CN104945386A - Pyrazole nitro imidazole derivative containing secnidazole framework and preparation method thereof and application - Google Patents
Pyrazole nitro imidazole derivative containing secnidazole framework and preparation method thereof and application Download PDFInfo
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- -1 Pyrazole nitro imidazole derivative Chemical class 0.000 title claims abstract description 23
- KPQZUUQMTUIKBP-UHFFFAOYSA-N 1-(2-methyl-5-nitro-1-imidazolyl)-2-propanol Chemical compound CC(O)CN1C(C)=NC=C1[N+]([O-])=O KPQZUUQMTUIKBP-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229960004076 secnidazole Drugs 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 24
- 229940058965 antiprotozoal agent against amoebiasis and other protozoal diseases nitroimidazole derivative Drugs 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
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- 239000003814 drug Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
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- WCDWBPCFGJXFJZ-UHFFFAOYSA-N etanidazole Chemical compound OCCNC(=O)CN1C=CN=C1[N+]([O-])=O WCDWBPCFGJXFJZ-UHFFFAOYSA-N 0.000 description 1
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- OBBCSXFCDPPXOL-UHFFFAOYSA-N misonidazole Chemical compound COCC(O)CN1C=CN=C1[N+]([O-])=O OBBCSXFCDPPXOL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pyrazole nitro imidazole derivative containing a secnidazole framework and a preparation method thereof and application. The structure of the pyrazole nitro imidazole derivative synthesized by secnidazole is shown as the formula (please see the formula in the specification), wherein R1 is selected from H, CH3, Br, CF3, OCH3, NO2, OCH2CH3, C1, F and I. The pyrazole nitro imidazole derivative has the obvious inhibiting effects on human hepatoma cells (HEPG2), human breast cancer cells (MCF-7), human cervical cancer cell lines (HeLa cells) and mouse melanoma cells (B16-F10), and therefore the pyrazole nitro imidazole derivative containing the secnidazole framework can be applied to prepare antineoplastic drugs.
Description
Technical field
The invention belongs to medicinal chemistry art, particularly relate to containing the pyrazoles nitro imidazole derivatives of secnidazole skeleton, its preparation method and application.
Background technology
EGF-R ELISA and homology HER-2/ErbB-2 protein kinase belong to I type or ErbB/HER receptor tyrosine kinase family, with the increment of cell, survive, stick, to move and differentiation has close ties.Be antibumor molecules target spot the most feasible in family four members, other be HER-3andHER-4 respectively.In mammary gland, ovary, nonsmall-cell lung cancer, often can find EGF-R ELISA and HER-2 overexpression or activated mutant, make them become the therapeutic goal of these cancers.EGF-R ELISA and HER-2 become current research focus, and their overexpression and abnormal activation can cause malignant transformation of cells usually.And they are bad with postoperative, radiation and chemotherapy tolerates and tumor-blood-vessel growth is relevant.The blockade of EGFR and ErbB-2 has been become an attractive method of oncotherapy by clinical verification.
In former research, secnidazole, a kind of nitroimidazoles medicine, because it is to the avidity of the molecule marker of hypoxic tumors or noumenal tumour low-oxygen area, has been widely studied and has used as radiosensitizer.2-nitro imidazole derivatives, such as Misonidazole, etanidazole, be in the news and had effective radiosensitizing effect.In machine-processed aspect, nitro imidazole derivatives shows the tendency in tumor area infiltration and accumulation, and can carry out the close isoelectric substance that reduction reaction generation can destroy protein and nucleic acid, and this causes sizable concern.As far as we know, the synthesis described in some reported literatures and the compound with EGFR inhibit activities are published in 2 modifications of nitroimidazole ring.Clearly, keying action is played in the metabolism activation of secnidazole hydroxyl and nitro.It is new that the hydroxyl that secnidazole derivative replaces may promise to be exploitation, effective and safe lead compound.
Summary of the invention
The object of the present invention is to provide a class as EGFR/HER-2 inhibitor containing the pyrazoles nitro imidazole derivatives of secnidazole skeleton, its preparation method and the application in cancer therapy drug thereof.
Technical scheme: a class containing the pyrazoles nitro imidazole derivatives of secnidazole skeleton, its structure such as formula shown,
Wherein, R
1be selected from H, CH
3, Br, CF
3, OCH
3, NO
2, OCH
2cH
3, Cl, F, I.
Prepare a method for the pyrazoles nitro imidazole derivatives containing secnidazole skeleton, the structure of the described pyrazoles nitro imidazole derivatives containing secnidazole skeleton such as formula shown,
Wherein, R
1be selected from H, CH
3, Br, CF
3, OCH
3, NO
2, OCH
2cH
3, Cl, F, I.
Preparation method comprises the steps:
Under step 1. room temperature condition, add structure successively such as formula the compound shown in A in reaction vessel, structure is such as formula the compound shown in B and dehydrated alcohol reaction.Then add rapidly NaOH to stir, TLC follows the tracks of reaction, fully after reaction, obtains structure such as formula the compound shown in C.
Step 2. adds Glacial acetic acid successively in reaction vessel, and hydrazine hydrate and structure are such as formula the compound shown in C, and 120 DEG C of backflows, TLC follows the tracks of reaction, fully after reaction, obtains structure such as formula the compound shown in D.
Step 3. adds dichloromethane solution successively in reaction vessel, structure such as formula the compound shown in D, secnidazole, and catalyzer EDC, DMAP.TLC follows the tracks of reaction, fully reacts, and obtains structure such as formula the compound shown in E.
In formula A ~ E, R
1be selected from H, CH
3, Br, CF
3, OCH
3, NO
2, OCH
2cH
3, Cl, F, I.
Pyrazoles nitro imidazole derivatives containing secnidazole skeleton is preparing the application in cancer therapy drug, and its structure is such as formula shown
Wherein, R
1be selected from H, CH
3, Br, CF
3, OCH
3, NO
2, OCH
2cH
3, Cl, F, I.
A kind of cancer therapy drug, comprises structure such as formula shown compound and medically acceptable carrier,
Wherein, R
1be selected from H, CH
3, Br, CF
3, OCH
3, NO
2, OCH
2cH
3, Cl, F, I.
The present invention is to human liver cancer cell (HEPG2), human breast cancer cell (MCF-7), Human cervical cancer cell lines (HeLa cell) and mouse melanin tumor cell (B16-F10) have obvious restraining effect, and therefore the pyrazoles nitro imidazole derivatives containing secnidazole skeleton of the present invention can be applied to and prepare antitumor drug.
Embodiment
In certain specific embodiment, the structural formula of preparation process of the present invention and associated products is as described below:
Prepare a method for the above-mentioned pyrazoles nitro imidazole derivatives containing secnidazole skeleton, it comprises the following steps:
Step 1. at room temperature, adds 20ml dehydrated alcohol in round-bottomed flask, then adds compound 2a-j (5mmol) successively, 4-formylbenzoate (5mmol) and NaOH/H
2o (1: 10) (5ml), at room temperature stirs 8 hours.Form throw out, leach after dripping hydrochloric acid (1M) to reaction soln.Recrystallization from ethanol, and with ice cold water (25mL) three washings, obtain pure products 3a-j.
Step 2. adds Glacial acetic acid 20ml in round-bottomed flask, then adds the compound 3a-j (1mmol) of synthesis, with hydrazine hydrate (4mmol).Stirring reaction at 120 DEG C, refluxes 12 hours, obtains compound 4a-j.
Step 3. adds dichloromethane solution 10ml in round-bottomed flask, then adds the compound 4a-j (2mmol) of synthesis, secnidazole (2mmol), EDCHCl (3mmol) and DMAP (1mmol).Stirred solution 56 DEG C spends the night, and TLC follows the tracks of reaction, after reaction terminates, filters, solid distilled water wash, last vacuum-drying, the solid obtained is dissolved in the purification of dehydrated alcohol recrystallization and obtains target compound 5a-j.
The preparation of embodiment one: 1-(2-5-nitro imidazole)-2-propyl group-4-(1-ethanoyl-3-phenyl-4,5-pyrazoline) methyl benzoate (5a)
At room temperature, in round-bottomed flask, add 20ml dehydrated alcohol, then add compound 2a (5mmol) successively, 4-formylbenzoate (5mmol) and NaOH/H
2o (1: 10) (5ml), at room temperature stirs 8 hours.Form throw out, leach after dripping hydrochloric acid (1M) to reaction soln.Recrystallization from ethanol, and with ice cold water (25mL) three washings, obtain compound 3a.In clean round-bottomed flask, add Glacial acetic acid 20ml, then add the compound 3a (1mmol) of above-mentioned synthesis, with hydrazine hydrate (4mmol).Stirring reaction at 120 DEG C, refluxes 12 hours, obtains compound 4a.In clean round-bottomed flask, add dichloromethane solution 10ml, then add the compound 4a (2mmol) of synthesis, secnidazole (2mmol), EDCHCl (3mmol) and DMAP (1mmol).Stirred solution 56 DEG C spends the night, and TLC follows the tracks of reaction, after reaction terminates, filters, solid distilled water wash, last vacuum-drying, the solid obtained is dissolved in the purification of dehydrated alcohol recrystallization and obtains target compound.White solid, productive rate 62%, m.p.87 ~ 89 DEG C, 1H NMR (DMSO-d6, 300MHz) δ: 8.00 (s, 1H, CH), 7.84 ~ 7.77 (m, 4H, ArH), 7.52 ~ 7.45 (m, 3H, ArH), 7.34 (d, J=5.70Hz, 2H, ArH), 5.64 ~ 5.58 (m, 1H, CH), 5.48 ~ 5.41 (m, 1H, CH2), 4.71 ~ 4.64 (m, 1H, CH), 4.61 ~ 4.52 (m, 1H, CH2), 3.96 ~ 3.85 (m, 1H, CH2), 3.21 ~ 3.13 (m, 1H, CH2), 2.44 (t, J=4.68Hz, 3H, CH3), 2.33 (s, 3H, CH3), 1.41 (d, J=4.77Hz, 3H, CH3) .ESI-MS:m/z 475.5 (M+).
The preparation of embodiment two 1-(2-5-nitro imidazole)-2-propyl group-4-(1-ethanoyl-3-(4-bromophenyl)-4,5-pyrazolines) methyl benzoate (5b)
Preparation method's reference example one.White solid, yield 65%, m.p.104 ~ 107 DEG C, 1H NMR (DMSO-d6, 300MHz) δ: 8.00 (s, 1H, CH), 7.91 (d, J=6.12Hz, 1H, ArH), 7.80 (d, J=6.27Hz, 1H, ArH), 7.76 ~ 7.71 (m, 2H, ArH), 7.68 (d, J=6.51Hz, 2H, ArH), 7.36 ~ 7.30 (m, 2H, ArH), 5.65 ~ 5.58 (m, 1H, CH), 5.49 ~ 5.41 (m, 1H, CH2), 4.70 ~ 4.64 (m, 1H, CH), 4.61 ~ 4.52 (m, 1H, CH2), 3.94 ~ 3.84 (m, 1H, CH2), 3.21 ~ 3.13 (m, 1H, CH2), 2.44 (t, J=4.36Hz, 3H, CH3), 2.32 (s, 3H, CH3), 1.41 (d, J=4.95Hz, 3H, CH3) .ESI-MS:m/z 554.4 (M+).
The preparation of embodiment three: 1-(2-5-nitro imidazole)-2-propyl group-4-(1-ethanoyl-3-(4-(trifluoromethyl) phenyl)-4,5-pyrazolines) methyl benzoate (5c)
Preparation method's reference example one.Cream colored solid, productive rate 64%, m.p.105 ~ 107 DEG C, 1HNMR (DMSO-d6, 300MHz) δ: 7.99 (t, J=3.15Hz, 3H, CH and ArH), 7.86 ~ 7.77 (m, 4H, ArH), 7.34 (d, J=6.18Hz, 2H, ArH), 5.67 ~ 5.62 (m, 1H, CH), 5.48 ~ 5.39 (m, 1H, CH2), 4.69 ~ 4.63 (m, 1H, CH), 4.60 ~ 4.51 (m, 1H, CH2), 3.98 ~ 3.88 (m, 1H, CH2), 3.26 ~ 3.18 (m, 1H, CH2), 2.43 (d, J=2.73Hz, 3H, CH3), 2.33 (s, 3H, CH3), 1.40 (d, J=4.89Hz, 3H, CH3) .ESI-MS:m/z 543.5 (M+).
The preparation of embodiment four: 1-(2-5-nitro imidazole)-2-propyl group-4-(1-ethanoyl-3-(4-p-methoxy-phenyl)-4,5-pyrazolines) methyl benzoate (5d)
Preparation method's reference example one.Cream-colored crystals, productive rate 70%, m.p.92 ~ 93 DEG C, 1H NMR (DMSO-d6, 300MHz) δ: 8.00 (s, 1H, CH), 7.80 (d, J=6.36Hz, 2H, ArH), 7.73 (d, J=6.15Hz, 2H, ArH), 7.35 ~ 7.30 (m, 2H, ArH), 7.03 (d, J=6.50Hz, 2H, ArH), 5.61 ~ 5.55 (m, 1H, CH), 5.51 ~ 5.39 (m, 1H, CH2), 4.70 ~ 4.64 (m, 1H, CH), 4.61 ~ 4.52 (m, 1H, CH2), 3.90 ~ 3.84 (m, 1H, CH2), 3.81 (s, 3H, CH3), 3.17 ~ 3.09 (m, 1H, CH2), 2.44 (d, J=3.09Hz, 3H, CH3), 2.30 (s, 3H, CH3), 1.41 (d, J=4.83Hz, 3H, CH3) .ESI-MS:m/z 505.5 (M+).
The preparation of embodiment five: 1-(2-5-nitro imidazole)-2-propyl group-4-(1-ethanoyl-3-(4-nitrophenyl)-4,5-pyrazolines) methyl benzoate (5e)
Preparation method's reference example one.Cream colored solid, productive rate 68%, m.p.197 ~ 199 DEG C, 1HNMR (DMSO-d6, 300MHz) δ: 8.32 (d, J=6.45Hz, 2H, ArH), 8.07 ~ 7.99 (m, 3H, CHand ArH), 7.81 (d, J=6.24Hz, 2H, ArH), 7.36 (d, J=6.12Hz, 2H, ArH), 5.72 ~ 5.63 (m, 1H, CH), 5.49 ~ 5.41 (m, 1H, CH2), 4.70 ~ 4.64 (m, 1H, CH), 4.61 ~ 4.52 (m, 1H, CH), 4.01 ~ 3.92 (m, 1H, CH2), 3.29 ~ 3.22 (m, 1H, CH2), 2.44 (t, J=4.2Hz, 3H, CH3), 2.36 (s, 3H, CH3), 1.41 (d, J=4.77Hz, 3H, CH3) ..ESI-MS:m/z 520.5 (M+).
The preparation of embodiment six: 1-(2-5-nitro imidazole)-2-propyl group-4-(1-ethanoyl-3-p-methylphenyl-4,5-pyrazoline) methyl benzoate (5f)
Preparation method's reference example one.White solid, productive rate 68%, m.p.102 ~ 103 DEG C, 1H NMR (DMSO-d6, 300MHz) δ: 8.00 (s, 1H, CH), 7.80 (d, J=6.27Hz, 2H, ArH), 7.68 (d, J=6.12Hz, 2H, ArH), 7.33 (d, J=6.32Hz, 2H, ArH), 7.29 (d, J=6.57Hz, 2H, ArH), 5.63 ~ 5.56 (m, 1H, CH), 5.48 ~ 5.39 (m, 1H, CH2), 4.70 ~ 4.64 (m, 1H, CH), 4.61 ~ 4.52 (m, 1H, CH2), 3.92 ~ 3.82 (m, 1H, CH2), 3.17 ~ 3.10 (m, 1H, CH2), 2.44 (d, J=3.10Hz, 3H, CH3), 2.36 (s, 3H, CH3), 2.31 (s, 3H, CH3), 1.41 (d, J=4.89Hz, 3H, CH3) .ESI-MS:m/z 489.5 (M+).
The preparation of embodiment seven: 1-(2-5-nitro imidazole)-2-propyl group-4-(1-ethanoyl-3-(4-chloro-phenyl-)-4,5-pyrazolines) methyl benzoate (5g)
Preparation method's reference example one.White solid, yield 72%, d, J=6.27Hz, 2H, ArH), 7.34 (d, J=6.06Hz, 2H, ArH), 5.65 ~ 5.58 (m, 1H, CH), 5.49 ~ 5.40 (m, 1H, CH2), 4.71 ~ 4.63 (m, 1H, CH), 4.62 ~ 4.52 (m, 1H, CH2), 3.93 ~ 3.84 (m, 1H, CH2), 3.21 ~ 3.13 (m, 1H, CH2), 2.44 (d, J=2.43Hz, 3H, CH3), 2.32 (s, 3H, CH3), 1.41 (d, J=4.77Hz, 3H, CH3) .ESI-MS:m/z 509.9 (M+).
The preparation of embodiment eight: 1-(2-5-nitro imidazole)-2-propyl group-4-(1-ethanoyl-3-(4-fluorophenyl)-4,5-pyrazolines) methyl benzoate (5h)
Preparation method's reference example one.White solid, productive rate 70%, m.p.88 ~ 90 DEG C, 1H NMR (DMSO-d6, 300MHz) δ: 7.99 (s, 1H, CH), 7.87 ~ 7.82 (m, 2H, ArH), 7.80 (d, J=6.24Hz, 2H, ArH), 7.32 (t, J=6.72Hz, 4H, ArH), 5.64 ~ 5.58 (m, 1H, CH), 5.50 ~ 5.40 (m, 1H, CH2), 4.71 ~ 4.63 (m, 1H, CH), 4.61 ~ 4.52 (m, 1H, CH2), 3.95 ~ 3.83 (m, 1H, CH2), 3.21 ~ 3.13 (m, 1H, CH2), 2.44 (d, J=2.88Hz, 3H, CH3), 2.32 (s, 3H, CH3), 1.41 (d, J=4.95Hz, 3H, CH3) .ESI-MS:m/z 493.5 (M+).
The preparation of embodiment nine: 1-(2-5-nitro imidazole)-2-propyl group-4-(1-ethanoyl-3-(4-iodophenyl)-4,5-pyrazolines) methyl benzoate (5i)
Preparation method's reference example one.White solid, productive rate 58%, m.p.117 ~ 119 DEG C, 1H NMR (DMSO-d6, 300MHz) δ: 7.99 (s, 1H, CH), 7.84 (d, J=6.12Hz, 2H, ArH), 7.79 (d, J=6.24Hz, 2H, ArH), 7.55 (d, J=6.18Hz, 2H, ArH), 7.32 (d, J=5.86Hz, 2H, ArH), 5.63 ~ 5.56 (m, 1H, CH), 5.49 ~ 5.39 (m, 1H, CH2), 4.71 ~ 4.62 (m, 1H, CH), 4.60 ~ 4.51 (m, 1H, CH2), 3.91 ~ 3.81 (m, 1H, CH2), 3.17 ~ 3.09 (m, 1H, CH2), 2.42 (d, J=2.64Hz, 3H, CH3), 2.30 (s, 3H, CH3), 1.40 (d, J=4.83Hz, 3H, CH3) .ESI-MS:m/z 601.4 (M+).
The preparation of embodiment ten: 1-(2-5-nitro imidazole)-2-propyl group-4-(1-ethanoyl-3-(4-ethoxyl phenenyl)-4,5-pyrazolines) methyl benzoate (5j)
Preparation method's reference example one.Faint yellow solid, productive rate 59%, m.p.92 ~ 94 DEG C, 1H NMR (DMSO-d6, 300MHz) δ: 8.00 (s, 1H, CH), 7.80 (d, J=6.21Hz, 2H, ArH), 7.71 (d, J=6.60Hz, 2H, ArH), 7.32 (d, J=6.42Hz, 2H, ArH), 7.00 (d, J=6.55Hz, 2H, ArH), 5.61 ~ 5.55 (m, 1H, CH), 5.49 ~ 5.41 (m, 1H, CH2), 4.70 ~ 4.64 (m, 1H, CH), 4.60 ~ 4.52 (m, 1H, CH2), 4.08 (q, J=5.25Hz, 2H, CH2), 3.90 ~ 3.79 (m, 1H, CH2), 3.17 ~ 3.08 (m, 1H, CH2), 2.44 (t, J=4.79Hz, 3H, CH3), 2.30 (s, 3H, CH3), 1.41 (d, J=4.74Hz, 3H, CH3), 1.34 (t, J=5.24Hz, 3H, CH3) .ESI-MS:m/z 519.5 (M+).
Embodiment 11: containing the Anticancer Activity in vitro progress of the pyrazoles nitro imidazole derivatives of secnidazole skeleton
Adopt MTT [3-(4,5)-bis-methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method measures pyrazoles nitro imidazole derivatives containing secnidazole skeleton to human liver cancer cell (HEPG2), human breast cancer cell (MCF-7), the inhibiting rate of Human cervical cancer cell lines (HeLa cell) and mouse melanin tumor cell (B16-F10) reaches drug level (half maximal inhibitory concentration, IC when 50%
50).
(1) preparation of nutrient solution: DMEM (basic medium) 89%, foetal calf serum 10%, Penicillin Streptomycin Solution (10000IU/mL, 10000 μ g/mL) 1%.
The cultivation of (2) four kinds of adherent cancer cells: utilize above-mentioned nutrient solution (nutrient solution volume is about 1/10 of culturing bottle capacity), at 37 DEG C, 5%CO
2cultivate in incubator, the growth conditions according to cancer cells judges the generation time.
(3) preparation of different concns medicine: utilize tri-distilled water (a small amount of DMSO hydrotropy) to prepare storing solution, in the every porocyte suspension after dosing, the final concentration of DMSO is generally no more than 0.05%-0.1%; With tri-distilled water, storing solution is diluted to six concentration gradients (10 μ g/mL, 2 μ g/mL, 0.4 μ g/mL, 0.08 μ g/mL, 0.016 μ g/mL, 0.003 μ g/mL); Be stored in-20 DEG C of refrigerators for subsequent use.
(4) cell incubation: tumour cell in vegetative period of taking the logarithm, tune concentration of cell suspension is 1-1.5 × 105/mL, adds in (100 μ L/ hole) in 96 well culture plates after mixing, at 37 DEG C, 5%CO
224h is cultivated in incubator.
(5) dosing: join in 96 well culture plates respectively by the medicine of the different concns gradient of having diluted, each concentration gradient establishes 3 flat hole, continues to cultivate 48h.Experiment is divided into experimental group (nutrient solution, cell, medicine), control group (nutrient solution and cell) and blank group (only having nutrient solution).
(6) survivaling cell detects: in 96 orifice plates after having cultivated 48h, add MTT (5mg/mL) 10 μ L/ hole; Place after 4h at 37 DEG C, remove supernatant liquor, add DMSO 150 μ L/ hole, vibrate to formazan crystallization and all dissolve; Automatic microplate reader is utilized to detect the optical density(OD) (OD value) in each hole at 570nm wavelength place.
The calculating of inhibiting rate:
(OD experiment represents the average optical of experimental group to growth inhibition ratio=(1-survival rate) × 100%=[1-(it is blank that OD tests-OD)/(it is blank that OD contrasts-OD)] × 100%, OD contrast represents the average optical of control group, and OD blank represents the average optical of blank group).
According to the typical curve of drug level-inhibitory rate of cell growth, ask its IC
50.
The listed pyrazoles nitro imidazole derivatives containing secnidazole skeleton of the present invention is to the suppression IC of tumour cell
50value (μm ol/mL) sees the following form
From above-mentioned experiment: the present invention is to human liver cancer cell (HEPG2), human breast cancer cell (MCF-7), Human cervical cancer cell lines (HeLa cell) and mouse melanin tumor cell (B16-F10) have obvious restraining effect, compared with control group, activity significantly improves.
Embodiment 12: containing the pyrazoles nitro imidazole derivatives anti tumor activity in vitro of secnidazole skeleton about Cytotoxic research
The present invention tests new synthetic compound 5c, 5e to the cytotoxicity of people's renal epithelial cell (293T), cytotoxicity result as following table, the toxicity suppressor T cell survival rate of each compound to 50% time concentration (CC
50) represent.
Experimental technique:
(1) cultivator renal epithelial cell (293T) is tending towards fusion until reach its logarithmic growth end of term cell, digests cell dispersion, be mixed with the cell suspension of 1 × 104/mL with cell culture fluid with cell dissociation buffer.Get 96 well culture plates, in every hole, add the cell suspension of 100 μ L.Horizontally rotating culture plate gently makes cell be evenly dispersed in the surface in ware hole.
(2) be placed in containing 5%CO
2in cell culture incubator, at 37 ± 2 DEG C of temperature, cultivate 24h.Discard original fluid, every hole adds the blank liquid of 100 μ L, negative controls, positive control solution, the test sample vat liquor of 100% and 50% concentration.Often organize and at least establish 8 holes.Note: lixiviate stoste or make the serial lixiviate diluent of thinner with substratum.When adopting 0.9% sodium chloride injection lixiviate, use 2 times of concentrated substratum when diluting lixiviate.
(3) be placed in containing 5%CO
2in incubator, cultivate at 37 ± 2 DEG C of temperature.Cultivate 48h.
(4) after date between each cultivation, every hole adds MTT solution 20 μ L, is placed in containing 5%CO
2in incubator, at 37 ± 2 DEG C of temperature, cultivate 5h.
(5) discard liquid in hole, every hole adds 200 μ L DMSO respectively, and culture plate is placed 10min, and level is rocked and made solution colour in hole even.
(6) measure absorbancy by microplate reader, wavelength adopts 570nm.
The CC recorded
50shown in seeing the following form.
From above-mentioned experiment: the present invention shows quite people's renal epithelial cell (293T) or is better than the cytotoxicity of positive control medicine, may be used for producing antitumor drug.
More than describe the preferred embodiment of the present invention in detail; but the present invention is not limited to the detail in above-mentioned embodiment, within the scope of technical conceive of the present invention; can carry out multiple equivalents to technical scheme of the present invention, these equivalents all belong to protection scope of the present invention.It should be noted that in addition, each the concrete technical characteristic described in above-mentioned embodiment, in reconcilable situation, can be combined by any suitable mode.In order to avoid unnecessary repetition, the present invention illustrates no longer separately to various possible array mode.In addition, also can carry out arbitrary combination between various different embodiment of the present invention, as long as it is without prejudice to thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (4)
1. a class is containing the pyrazoles nitro imidazole derivatives of secnidazole skeleton, its structure such as formula shown,
Wherein, R
1be selected from H, CH
3, Br, CF
3, OCH
3, NO
2, OCH
2cH
3, Cl, F, I.
2. prepare a method for the pyrazoles nitro imidazole derivatives containing secnidazole skeleton, it is characterized in that, the structure of the described pyrazoles nitro imidazole derivatives containing secnidazole skeleton such as formula shown,
Wherein, R
1be selected from H, CH
3, Br, CF
3, OCH
3, NO
2, OCH
2cH
3, Cl, F, I.
Preparation method comprises the steps:
Under step 1. room temperature condition, add structure successively such as formula the compound shown in A in reaction vessel, structure is such as formula the compound shown in B and dehydrated alcohol reaction.Then add rapidly NaOH to stir, TLC follows the tracks of reaction, fully after reaction, obtains structure such as formula the compound shown in C.
Step 2. adds Glacial acetic acid successively in reaction vessel, and hydrazine hydrate and structure are such as formula the compound shown in C, and 120 DEG C of backflows, TLC follows the tracks of reaction, fully after reaction, obtains structure such as formula the compound shown in D.
Step 3. adds dichloromethane solution successively in reaction vessel, and structure is such as formula the compound shown in D, and secnidazole, and catalyzer EDC, DMAP, TLC follow the tracks of reaction, fully react, and obtain structure such as formula the compound shown in E.
In formula A ~ E, R
1be selected from H, CH
3, Br, CF
3, OCH
3, NO
2, OCH
2cH
3, Cl, F, I.
3. contain the pyrazoles nitro imidazole derivatives of secnidazole skeleton preparing the application in cancer therapy drug, it is characterized in that, its structure is such as formula shown
Wherein, R
1be selected from H, CH
3, Br, CF
3, OCH
3, NO
2, OCH
2cH
3, Cl, F, I.
4. a cancer therapy drug, is characterized in that, comprises structure such as formula shown compound and medically acceptable carrier,
Wherein, R
1be selected from H, CH
3, Br, CF
3, OCH
3, NO
2, OCH
2cH
3, Cl, F, I.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5574167A (en) * | 1994-01-10 | 1996-11-12 | Jaber; Santiago A. B. | Alkanoic and benzoic esters of 1-(2-hydroxypropyl)-2-methyl-5-nitromoimidazole |
| CN101199516A (en) * | 2007-12-19 | 2008-06-18 | 合肥工业大学 | Benzoyl secnidazole dispersant sheet and preparing method thereof |
| CN103450092A (en) * | 2012-05-29 | 2013-12-18 | 南京大学 | Synthesis and preparation method of metronidazole-sulfanilamide derivatives |
| CN104447705A (en) * | 2014-10-21 | 2015-03-25 | 南京大学 | Synthesis and bioactivity evaluation of 1-indoleacetic acid-5-nitroimidazole-containing derivative thereof |
-
2015
- 2015-07-06 CN CN201510397317.8A patent/CN104945386B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5574167A (en) * | 1994-01-10 | 1996-11-12 | Jaber; Santiago A. B. | Alkanoic and benzoic esters of 1-(2-hydroxypropyl)-2-methyl-5-nitromoimidazole |
| CN101199516A (en) * | 2007-12-19 | 2008-06-18 | 合肥工业大学 | Benzoyl secnidazole dispersant sheet and preparing method thereof |
| CN103450092A (en) * | 2012-05-29 | 2013-12-18 | 南京大学 | Synthesis and preparation method of metronidazole-sulfanilamide derivatives |
| CN104447705A (en) * | 2014-10-21 | 2015-03-25 | 南京大学 | Synthesis and bioactivity evaluation of 1-indoleacetic acid-5-nitroimidazole-containing derivative thereof |
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