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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- CN101284827A CN101284827A CNA2008100117005A CN200810011700A CN101284827A CN 101284827 A CN101284827 A CN 101284827A CN A2008100117005 A CNA2008100117005 A CN A2008100117005A CN 200810011700 A CN200810011700 A CN 200810011700A CN 101284827 A CN101284827 A CN 101284827A
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- naphthalimide
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- ethyl
- triazolyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 54
- -1 triazole ring naphthoyl imines Chemical class 0.000 title claims description 30
- 230000000118 anti-neoplastic effect Effects 0.000 title claims description 15
- 238000000034 method Methods 0.000 title description 6
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 150000003852 triazoles Chemical class 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- LUEYUHCBBXWTQT-UHFFFAOYSA-N 4-phenyl-2h-triazole Chemical compound C1=NNN=C1C1=CC=CC=C1 LUEYUHCBBXWTQT-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 150000008065 acid anhydrides Chemical class 0.000 claims description 7
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 7
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 5
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 5
- 229960005055 sodium ascorbate Drugs 0.000 claims description 5
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 3
- 235000010288 sodium nitrite Nutrition 0.000 claims description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 150000003141 primary amines Chemical class 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 abstract description 20
- 210000004881 tumor cell Anatomy 0.000 abstract description 15
- 230000012010 growth Effects 0.000 abstract description 8
- 206010028980 Neoplasm Diseases 0.000 abstract description 7
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 208000032839 leukemia Diseases 0.000 abstract description 5
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 2
- 201000011510 cancer Diseases 0.000 abstract description 2
- 201000005202 lung cancer Diseases 0.000 abstract description 2
- 208000020816 lung neoplasm Diseases 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 abstract 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 abstract 1
- 238000006482 condensation reaction Methods 0.000 abstract 1
- 238000006193 diazotization reaction Methods 0.000 abstract 1
- 230000002518 glial effect Effects 0.000 abstract 1
- 239000011159 matrix material Substances 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 11
- 238000004896 high resolution mass spectrometry Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 9
- 230000002194 synthesizing effect Effects 0.000 description 9
- 238000010189 synthetic method Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000012491 analyte Substances 0.000 description 4
- 230000005907 cancer growth Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 3
- 208000032612 Glial tumor Diseases 0.000 description 3
- 206010018338 Glioma Diseases 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 201000005249 lung adenocarcinoma Diseases 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 229940043267 rhodamine b Drugs 0.000 description 3
- 238000007447 staining method Methods 0.000 description 3
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 2
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- IMUDHTPIFIBORV-UHFFFAOYSA-N aminoethylpiperazine Chemical compound NCCN1CCNCC1 IMUDHTPIFIBORV-UHFFFAOYSA-N 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 235000011194 food seasoning agent Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000009830 intercalation Methods 0.000 description 2
- 230000002687 intercalation Effects 0.000 description 2
- 229910000474 mercury oxide Inorganic materials 0.000 description 2
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 2
- 239000010813 municipal solid waste Substances 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 235000014347 soups Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 150000000177 1,2,3-triazoles Chemical class 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical group C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 1
- XXVLKDRPHSFIIB-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 XXVLKDRPHSFIIB-UHFFFAOYSA-N 0.000 description 1
- WSNKEJIFARPOSQ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(1-benzothiophen-2-ylmethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC3=C(S2)C=CC=C3)C=CC=1 WSNKEJIFARPOSQ-UHFFFAOYSA-N 0.000 description 1
- UPALIKSFLSVKIS-UHFFFAOYSA-N 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione Chemical compound NC1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 UPALIKSFLSVKIS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229960004701 amonafide Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229950001745 mitonafide Drugs 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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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