CN101284827A - Antineoplastic compounds containing triazole ring naphthoyl imines and method for preparing same - Google Patents
Antineoplastic compounds containing triazole ring naphthoyl imines and method for preparing same Download PDFInfo
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Abstract
The invention provides an anti-tumor compound containing triazole cycle naphthalimide and a preparation method for the same, which belongs to the bio-organic synthesis field. The anti-tumor compound containing triazole cycle naphthalimide introduces five-member 1, 2, 3-triazole cycle on a naphthalimide matrix in a substituted group mode and designs, and synthesizes compounds through nitro reduction, diazotization, azide substitution reaction, Click Chemistry and amino condensation reaction. The compound has good anti-tumor activities, has better inhibition function on the normal growth of various tumor cells (such as human lung cancer, glial cancer and so on) from different tissues and hereditary variation cells( such as leukemia cell and so on) from different sources.
Description
Technical field
The present invention relates to a class and contain triazole ring naphthoyl imines antineoplastic compound and preparation method thereof, it belongs to biological organic synthesis field.
Background technology
Single naphthoyl imide compounds of introducing nitrogenous hetero atom substituents on aromatic ring has good anti-cancer activity, wherein active best amonafide (N-(beta-dimethyl-amino-ethyl)-3-amido-1, the 8-naphthalimide) (Malviya V K, Liu P Y, Alberts D S, et al.Am.J.Clin.Oncol., 1992,15:41-44.) and mitonafide (N-(beta-dimethyl-amino-ethyl)-3-nitro-1,8-naphthalimide) (Brana M.F, SantosA., Roldan C.M., et al.Eur.J.Med.Chem.Chim.Ther., 1981,16,207-212) entered phase ii clinical trial.This compounds can suppress the growth of tumour cell effectively, and its mechanism of action is that intercalation is gone between the base pair of DNA, suppresses the synthetic of DNA and RNA, and can suppress topoisomerase II, thereby reach the purpose that suppresses tumour.
Can learn thus,, improve its intercalation ability, thereby improve its anti-tumor activity DNA if 5 introducings have the active nitrogen-containing group of good biological on aromatic ring.
Summary of the invention
Of the present invention contain the triazole ring naphthoyl imines antineoplastic compound mainly 5 on aromatic ring system introduce five yuan of triazole ring, by aromatic ring substituent form design synthesized a class novel contain 1,2,3-triazoles lopps naphthalimide compound.Its objective is: synthesized the naphthalimide compound that a class contains the 1,2,3-triazoles ring, evidence its inhibition ability the tumor cell in vitro growth by link reaction (Click chemistry) design.
The present invention solves the problems of the technologies described above the technical scheme that is adopted: a class contains the triazole ring naphthoyl imines antineoplastic compound, and its chemical molecular general structure is as follows:
In the formula (1):
R
1For the C1-C6 alkyl,
Or
Or phenyl ring.
Wherein, R
5, R
6All be all methyl, ethyl, or R
5+ R
6Be piperazine ring, morpholine ring, thiomorpholine ring, n=2～4.
Described antineoplastic compound is respectively N-(N
/, N
/-dimethyl aminoethyl) Phenyltriazole base naphthalimide, N-(N
/, N
/-diethylamide ethyl) Phenyltriazole base naphthalimide, N-butyl phenyl triazolyl naphthalimide, N-(2
/-hydroxyethyl) Phenyltriazole base naphthalimide, N-(2
/-piperazinyl ethyl) Phenyltriazole base naphthalimide, N-(N
/, N
/-dimethyl aminoethyl) triazolyl naphthalimide, N-(N
/, N
/-diethylamide ethyl) triazolyl naphthalimide, N-triazbutil base naphthalimide, N-(2
/-hydroxyethyl) triazolyl naphthalimide, N-(2
/-piperazinyl ethyl) triazolyl naphthalimide.
The described preparation method who contains the triazole ring naphthoyl imines antineoplastic compound: with 3-nitro-1,8 naphthalene acid anhydride is raw material, makes catalyzer in room temperature with Pd/C in the DMF solvent, 1.5MPa H
2Under reduced 3 hours, obtain an intermediate compound; This intermediate compound adds the sodium azide aqueous solution of 1 times of molar weight in 0～5 ℃ of sodium nitrite in aqueous solution that is suspended in 1 times of molar weight of adding among the dense HCl after half an hour, react after 1 hour, filters and obtains another intermediate compound; This intermediate compound is by " Click Chemistry " reaction, promptly at CuSO
4Exist down with sodium ascorbate, add phenylacetylene or feed acetylene gas in solvent tertiary butanol and water, product that obtains and corresponding primary amines reflux in ethanol and can obtain the above-described naphthalimide compound that contains triazole ring in 3 hours.
Introduce below and contain triazole ring naphthoyl imines antineoplastic compound synthetic route:
R in the formula
1Definition with mentioned above identical.
With 3-nitro-1,8 naphthalene acid anhydride (compound (2)) is raw material, passes through the step a (reaction conditions of step a: Pd/C catalyzer, 1.5MPa H successively
2, room temperature reaction 3 hours), step b (step b reaction conditions: HCl/NaNO
2, ice-water bath reaction down dripped NaN after 2 hours
3Solution reacted 1 hour down at 0～5 ℃) and the step c (reaction conditions of step c: t-BuOH/H
2O is at CuSO
4Exist down with sodium ascorbate, add phenylacetylene, reaction is 8 hours under room temperature.) obtain compound (3).Compound (3) is through the steps d (reaction conditions of steps d: with H
2NR
1, in ethanol, refluxed 3 hours) and obtain target compound (4).
Be raw material with 3-nitro-1,8 naphthalene acid anhydride (compound (2)) in addition, pass through the step a (reaction conditions of step a: Pd/C catalyzer, 1.5MPa H successively
2, room temperature reaction 3 hours), step b (step b reaction conditions: HCl/NaNO
2, ice-water bath reaction down dripped NaN after 2 hours
3Solution reacted 1 hour down at 0～5 ℃) and the step e (reaction conditions of step e: t-BuOH/H
2O is at CuSO
4Exist with sodium ascorbate, feed acetylene gas, reaction is 8 hours under room temperature) obtain compound (5).Compound (5) is through the step f (reaction conditions of step f: with H
2NR
1, in ethanol, refluxed 3 hours) and obtain target compound (6).
The following describes and contain the experimental technique of triazole ring naphthoyl imines antineoplastic compound tumour cell vitro inhibition growth activity:
(1) compound adopts the tetrazole reduction method that MOLT-4 human leukemia cell line, U251 human glioma cell strain are experimentized to tumour cell vitro inhibition growth activity.Method is by different tumor growth rates, and the tumour cell 90 μ L/ holes that some amount are in logarithmic phase are inoculated in the 96 hole microtest plates, adds soup 10 μ L/ holes behind the cultivation 24h, and to each cell strain, each concentration is three multiple holes.If establishing acellular zeroing hole medicine, other have color will do the acellular zeroing of relative medicine concentration hole.Tumour cell is at 37 ℃, 5%CO
2After cultivating 48h under the condition, add MTT (Sigma) liquid 5mg/mL and prepare the 20L/ hole with physiological saline; After continue cultivating 4h, (the 50 μ L/ holes of 10%SDS-5% isopropylcarbinol-0.01mol/1HCl) are in CO to add three liquid
2Spend the night in the incubator.Survey the OD570 value with microplate reader then.Calculate the inhibiting rate of analyte by following formula to growth of cancer cells:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%.
(2) adopt sulphonyl rhodamine B protein staining method that the A-549 human lung adenocarcinoma cell line is experimentized, method is according to cell growth rate, the tumour cell that will be in logarithmic phase is inoculated in 96 well culture plates with 90 μ L/ holes, adherent growth 24h, dosing 10 μ L/ holes again.Each concentration is established three multiple holes.And the physiological saline solvent of establishing respective concentration contrasts and acellular zeroing hole.Tumour cell is at 37 ℃, 5%CO
2Cultivated 72 hours under the condition, the nutrient solution that inclines then with 10% cold TCA fixed cell, is used distilled water wash 5 times, seasoning in the air behind 4 ℃ of placement 1h.Add SRB (Sigma) the 4mg/mL solution 100 μ L/ holes by the preparation of 1% Glacial acetic acid then, the 15min that dyes in the room temperature removes supernatant liquor, with 1% acetic acid washing 5 times, dry air.The Tris solution that adds 150 μ L/ holes at last, microplate reader 520nm wavelength are measured the A value down.Calculate the inhibiting rate of analyte by following formula to growth of cancer cells:
Tumor control rate=(A
540 control wells-A
540 dosing holes)/A
540 control wells* 100%.
The invention has the beneficial effects as follows: this triazole ring naphthoyl imines antineoplastic compound that contains is by introduce five yuan 1 on the naphthalimide parent, 2, the 3-triazole ring, come compound is designed synthetic with the substituting group form, this compounds has good antineoplastic activity, and the normal growth of the tumour cell (as people's lung cancer, neuroglia cancer etc.) of multiple different tissue sources and the heritable variation cell of multiple different sources (as leukemia cell etc.) is had good inhibitory effect.
Embodiment
The present invention is further illustrated below by embodiment.
Embodiment 1:
N-(N
/, N
/-dimethyl amido ethyl)-5-(4-phenyl-[1,2,3]-triazole)-naphthalimide (compound 1) synthetic:
(1) in the 200ml autoclave, add 7.5g 3-nitro-1,8 naphthalene acid anhydride, 0.5g Pd/C catalyzer and DMF 50ml, emptying 6 times charges into 1.5MPa hydrogen, and reaction is 3 hours under room temperature, stopped reaction when hydrogen pressure no longer descends.Leach the Pd/C catalyzer, filtrate is poured in the 500ml frozen water, separate out the orange precipitation, filter, washing, oven dry gets orange solid 5.7g, productive rate 86.7%.Fusing point＞300 ℃
(2) in the 100ml bottle with two necks, add 4.1g 3-amido-1,8 naphthalene acid anhydride, the 30ml concentrated hydrochloric acid was with trash ice cooling 20 minutes.1.2g NaNO2 is dissolved in the 15ml water, is added dropwise in the reaction system, add in 1 hour, continue reaction 1 hour, temperature is no more than 5 ℃.Then 1.1g NaN3 is dissolved in the 10ml water, is added dropwise to reaction system, reacted 1 hour, withdraw from trash ice and bathe.Reaction solution is poured in the 300ml frozen water, separated out yellow mercury oxide, filter, be washed to neutrality, oven dry obtains yellow solid 4.0g, productive rate 86.9%.IR(KBr，cm-1)：3050，2155，1770，1730，1601，1521。
(3) in 100ml single port bottle, add 2.0g (8.2mmol) 3-nitrine-1,8 naphthalene acid anhydride, 0.85g (8.2mmol) phenylacetylene and 10ml t-BuOH and 10ml water mixed liquid, add 88mg (0.4mmol) sodium ascorbate again and 10mg (0.04mmol) CuSO45H20 at room temperature reacted 8 hours, TLC follows the tracks of reaction to fully, and reaction solution is poured in the 300ml frozen water, separate out yellow mercury oxide, leave standstill, filter, washing, the yellow solid 2.65g of oven dry, productive rate 92.3%.Fusing point＞300 ℃.
1H?NMR(d6-DMSO，400MHz)：δ(ppm)：7.25(t，J1＝6.8Hz，J2＝7.2Hz，1H)，7.31(t，J1＝7.2Hz，J2＝7.6Hz，2H)，7.62(m，3H)，8.21(m，2H)，8.41(s，1H)，8.62(s，1H)，9.01(s，1H)。
HR-MS (m/z): C
20H
11N
3O
3, calculated value: 341.0800, measured value: 341.0789.
(4) in 25ml single port bottle, add 0.47g step (3) synthetic product and dehydrated alcohol 15ml, add N/ again, N/-dimethyl-ethylenediamine 0.3ml.Magnetic agitation, temperature rising reflux 3 hours, TLC are followed the tracks of reaction to complete.Filter, the gained solid separates through silica gel column chromatography, obtains target product (compound 1) 0.47g, productive rate 83%.205.3～206.1 ℃ of fusing points.
1H?NMR(d6-DMSO，400MHz)：δ(ppm)：2.25(s，6H)，2.57(t，J1＝6.4Hz，J2＝6.8Hz，2H)，4.17(t，J1＝6.4Hz，J2＝6.8Hz，2H)，7.40(t，J1＝7.2Hz，J2＝7.2Hz，1H)，7.51(t，J1＝7.6Hz，J2＝7.6Hz，2H)，7.95(m，3H)，8.50(m，2H)，8.92(s，1H)，8.99(s，1H)，9.59(s，1H)。
HR-MS (m/z): C
24H
21N
5O
2, calculated value: 411.1695, measured value: 411.1703.
IR(KBr，cm-1)：2942，2775，1698，1662，1596，1477，1384，1338，1261，1238，1151，1043，883，781。
Embodiment 2:
Synthesizing of N-(N/, N/-diethyl amido ethyl)-5-(4-phenyl-[1,2,3]-triazole)-naphthalimide (compound 2):
Remove and use N/, the N/-diethyl ethylenediamine substitutes N/, and outside the N/-dimethyl-ethylenediamine, other synthetic method of purification that reaches obtains target compound 2,191.1～192.3 ℃ of fusing points with embodiment 1.
1H?NMR(d6-DMSO，400MHz)：δ(ppm)：0.97(t，J1＝6.8Hz，J2＝7.2Hz，6H)，2.50(m，4H)，2.68(t，J1＝7.2Hz，J2＝7.2Hz，2H)，4.12(t，J1＝6.8Hz，J2＝7.2Hz，2H)，7.42(t，J1＝7.6Hz，J2＝7.2Hz，1H)，7.52(t，J1＝7.6Hz，J2＝7.6Hz，2H)，7.98(m，3H)，8.50(m，2H)，8.93(d，J＝2Hz，1H)，9.0(d，J＝2.4Hz，1H)，9.62(s，1H)。
HR-MS (m/z): C
26H
25N
5O
2, calculated value: 439.2008, measured value: 439.2001.
IR(KBr，cm-1)：2971，2803，1702，1664，1627，1517，1477，1380，1361，1290，1257，1203，1172，1050，881，765。
Embodiment 3:
Synthesizing of N-butyl-5-(4-phenyl-[1,2,3]-triazole)-naphthalimide (compound 3):
Remove with n-Butyl Amine 99 and substitute N/, outside the N/-dimethyl-ethylenediamine, other synthetic method of purification that reaches obtains target compound 3,195.5～196.7 ℃ of fusing points with embodiment 1.
1H?NMR(d6-DMSO，400MHz)：δ(ppm)：0.94(t，J1＝7.2Hz，J2＝7.2Hz，3H)，1.37(m，2H)，1.64(m，2H)，4.05(t，J1＝7.2Hz，J2＝7.6Hz，2H)，7.41(t，J1＝7.2Hz，J2＝7.6Hz，1H)，7.52(t，J1＝7.6Hz，J2＝7.6Hz，2H)，7.97(m，3H)，8.51(m，2H)，8.93(d，J＝1.6Hz，1H)，9.0(d，J＝2.4Hz，1H)，9.62(s，1H)。
HR-MS (m/z): C
24H
20N
4O
2, calculated value: 396.1586, measured value: 396.1590.
IR(KBr，cm-1)：2950，1708，1669，1630，1510，1472，1378，1361，1293，1245，1201，1172，1055，883，780。
Embodiment 4:
Synthesizing of N-(2/-hydroxyethyl)-5-(4-phenyl-[1,2,3]-triazole)-naphthalimide (compound 4):
Remove with thanomin and substitute N/, outside the N/-dimethyl-ethylenediamine, other synthetic method of purification that reaches obtains target compound 4,257.3～258.6 ℃ of fusing points with embodiment 1.
1H?NMR(d6-DMSO，400MHz)：δ(ppm)：3.61(d，J＝5.6Hz，2H)，4.20(d，J＝5.2Hz，2H)，4.92(s，1H)，7.42(t，J1＝6.8Hz，J2＝6.8Hz，1H)，7.53(t，J1＝6.4Hz，J2＝7.2Hz，2H)，7.97(m，3H)，8.52(m，2H)，8.93(s，1H)，9.00(s，1H)，9.60(s，1H)。
HR-MS (m/z): C
22H
16N
4O
3, calculated value: 384.1222 measured values: 384.1230.
IR(KBr，cm-1)：3630，1710，1655，1600，1510，1450，1330，1230，1156，1112，1015，825。
Embodiment 5:
Synthesizing of N-(2/-piperazinyl ethyl)-5-(4-phenyl-[1,2,3]-triazole)-naphthalimide (compound 5):
Remove with 1-(2-amino-ethyl) piperazine and substitute N/, outside the N/-dimethyl-ethylenediamine, other synthetic method of purification that reaches obtains target compound 5,250.2～251.7 ℃ of fusing points with embodiment 1.
1H?NMR(d6-DMSO，400MHz)：δ(ppm)：2.50(s，4H，NHCH
2NCH
2)，2.60(t，J1＝6.8Hz，J2＝7.2Hz，2H)，2.76(s，4H，NCH
2)，4.19(t，J1＝6.4Hz，J2＝6.4Hz，2H)，7.41(t，J1＝7.2Hz，J2＝7.2Hz，1H)，7.53(t，J1＝7.6Hz，J2＝7.6Hz，2H)，7.96(m，3H)，8.52(m，2H)，8.95(s，1H)，9.01(s，1H)，9.63(s，1H)。
HR-MS (m/z): C
26H
24N
6O
2, calculated value: 452.1961, measured value: 452.1986.
IR(KBr，cm-1)：2919，1700，1662，1625，1590，1519，1436，1234，1149，1041，840。
Embodiment 6:
Synthesizing of N-(N/, N/-dimethyl amido ethyl)-5-([1,2,3]-triazole)-naphthalimide (compound 6)
Except that substituting the phenylacetylene with acetylene, other synthetic method of purification that reaches obtains target compound 6,226.3～227.5 ℃ of fusing points with embodiment 1.
H?NMR(d6-DMSO，400MHz)：δ(ppm)：2.24(s，6H)，2.51(t，J1＝6.4Hz，J2＝6.8Hz，2H)，4.18(t，J1＝6.4Hz，J2＝6.8Hz，2H)，7.96(t，J1＝7.6Hz，J2＝8Hz，1H)，8.10(d，J＝1.2Hz，1H)，8.53(t，J1＝7.2Hz，J2＝7.2Hz，2H)，8.93(d，J＝2.4Hz，1H)，9.02(d，J＝2Hz，1H)，9.16(d，J＝1.2Hz，1H)。
HR-MS (m/z): C
18H
17N
5O
2, calculated value: 335.1382, measured value: 335.1382.
IR(KBr，cm-1)：2923，2815，2771，1700，1656，1627，1598，1471，1381，1292，1240，1174，1058，890，790。
Embodiment 7:
Synthesizing of N-(N/, N/-diethyl amido ethyl)-5-([1,2,3]-triazole)-naphthalimide (compound 7):
Remove and use N/, the N/-diethyl ethylenediamine substitutes N/, and outside the N/-dimethyl-ethylenediamine, other synthetic method of purification that reaches obtains target compound 7,200.5～201.5 ℃ of fusing points with embodiment 6.
1H?NMR(d6-DMSO，400MHz)：δ(ppm)：0.97(t，J1＝7.2Hz，J2＝6.8Hz，6H)，2.56(s，4H)，2.68(s，2H)，4.13(t，J1＝7.2Hz，J2＝6.8Hz，2H)，7.95(t，J1＝7.6Hz，J2＝7.6Hz，1H)，8.10(s，1H)，8.52(t，J1＝7.6Hz，J2＝6.4Hz，2H)，8.93(d，J＝2Hz，1H)，9.02(d，J＝2Hz，1H)，9.16(s，1H)。
HR-MS (m/z): C
20H
21N
5O
2, calculated value: 363.1695, measured value: 363.1701.
IR(KBr，cm-1)：2925，2811，2750，1711，1651，1616，1601，1462，1376，1276，1233，1168，1043，891，793。
Embodiment 8:
Synthesizing of N-butyl-5-([1,2,3]-triazole)-naphthalimide (compound 8):
Remove with n-Butyl Amine 99 and substitute N/, outside the N/-dimethyl-ethylenediamine, other synthetic method of purification that reaches obtains target compound 8,191.9～193.1 ℃ of fusing points with embodiment 6.
1H?NMR(d6-DMSO，400MHz)：δ(ppm)：0.94(t，J1＝7.2Hz，J2＝7.6Hz，3H)，1.37(m，2H)，1.64(m，2H)，4.05(t，J1＝7.2Hz，J2＝7.2Hz，2H)，7.94(t，J1＝8Hz，J2＝7.6Hz，1H)，8.10(s，1H)，8.50(m，2H)，8.89(d，J＝2Hz，1H)，8.99(d，J＝2Hz，1H)，9.15(s，1H)。
HR-MS (m/z): C
18H
16N
4O
2, calculated value: 320.1273, measured value: 320.1278.
IR(KBr，cm-1)：2930，2825，2750，1706，1655，1613，1601，1451，1376，1280，1233，1150，1052，890，795。
Embodiment 9:
Synthesizing of N-(2/-hydroxyethyl)-5-([1,2,3]-triazole)-naphthalimide (compound 9):
Remove with thanomin and substitute N/, outside the N/-dimethyl-ethylenediamine, other synthetic method of purification that reaches obtains target compound 9,257.3～258.6 ℃ of fusing points with embodiment 6.
1H?NMR(d6-DMSO，400MHz)：δ(ppm)：3.71(d，J＝5.6Hz，2H)，4.35(d，J＝5.2Hz，2H)，4.96(s，1H)，7.93(t，J1＝8Hz，J2＝7.6Hz，1H)，8.09(s，1H)，8.51(m，2H)，8.89(d，J＝2Hz，1H)，8.98(d，J＝2.4Hz，1H)，9.16(s，1H)。
HR-MS (m/z): C
16H
12N
4O
3, calculated value 308.0909: measured value: 308.0915.
IR(KBr，cm-1)：3660，1706，1651，1607，1518，1432，1330，1235，1152，1111，1012，821。
Embodiment 10:
Synthesizing of N-(2/-piperazinyl ethyl)-5-([1,2,3]-triazole)-naphthalimide (compound 10):
Remove with 1-(2-amino-ethyl) piperazine and substitute N/, outside the N/-dimethyl-ethylenediamine, other synthetic method of purification that reaches obtains target compound 10,250.2～251.7 ℃ of fusing points with embodiment 6.
1H?NMR(d6-DMSO，400MHz)：δ(ppm)：2.53(s，4H，NHCH
2NCH
2)，2.65(t，J1＝7.2Hz，J2＝7.2Hz，2H)，2.78(s，4H，NCH
2)，4.19(t，J1＝6.8Hz，J2＝7.2Hz，2H)，7.92(t，J1＝7.2Hz，J2＝7.6Hz，1H)，8.09(s，1H)，8.51(m，2H)，8.88(d，J＝2.4Hz，1H)，8.99(d，J＝2Hz，1H)，9.15(s，1H)。
HR-MS (m/z): C
20H
20N
6O
2, calculated value: 376.1648, measured value: 376.1645.
IR(KBr，cm-1)：2911，1705，1650，1610，1590，1510，1429，1229，1130，1050，833。
Embodiment 11:
Measure the extracorporeal suppression tumor cell growth activity of compound:
(microculture tetrozolium, MTT) reduction method is carried out body outer suppressioning test to MOLT-4 human leukemia cell and U251 human glioma cell with tetrazolium.
The concrete operations of tetrazolium (MTT) reduction method are: by different tumor growth rates, the tumour cell 90 μ l/ holes that some amount are in logarithmic phase are inoculated in the 96 hole microtest plates, add soup 10 μ l/ holes after cultivating 24h, to each cell strain, each concentration is three multiple holes.If establishing acellular zeroing hole medicine, other have color will do the acellular zeroing of relative medicine concentration hole.Tumour cell is cultivated after 48 hours under 37 ℃, 5%CO2 condition, adds MTT (Sigma) liquid 5mg/ml and prepares 20 μ l/ holes with physiological saline; Continue to cultivate after 4 hours, (spend the night in the CO2 incubator in the 50 μ l/ holes of 10%SDS-5% isopropylcarbinol-0.01mol/1HCl) to add three liquid.Survey the OD570 value with microplate reader then.Calculate the inhibiting rate of analyte by following formula to growth of cancer cells:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%.
Table 1. compound 1-10 is to U251 human glioma cell's growth inhibition ratio
Table 2. compound 2 and 7 couples of MOLT-4 human leukemia cells' growth inhibition ratio
(Sulforhodamine B, SRB) the protein staining method is carried out body outer suppressioning test to the A-549 human lung adenocarcinoma cell with the sulphonyl rhodamine B.
Sulphonyl rhodamine B (Sulforhodamine B, SRB) concrete operations of protein staining method are as follows: according to cell growth rate, the tumour cell that will be in logarithmic phase is inoculated in 96 well culture plates with 90 μ l/ holes, and adherent growth 24 hours is dosing 10 μ l/ holes again.Each concentration is established three multiple holes.And the physiological saline solvent of establishing respective concentration contrasts and acellular zeroing hole.Tumour cell was cultivated 72 hours under 37 ℃, 5%CO2 condition, and the nutrient solution that inclines then with 10% cold TCA fixed cell, is placed after 1 hour the usefulness distilled water wash 5 times, seasoning in the air for 4 ℃.Add SRB (Sigma) the 4mg/ml solution 100 μ l/ holes by the preparation of 1% Glacial acetic acid then, dyeing is 15 minutes in the room temperature, removes supernatant liquor, with 1% acetic acid washing 5 times, dry air.The Tris solution that adds 150 μ l/ holes at last, microplate reader 520nm wavelength are measured the A value down.Calculate the inhibiting rate of analyte by following formula to growth of cancer cells:
Tumor control rate=(A540
Control wells-A540
Dosing holes)/A540
Control wells* 100%.
Table 3: the growth inhibition ratio of compound 2 and 7 pairs of A-549 human lung adenocarcinoma cells
From above data as can be seen, compound has significant inhibition activity of tumor cells.
Claims (3)
1, a class contains the triazole ring naphthoyl imines antineoplastic compound, it is characterized in that the chemical molecular general structure of this compound is as follows:
In the formula:
R
1Be C
1-C
6Alkyl,
Or
Be H or phenyl ring;
Wherein, R
5, R
6All be all methyl, ethyl, or R
5+ R
6Be piperazine ring, morpholine ring, thiomorpholine ring, n=2～4.
2, according to the described triazole ring naphthoyl imines antineoplastic compound that contains of claim 1, it is characterized in that: described antineoplastic compound is respectively N-(N
/, N
/-dimethyl aminoethyl) Phenyltriazole base naphthalimide, N-(N
/, N
/-diethylamide ethyl) Phenyltriazole base naphthalimide, N-butyl phenyl triazolyl naphthalimide, N-(2
/-hydroxyethyl) Phenyltriazole base naphthalimide, N-(2
/-piperazinyl ethyl) Phenyltriazole base naphthalimide, N-(N
/, N
/-dimethyl aminoethyl) triazolyl naphthalimide, N-(N
/, N
/-diethylamide ethyl) triazolyl naphthalimide, N-triazbutil base naphthalimide, N-(2
/-hydroxyethyl) triazolyl naphthalimide or N-(2
/-piperazinyl ethyl) triazolyl naphthalimide.
3, the described preparation method who contains the triazole ring naphthoyl imines antineoplastic compound is characterized in that: with 3-nitro-1,8 naphthalene acid anhydride is raw material, makes catalyzer with Pd/C in the DMF solvent, in room temperature, and 1.5MPa H
2Under reduced 3 hours, obtain an intermediate compound; This intermediate compound adds the sodium azide aqueous solution of 1 times of molar weight in 0～5 ℃ of sodium nitrite in aqueous solution that is suspended in 1 times of molar weight of adding among the dense HCl after half an hour, react after 1 hour, filters and obtains another intermediate compound; This intermediate compound is by " Click Chemistry " reaction, promptly at CuSO
4Exist down with sodium ascorbate, add phenylacetylene or feed acetylene gas in solvent tertiary butanol and water, product that obtains and corresponding primary amines reflux in ethanol and can obtain the above-described naphthalimide compound that contains triazole ring in 3 hours.
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