solvent recrystallization then, vacuum-drying with methyl alcohol, ether washing, get dinuclear complex (8), productive rate 84%.[(LaC
22H
18N
3O
2)
2C
8H
4O
4] (ClO
4)
2H
2O ultimate analysis (%): calculated value C, 45.55; H, 3.09; N, 6.13; La, 20.28; Experimental value: C, 45.68; H, 3.06; N, 6.18; La, 20.39; IR (KBr) 3420,1623,1590,1390,1357,1092,854,625,480,219cm
-1FABMS, m/z 1154 ([
139(LaC
22H
18N
3O
2)
2C
8H
4O
4]
2+); Λ
m(CH
3OH) 198.4Scm
2Mol
-1UV-visible (H
2O), λ
Max/ nm (log ε): 201 (6.53), 226 (6.85), 276 (6.72).
Embodiment 2
The first step, 8-nitroquinoline (1) synthetic
Removing raw materials used is 69g (0.5mol) o-Nitraniline, 86g (0.375mol) As
2O
5And outside 184g (2mol) glycerine, other is with embodiment 1.
Second step, 8-quinolylamine (2) synthetic
Except that adding 9.68g (0.204mol) reduced iron powder, other is with embodiment 1.
The 3rd step, 2-methyl isophthalic acid, 10-phenanthroline (3) synthetic
Remove and add the anhydrous AlCl of 134g (1mol)
3Neutralization drips outside 84g (1.2mol) crotonic aldehyde, and other is with embodiment 1.
The 4th step, 1,10-phenanthroline-2-formaldehyde (4) synthetic
Remove SeO with 4.4g (0.04mol)
2Outward, other is with embodiment 1.
The 5th step, N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine (5) synthetic
Remove NaBH with 1.134g (0.03mol)
4Outward, other is with embodiment 1.
The 6th step, 1: 1 type monokaryon La (III) title complex (6) synthetic
Remove and take by weighing 2.72g (5mmol) La (ClO
4)
36H
2Outside the O, other is with embodiment 1.
The 7th step, 1: 2 type monokaryon La (III) title complex (7) synthetic
With embodiment 1.
The 8th step, double-core La (III) title complex (8) synthetic
With embodiment 1.
Embodiment 3
The first step, 8-nitroquinoline (1) synthetic
Removing raw materials used is 69g (0.5mol) o-Nitraniline, 103.2g (0.45mol) As
2O
5And outside 230g (2.5mol) glycerine, other is with embodiment 1.
Second step, 8-quinolylamine (2) synthetic
Except that adding 11.4g (0.24mol) reduced iron powder, other is with embodiment 1.
The 3rd step, 2-methyl isophthalic acid, 10-phenanthroline (3) synthetic
Remove and add the anhydrous AlCl of 201g (1.5mol)
3Neutralization drips outside 126g (1.5mol) crotonic aldehyde, and other is with embodiment 1.
The 4th step, 1,10-phenanthroline-2-formaldehyde (4) synthetic
Remove SeO with 5.5g (0.05mol)
2Outward, other is with embodiment 1.
The 5th step, N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine (5) synthetic
Remove NaBH with 1.32g (0.035mol)
4Outward, other is with embodiment 1.
The 6th step, 1: 1 type monokaryon La (III) title complex (6) synthetic
Remove and take by weighing 3.264g (6mmol) La (ClO
4)
36H
2Outside the O, other is with embodiment 1.
The 7th step, 1: 2 type monokaryon La (III) title complex (7) synthetic
With embodiment 1.
The 8th step, double-core La (III) title complex (8) synthetic
Except that adding 106mg (0.5mmol) para-phthalic sodium, other is with embodiment 1.
Embodiment 4
With N-(1 of the present invention, 10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex as cancer therapy drug, external antitumour activity to 1: 1 mononuclear coordination compound (6), 1: 2 type mononuclear coordination compound (7) and bridged binuclear title complex (8) adopts srb assay to test, and has tested it to human prostata cancer PC-3MIE8 cell, people's liver cancer Bel-7402 cell, human cervical carcinoma Hela cell, people's cancer of the stomach GC-823 cell, human leukemia HL-60 cell and human breast carcinoma MDA-MB-435 cells in vitro anti-tumor activity.The srb assay operating process is as follows: cultivated in advance 1 day, and drug treating 2 days, trichoroacetic acid(TCA) is fixed 1 hour, washing, drying added SRB 30 minutes, washing, drying, dissolving, the 540nm inspection is read.Test result is that title complex (6) is IC to human leukemia HL60 cell antitumour activity
50=4.47 μ moldm
-3, be IC to the antitumour activity of human prostata cancer PC-3MIE8 cell
50=8.54 μ moldm
-3, be IC to the antitumour activity of people's liver cancer Bel-7402 cell
50=7.66 μ moldm
-3, to the antitumour activity of people's cancer of the stomach BGC-823 cell to IC
50=20.02 μ moldm
-3, be IC to human cervical carcinoma Hela cell's antitumour activity
50=9.26 μ moldm
-3, be IC to the antitumour activity of human breast carcinoma MDA-MB-435 cell
50=24.57 μ moldm
-3Title complex (7) is IC to human leukemia HL60 cell antitumour activity
50=3.13 μ moldm
-3, be IC to the antitumour activity of human prostata cancer PC-3MIE8 cell
50=5.81 μ moldm
-3, be IC to the antitumour activity of people's liver cancer Bel-7402 cell
50=3.15 μ moldm
-3, be IC to human cervical carcinoma Hela cell's antitumour activity
50=4.57 μ moldm
-3, be IC to the antitumour activity of people's cancer of the stomach BGC-823 cell
50=4.53 μ moldm
-3, be IC to the antitumour activity of human breast carcinoma MDA-MB-435 cell
50=13.78 μ moldm
-3Title complex (8) is IC to human leukemia HL60 cell antitumour activity
50=4.67 μ moldm
-3, be IC to the antitumour activity of human prostata cancer PC-3MIE8 cell
50=12.36 μ moldm
-3, be IC to the antitumour activity of people's liver cancer Bel-7402 cell
50=5.85 μ moldm
-3, be IC to the antitumour activity of human cervical carcinoma Hale cell
50=6.86 μ moldm
-3, be IC to the antitumour activity of people's cancer of the stomach BGC-823 cell
50=16.13 μ moldm
-3, be IC to the antitumour activity of human breast carcinoma MDA-MB-435 cell
50=21.05 μ moldm
-3
Embodiment 5
The contrast experiment.
I. with the contrast experiment of other various cancer therapy drugs
Test result sees Table 1, and visible title complex (6) is to human leukemia HL60 cell antitumour activity (IC
50=4.47 μ moldm
-3) be higher than cis-platinum (IC
50=6.0 μ moldm
-3), to the antitumour activity (IC of human prostata cancer PC-3MIE8 cell
50=8.54 μ moldm
-3) be higher than melatonin (IC
50=1.2mmoldm
-3), to the antitumour activity (IC of people's liver cancer Bel-7402 cell
50=7.66 μ moldm
-3) be higher than cis-platinum (IC
50=7.7 μ moldm
-3), to the antitumour activity (IC of people's cancer of the stomach B6C-823 cell
50=20.02 μ moldm
-3) be higher than Zhengguangmycin A5 (IC
50=0.771mmoldm
-3), Zorubicin (IC
50=0.56mmoldm
-3), cytarabine (IC
50=89mmoldm
-3) and bleomycin (IC
50=0.771mmoldm
-3), to the antitumour activity (IC of human breast carcinoma MDA-MB-435 cell
50=24.57 μ moldm
-3) be higher than cis-platinum (IC
50=30 μ moldm
3); Title complex (7) is to human leukemia HL60 cell antitumour activity (IC
50=3.13 μ moldm
-3) be higher than cis-platinum (IC
50=6.0 μ moldm
-3), to the antitumour activity (IC of human prostata cancer PC-3MIE8 cell
50=5.81 μ moldm
-3) be higher than melatonin (IC
50=1.2mmoldm
-3), to the antitumour activity (IC of people's liver cancer Bel-7402 cell
50=3.15 μ moldm
-3) be higher than cis-platinum (IC
50=7.7 μ moldm
-3), to human cervical carcinoma Hela cell's antitumour activity (IC
50=4.57 μ moldm
-3) be higher than cis-platinum (IC
50=4.63 μ moldm
-3) and aclacinomycin (IC
50=8.41 μ moldm
-3), to the antitumour activity (IC of people's cancer of the stomach BGC-823 cell
50=4.53 μ moldm
-3) be higher than Zhengguangmycin A5, Zorubicin, cytarabine, bleomycin and cis-platinum (IC
50=6.8 μ moldm
-3), to the antitumour activity (IC of human breast carcinoma MDA-MB-435 cell
50=13.78 μ moldm
-3) be higher than cis-platinum (IC
50=30 μ moldm
3); Title complex (8) is to human leukemia HL60 cell antitumour activity (IC
50=4.67 μ moldm
-3) be higher than cis-platinum (IC
50=6.0 μ moldm
3), to the antitumour activity (IC of human prostata cancer PC-3MIE8 cell
50=12.36 μ moldm
-3) be higher than melatonin (IC
50=1,200mmoldm
3), to the antitumour activity (IC of people's liver cancer Bel-7402 cell
50=5.85 μ moldm
-3) be higher than cis-platinum (IC
50=7.7 μ moldm
3), be IC to human cervical carcinoma Hela cell's antitumour activity
50=6.86 μ moldm
-3Be higher than aclacinomycin (8.41 μ moldm
-3), to the antitumour activity (IC of people's cancer of the stomach BGC-823 cell
50=16.13 μ moldm
-3) be higher than Zhengguangmycin A5, Zorubicin, cytarabine, bleomycin, to the antitumour activity (IC of human breast carcinoma MDA-MB-435 cell
50=21.05 μ moldm
-3) be higher than cis-platinum (IC
50=30 μ moldm
3).
Above-mentioned three title complexs are to the antitumour activity of human leukemia HL60 cell, all be higher than cis-platinum to the antitumour activity of people's liver cancer Bel-7402 cell with to the antitumour activity activity of human breast carcinoma MAD-MB-435 cell, title complex (7) particularly, it all is higher than cis-platinum to the antitumour activity (except that PC-3MIE8) of various cancer cells.
Table 1 title complex (6), (7) and (8) and several contrast are to the IC of different knurl strains
50Value (μ M)
| Title complex | Cell line | |||||
| HL60 | PC-3MIE8 | Bel-7402 | Hela | BGC-823 | MDA-MB-435 | |
| Complex (6) complex (7) complex (8) cis-platinum epiphysin aclacinomycin bleomycin A5 adriamycin cytarabine bleomycin | 4.47 3.13 4.67 6.0 | 8.54 5.81 12.36 4.66 1200 | 7.66 3.15 5.85 7.7 | 9.26 4.57 6.86 4.63 8.41 | 20.02 4.53 16.13 6.8 771 560 89000 771 | 24.57 13.78 21.05 30 |
II. the contrast of diamine bridge linking ortho phenanthroline hydrous lanthanum (III) title complex of introducing with CN 200410018701.4
Table 2 has been listed the contrast experiment's who formerly applies for a patent diamine bridge linking ortho phenanthroline hydrous lanthanum (III) title complex and other various cancer therapy drugs test result.
Table 2 diamine bridge linking ortho phenanthroline hydrous lanthanum (III) title complex La (L1～3) and several contrast are to the IC of different knurl strains
50Value (μ M)
| Title complex | Cell line | |||||
| HL60 | PC-3MIE8 | Bel-7402 | Hela | BGC-823 | MDA-MB-435 | |
| La (L1) La (L2) La (L3) cis-platinum epiphysin aclacinomycin bleomycin A5 adriamycin cytarabine bleomycin | 9.51 8.63 45.6 6.0 | 5.54 5.60 5.59 4.66 1200 | 5.41 6.26 6.53 7.7 | 4.98 6.08 5.85 4.63 8.41 | 13.52 5.8 5.75 6.8 771 560 89000 771 | 32.56 5.52 5.93 30 |
Data in comparison sheet 1 and the table 2 as seen, title complex of the present invention (6), (7) and (8) all are higher than diamine bridge linking ortho phenanthroline hydrous lanthanum (III) title complex La (L1～3) to the antitumour activity of human leukemia HL60 cell; Title complex of the present invention (7) is higher than diamine bridge linking ortho phenanthroline hydrous lanthanum (III) title complex La (L1～3) to the antitumour activity of people's liver cancer Bel-7402 cell, and title complex of the present invention (8) is higher than diamine bridge linking ortho phenanthroline hydrous lanthanum (III) title complex La (L2～3) to the antitumour activity of people's liver cancer Bel-7402 cell; Title complex of the present invention (7) is higher than diamine bridge linking ortho phenanthroline hydrous lanthanum (III) title complex La (L1～3) to human cervical carcinoma Hela cell's antitumour activity; Title complex of the present invention (7) is higher than diamine bridge linking ortho phenanthroline hydrous lanthanum (III) title complex La (L1～3) to the antitumour activity of people's cancer of the stomach BGC-823 cell; Title complex of the present invention (6), (7) and (8) all are higher than diamine bridge linking ortho phenanthroline hydrous lanthanum (III) title complex La (L1) to the antitumour activity activity of human breast carcinoma MAD-MB-435 cell.
Claims (3)
1. the amino acid coordination compound of a lanthanum, it is characterized in that: chemical name is that N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex, be to have a compound shown in following chemical structural formula (6), (7) or (8),
2. according to the preparation method of the amino acid coordination compound of the described a kind of lanthanum of claim 1, it is characterized in that synthetic route is as follows:
Operation steps is: with o-Nitraniline, arsenic powder and glycerine is raw material, and its mol ratio is an o-Nitraniline: arsenic powder: glycerine=1: 0.6～0.9: 3～5, and at 130-135 ℃ and dense H
2SO
4Reacted 7～8 hours, and obtained 8-nitroquinoline (1), react with reduced iron powder in acetum (1), (1) mol ratio with reduced iron powder is 1: 3～5,70 ℃ of reactions 2～3 hours, obtains 8-quinolylamine (2), (2) in 30% hydrochloric acid soln, with anhydrous AlCl
3, the reaction of o-NP and crotonic aldehyde, (2), anhydrous AlCl
3The mol ratio of o-NP and crotonic aldehyde is 1: 0.5～1.5: 1～1.5: 1～1.5, reacted 1～2 hour down at 90 ℃, obtain the 2-methyl isophthalic acid, 10-phenanthroline (3), (3) in moisture 4% dioxane, react with tin anhydride, (3) be 1: 1.5～2.5 with the tin anhydride mol ratio, refluxed 30 minutes, obtain 1,10-phenanthroline-2-formaldehyde (4), (4) react in the aqueous solution with α-phenylalanine, use sodium borohydride reduction again, (4), α-phenylalanine and sodium borohydride mol ratio are 1: 1: 5～7, obtain N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine (5), (5) in methyl alcohol, react with the perchloric acid lanthanum, (5) get 1: 8～12 and 2: 1 respectively with the mol ratio of perchloric acid lanthanum, by obtain 1: 1 type monokaryon of product N-(1 respectively with methanol mixed solvent recrystallization, 10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex (6) and 1: 2 type monokaryon N-(1,10-phenanthroline-2-methylene radical)-α-phenylalanine closes lanthanum (III) title complex (7), again with title complex (6) and terephthaldehyde's acid-respons, (6) mol ratio with terephthalic acid is 1: 0.5～1, N-(1, the 10-phenanthroline-2-methylene radical)-α-phenylalanine that obtains product terephthalic acid bridged binuclear closes lanthanum (III) title complex (8).
3. according to the preparation method of the amino acid coordination compound of the described a kind of lanthanum of claim 2, it is characterized in that: in the operation steps, o-Nitraniline, arsenic powder and glycerine are that the mol ratio of raw material is 1: 0.75: 4; (1) mol ratio with reduced iron powder is 1: 4.25; (2), anhydrous AlCl
3, o-NP and crotonic aldehyde mol ratio be 1: 1: 1: 1.2; (3) it is 1: 2 with the tin anhydride mol ratio; (4), phenylalanine and sodium borohydride mol ratio are 1: 1: 6; (5) got respectively 1: 10 and 2: 1 with the mol ratio of perchloric acid lanthanum.
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