CN104945386B - Pyrazoles nitro imidazole derivatives, its preparation method and the application of one class skeleton containing secnidazole - Google Patents
Pyrazoles nitro imidazole derivatives, its preparation method and the application of one class skeleton containing secnidazole Download PDFInfo
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- 0 CC(C[n]1c([N+]([O-])=O)cnc1C)OC(c1ccc(C(C2)N(C(C)=O)N=C2c2ccc(*)cc2)cc1)=O Chemical compound CC(C[n]1c([N+]([O-])=O)cnc1C)OC(c1ccc(C(C2)N(C(C)=O)N=C2c2ccc(*)cc2)cc1)=O 0.000 description 6
- WXFJAWWXWDNJPZ-UHFFFAOYSA-N CC(C[n]1c([N+]([O-])=O)cnc1C)OC(c1ccc(C(C2)N(C(C)=O)N=C2c2ccc(C)cc2)cc1)=O Chemical compound CC(C[n]1c([N+]([O-])=O)cnc1C)OC(c1ccc(C(C2)N(C(C)=O)N=C2c2ccc(C)cc2)cc1)=O WXFJAWWXWDNJPZ-UHFFFAOYSA-N 0.000 description 1
- GOUHYARYYWKXHS-UHFFFAOYSA-N OC(c1ccc(C=O)cc1)=O Chemical compound OC(c1ccc(C=O)cc1)=O GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 description 1
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- 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
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Abstract
The invention discloses pyrazoles nitro imidazole derivatives, its preparation method and the application of class skeleton containing secnidazole, the structure of the pyrazoles nitro imidazole derivatives synthesized by secnidazole as shown in formula,Wherein, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、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 cells) and mouse melanin tumor cell (B16 F10) have obvious inhibitory action, therefore the pyrazoles nitro imidazole derivatives of the skeleton containing secnidazole of the present invention can apply to prepare antineoplastic.
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to the skeleton containing secnidazole pyrazoles nitro imidazole derivatives, its
Preparation method and application.
Background technology
EGF-R ELISA and homologous HER-2/ErbB-2 protein kinases belong to I types or ErbB/HER acceptor junket ammonia
Acid kinase family, increment with cell, survives, sticks, migrating and differentiation has close ties.It has been in four members of family
Most viable antibumor molecules target spot, others are HER-3and HER-4 respectively.In mammary gland, ovary, non-small cell lung cancer
EGF-R ELISA and HER-2 overexpressions or activated mutant can often be found so that they turn into these cancers
Therapeutic purpose.EGF-R ELISA and HER-2 turn into current research focus, their overexpression and abnormal activation
Malignant transformation of cells can generally be caused.And they are relevant with postoperative bad, radiation and chemotherapy tolerance and Tumor Angiongesis.
EGFR and ErbB-2 block is turned into an attractive method of oncotherapy by clinical verification.
In previous studies, secnidazole, a kind of nitroimidazoles medicine, because it is swollen to hypoxic tumors or entity
The affinity of the molecular labeling of knurl low-oxygen area, has been widely studied and has been used as radiosensitizer.2- nitro imidazole derivatives, than
Such as Misonidazole, etanidazole, effective radiosensitizing effect is had been reported to have.In mechanism aspect, nitro glyoxaline derives
Thing shows the tendency permeated and accumulated in tumor area, it is possible to carry out reduction reaction and produce that protein and nucleic acid can be destroyed
Electrophilic material, this causes sizable concern.As far as we know, described in some reported literatures synthesis and suppress with EGFR
The compound of activity has been published in 2 modifications of nitroimidazole ring.It is obvious that the metabolism activation of secnidazole hydroxyl and nitro
Middle performance key effect.The hydroxyl of secnidazole derivative substitution, which may be promised to be, to be developed newly, effective and safety
Lead compound.
The content of the invention
It is an object of the invention to provide pyrazoles nitre of the class as the skeleton containing secnidazole of EGFR/HER-2 inhibitor
Base imdazole derivatives, its preparation method and its application in cancer therapy drug.
Technical scheme:The pyrazoles nitro imidazole derivatives of one class skeleton containing secnidazole, its structure as shown in formula,
Wherein, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、Cl、F、I。
A kind of method for the pyrazoles nitro imidazole derivatives for preparing the skeleton containing secnidazole, the skeleton containing secnidazole
The structure of pyrazoles nitro imidazole derivatives as shown in formula,
Wherein, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、Cl、F、I。
Preparation method comprises the following steps:
Under step 1. room temperature condition, compound of the structure as shown in formula A, structure such as formula B are sequentially added into reaction vessel
Shown compound and absolute ethyl alcohol reaction.Then NaOH stirrings are rapidly added, TLC tracking reactions fully after reaction, are obtained
Compound of the structure as shown in formula C.
Step 2. adds glacial acetic acid, the compound of hydrazine hydrate and structure as shown in formula C, 120 into reaction vessel successively
DEG C backflow, TLC tracking reaction, fully reaction after, obtain compound of the structure as shown in formula D.
Step 3. adds dichloromethane solution into reaction vessel successively, and compound of the structure as shown in formula D fills in gram nitre
Azoles, and catalyst EDC, DMAP.TLC tracking reactions, fully reaction obtains compound of the structure as shown in formula E.
In formula A~E, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、Cl、F、I。
Application of the pyrazoles nitro imidazole derivatives of the skeleton containing secnidazole in cancer therapy drug is prepared, its structure such as formula institute
Show
Wherein, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、Cl、F、I。
A kind of cancer therapy drug, including structure the compound and medically acceptable carrier as shown in formula,
Wherein, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、Cl、F、I。
The present invention is to human liver cancer cell (HEPG2), human breast cancer cell (MCF-7), and (HeLa is thin for Human cervical cancer cell lines
Born of the same parents) and mouse melanin tumor cell (B16-F10) have an obvious inhibitory action, therefore the skeleton containing secnidazole of the present invention
Pyrazoles nitro imidazole derivatives can apply to prepare antineoplastic.
Embodiment
In some specific embodiment, preparation process of the invention and the structural formula of associated products are as described below:
A kind of method for the pyrazoles nitro imidazole derivatives for preparing the above-mentioned skeleton containing secnidazole, it comprises the following steps:
Step 1. at room temperature, 20ml absolute ethyl alcohols is added into round-bottomed flask, compound 2a-j is sequentially added
(5mmol), 4- formylbenzoates (5mmol) and NaOH/H2O (1: 10) (5ml), is stirred at room temperature 8 hours.Form precipitation
Filtered out after thing, dropwise addition hydrochloric acid (1M) to reaction solution.Recrystallize, and with three washings of ice cold water (25mL), obtain from ethanol
Pure products 3a-j.
Step 2. adds glacial acetic acid 20ml into round-bottomed flask, the compound 3a-j (1mmol) of synthesis is added, with hydration
Hydrazine (4mmol).The stirring reaction at 120 DEG C, flows back 12 hours, obtains compound 4a-j.
Step 3. adds dichloromethane solution 10ml into round-bottomed flask, adds the compound 4a-j (2mmol) of synthesis,
Secnidazole (2mmol), EDCHCl (3mmol) and DMAP (1mmol).56 DEG C of agitating solution overnight, react, instead by TLC tracking
After should terminating, filtering, solid distillation water washing is finally dried in vacuo, and obtained solid is dissolved in into absolute ethyl alcohol recrystallization carries
It is pure to obtain target compound 5a-j.
Embodiment one:1- (2- 5-nitro imidazoles) -2- propyl group -4- (1- acetyl group -3- phenyl -4,5- dihydro pyrroles
Azoles) methyl benzoate (5a) preparation
At room temperature, 20ml absolute ethyl alcohols are added into round-bottomed flask, compound 2a (5mmol), 4- first is sequentially added
Acyl group benzoic acid (5mmol) and NaOH/H2O (1: 10) (5ml), is stirred at room temperature 8 hours.Sediment is formed, hydrochloric acid is added dropwise
(1M) is to filtering out after reaction solution.Recrystallized from ethanol, and with three washings of ice cold water (25mL), obtain compound 3a.To
Glacial acetic acid 20ml is added in clean round-bottomed flask, the compound 3a (1mmol) of above-mentioned synthesis is added, with hydrazine hydrate
(4mmol).The stirring reaction at 120 DEG C, flows back 12 hours, obtains compound 4a.Dichloro is added into clean round-bottomed flask
Dichloromethane 10ml, adds the compound 4a (2mmol) of synthesis, secnidazole (2mmol), EDCHCl (3mmol) and
DMAP(1mmol).56 DEG C of agitating solution overnight, after reaction terminates, filter, solid distillation water washing, most by TLC tracking reactions
After be dried in vacuo, by obtained solid be dissolved in absolute ethyl alcohol recrystallization purification obtain target compound.White solid, yield
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 1- of embodiment two (2- 5-nitro imidazoles) -2- propyl group -4- (1- acetyl group -3- (4- bromophenyls) -4,5- bis-
Hydrogen pyrazoles) methyl benzoate (5b) preparation
Preparation method reference implementation 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+).
Embodiment three:1- (2- 5-nitro imidazoles) -2- propyl group -4- (1- acetyl group -3- (4- (trifluoromethyl) benzene
Base) -4,5- pyrazolines) methyl benzoate (5c) preparation
Preparation method reference implementation example one.Cream colored solid, yield 64%, m.p.105~107 DEG C;1H NMR(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+).
Example IV:1- (2- 5-nitro imidazoles) -2- propyl group -4- (1- acetyl group -3- (4- methoxyphenyls) -4,
5- pyrazolines) methyl benzoate (5d) preparation
Preparation method reference implementation example one.Cream-colored crystals, yield 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+).
Embodiment five:1- (2- 5-nitro imidazoles) -2- propyl group -4- (1- acetyl group -3- (4- nitrobenzophenones) -4,5-
Pyrazoline) methyl benzoate (5e) preparation
Preparation method reference implementation example one.Cream colored solid, yield 68%, m.p.197~199 DEG C;1H NMR(DMSO-
D6,300MHz) δ:8.32 (d, J=6.45Hz, 2H, ArH), 8.07~7.99 (m, 3H, CH and 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+).
Embodiment six:1- (2- 5-nitro imidazoles) -2- propyl group -4- (1- acetyl group -3- p-methylphenyl -4,5- dihydros
Pyrazoles) methyl benzoate (5f) preparation
Preparation method reference implementation example one.White solid, yield 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+).
Embodiment seven:1- (2- 5-nitro imidazoles) -2- propyl group -4- (1- acetyl group -3- (4- chlorphenyls) -4,5- bis-
Hydrogen pyrazoles) methyl benzoate (5g) preparation
Preparation method reference implementation 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+).
Embodiment eight:1- (2- 5-nitro imidazoles) -2- propyl group -4- (1- acetyl group -3- (4- fluorophenyls) -4,5- bis-
Hydrogen pyrazoles) methyl benzoate (5h) preparation
Preparation method reference implementation example one.White solid, yield 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+).
Embodiment nine:1- (2- 5-nitro imidazoles) -2- propyl group -4- (1- acetyl group -3- (4- iodophenyls) -4,5- bis-
Hydrogen pyrazoles) methyl benzoate (5i) preparation
Preparation method reference implementation example one.White solid, yield 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+).
Embodiment ten:1- (2- 5-nitro imidazoles) -2- propyl group -4- (1- acetyl group -3- (4- ethoxyl phenenyls) -4,
5- pyrazolines) methyl benzoate (5j) preparation
Preparation method reference implementation example one.Faint yellow solid, yield 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:The Anticancer Activity in vitro progress of the pyrazoles nitro imidazole derivatives of the skeleton containing secnidazole
Plug gram nitre is contained to determine using MTT [3- (4,5)-bis- methyl -2- thiazoles-(2,5)-phenyl bromination tetrazole is blue] methods
The pyrazoles nitro imidazole derivatives of azoles skeleton are to human liver cancer cell (HEPG2), human breast cancer cell (MCF-7), and human cervical carcinoma is thin
The inhibiting rate of born of the same parents system (HeLa cells) and mouse melanin tumor cell (B16-F10) reaches drug concentration (half when 50%
Maximal inhibitory concentration, IC50)。
(1) preparation of nutrient solution:DMEM (basal medium) 89%, hyclone 10%, Penicillin Streptomycin Solution
(10000IU/mL, 10000 μ g/mL) 1%.
The culture of (2) four kinds of adherent cancer cells:Using above-mentioned nutrient solution, (nutrient solution volume is about the 1/ of blake bottle capacity
10), in 37 DEG C, 5%CO2Cultivated in incubator, the generation time is judged according to the growth conditions of cancer cell.
(3) preparation of various concentrations medicine:Storing solution, every hole after dosing are prepared using tri-distilled water (a small amount of DMSO hydrotropies)
DMSO final concentration is usually no more than 0.05%-0.1% in cell suspension;Storing solution is diluted to six concentration ladders with tri-distilled water
Spend (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);It is stored in -20 DEG C of refrigerators
It is standby.
(4) cell incubation:Take the logarithm growth period tumour cell, tune concentration of cell suspension is 1-1.5 × 105/mL, after mixing
(100 μ L/ holes) is added in 96 well culture plates, in 37 DEG C, 5%CO224h is cultivated in incubator.
(5) dosing:The medicine of the various concentrations gradient diluted is added separately in 96 well culture plates, each concentration ladder
Degree sets 3 flat hole, continues to cultivate 48h.Experiment is divided into experimental group (nutrient solution, cell, medicine), control group (nutrient solution and cell)
With blank group (only nutrient solution).
(6) survivaling cell is detected:In 96 orifice plates after having cultivated 48h, plus the μ L/ holes of MTT (5mg/mL) 10;Put at 37 DEG C
Put after 4h, remove supernatant, plus the μ L/ holes of DMSO 150, vibration to formazan crystallizations all dissolvings;Existed using automatic ELIASA
The optical density (OD values) in each hole is detected at 570nm wavelength.
The calculating of inhibiting rate:
Growth inhibition ratio=(1- survival rates) × 100%=[1- (OD experiment-OD blank)/(OD control-OD blank)] ×
100% (OD experiments represent the average optical density of experimental group, and OD controls represent the average optical density of control group, and OD blank represents empty
The average optical density organized in vain).
According to the standard curve of drug concentration-inhibitory rate of cell growth, its IC is sought50。
Suppression IC of the pyrazoles nitro imidazole derivatives of the listed skeleton containing secnidazole of the invention to tumour cell50It is worth (μ
Mol/mL) it see the table below
It was found from above-mentioned experiment:The present invention is to human liver cancer cell (HEPG2), human breast cancer cell (MCF-7), human cervical carcinoma
Cell line (HeLa cells) and mouse melanin tumor cell (B16-F10) have obvious inhibitory action, compared with control group, living
Property is significantly improved.
Embodiment 12:The pyrazoles nitro imidazole derivatives anti tumor activity in vitro of the skeleton containing secnidazole is on cell toxicant
The research of property
The present invention tests new synthesis compound 5c, 5e to people's renal epithelial cell (293T) cytotoxicity, cytotoxicity
As a result such as following table, the toxicity suppression T cell survival rate to concentration (CC when 50% of each compound50) represent.
Experimental method:
(1) culture people's renal epithelial cell (293T) is disappeared up to reaching that its logarithmic growth end of term cell tends to fusion with cell
Change liquid digestion cell dispersion, 1 × 104/mL cell suspension is configured to cell culture fluid.96 well culture plates are taken, in every hole
Add 100 μ L cell suspension.Gently horizontally rotate the surface that culture plate makes cell be evenly dispersed in ware hole.
(2) it is placed in containing 5%CO2In cell culture incubator, 24h is cultivated at a temperature of 37 ± 2 DEG C.Original fluid is discarded, per hole
Add 100 μ L blank control liquid, negative controls, positive control solution, the test specimen leaching liquor of 100% and 50% concentration.
Every group at least sets 8 holes.Note:Extraction stoste or the series extraction dilution for making diluent with culture medium.Noted using 0.9% sodium chloride
When penetrating immersion and carrying, 2 times of culture mediums of concentration are used when diluting extraction.
(3) it is placed in containing 5%CO2In incubator, cultivated at a temperature of 37 ± 2 DEG C.Cultivate 48h.
(4) the μ L of MTT solution 20 are added per hole, are placed in containing 5%CO after the phase between each culture2In incubator, at 37 ± 2 DEG C
At a temperature of cultivate 5h.
(5) liquid in hole is discarded, 200 μ L DMSO is separately added into per hole, culture plate is placed into 10min, level, which is rocked, makes hole
Interior solution colour is uniform.
(6) absorbance is determined with ELIASA, wavelength uses 570nm.
The CC measured50It see the table below shown.
It was found from above-mentioned experiment:The present invention is shown quite or better than positive control to people's renal epithelial cell (293T)
The cytotoxicity of medicine, can be used for producing antineoplastic.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of equivalents can be carried out to technical scheme, this
A little equivalents belong to protection scope of the present invention.It is further to note that described in above-mentioned embodiment
Each particular technique feature, in the case of reconcilable, can be combined by any suitable means.In order to avoid not
Necessary repetition, the present invention no longer separately illustrates to various possible combinations.In addition, a variety of implementations of the present invention
It can also be combined between mode, as long as it is without prejudice to the thought of the present invention, it is public that it should equally be considered as institute of the invention
The content opened.
Claims (4)
1. the pyrazoles nitro imidazole derivatives of class skeleton containing secnidazole, its structure as shown in formula,
Wherein, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、Cl、F、I。
2. a kind of method for the pyrazoles nitro imidazole derivatives for preparing the skeleton containing secnidazole, it is characterised in that described containing plug gram
The structure of the pyrazoles nitro imidazole derivatives of nitre azoles skeleton as shown in formula,
Wherein, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、Cl、F、I;
Preparation method comprises the following steps:
Under step 1. room temperature condition, compound of the structure as shown in formula A is sequentially added into reaction vessel, structure is as shown in formula B
Compound and absolute ethyl alcohol reaction;Then NaOH stirrings are rapidly added, TLC tracking reactions fully after reaction, obtain structure
Compound as shown in formula C;
Step 2. adds glacial acetic acid, the compound of hydrazine hydrate and structure as shown in formula C, 120 DEG C times into reaction vessel successively
Stream, TLC tracking reactions, fully after reaction, obtains compound of the structure as shown in formula D;
Step 3. adds dichloromethane solution into reaction vessel successively, compound of the structure as shown in formula D, secnidazole, with
And catalyst EDC, DMAP, TLC tracking reaction, fully react, obtain compound of the structure as shown in formula E;
In formula A~E, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、Cl、F、I。
3. application of the pyrazoles nitro imidazole derivatives of the skeleton containing secnidazole in cancer therapy drug is prepared, it is characterised in that its
Structure is as shown in formula
Wherein, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、Cl、F、I。
4. a kind of cancer therapy drug, it is characterised in that including compound of the structure as shown in formula and medically acceptable carrier,
Wherein, R1Selected from H, CH3、Br、CF3、OCH3、NO2、OCH2CH3、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 |
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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 |
Non-Patent Citations (1)
Title |
---|
Synthesis, molecular modeling, and biological evaluation of cinnamic acid metronidazole ester derivatives as novel anticancer agents;Yong Qian et al.;《Bioorganic&Medicinal Chemistry》;20100608;第18卷;4991-4996 * |
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