CN104546844A - Application of (E)-N-piperonyl-1-(3-(6-chloropyridine)methyl)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazide - Google Patents

Application of (E)-N-piperonyl-1-(3-(6-chloropyridine)methyl)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazide Download PDF

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CN104546844A
CN104546844A CN201510044974.4A CN201510044974A CN104546844A CN 104546844 A CN104546844 A CN 104546844A CN 201510044974 A CN201510044974 A CN 201510044974A CN 104546844 A CN104546844 A CN 104546844A
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methoxyphenyl
chloropyridine
methyl
carbohydrazide
piperonyl
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张尚立
马剑锋
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Shandong University
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Shandong University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

The invention discloses an application of a compound (E)-N-piperonyl-1-(3-(6-chloropyridine)methyl)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazide in preparing anti-colon cancer medicines. The experimental results indicate that the compound has an obvious effect on inhibiting the proliferation of human colon cancer HCT-116 cells and causing apoptosis, and lays a foundation for developing novel anti-colon cancer medicines.

Description

(E) application of-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide
Technical field
The present invention relates to (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide and prepare the application in drugs against colon cancer.
Background technology
Colon cancer is common malignant tumor of digestive tract, accounts for the second of gastroenteric tumor.The therapeutic modality of colon cancer mainly contains operation, radiotherapy, chemotherapy, traditional Chinese medical herbal treatment, immunization therapy, gene therapy etc.Wherein chemotherapy is absolutely necessary treatment means in Therapeutic cancer.But chemotherapeutics faces severe bottleneck at present: one is to select chemotherapeutics few at present, and drug resistance phenomenon is serious.Two is that chemotherapeutics also exists serious untoward reaction, ubiquity digestive tract reaction, bone marrow depression, neurotoxicity etc.Determined curative effect to be developed is had and safe and reliable cancer therapy drug product is substituted based on this.
Acylhydrazone shows the pharmacologically actives such as good antiinflammatory, sterilization, convulsion, antitumor, anti-diabetic, tuberculosis pathogenic bacteria because of its special chemical constitution-CONHN=CH-.The acyl hydrazone derivative described in the patent JP52027775 reported for work, US3513165, US3972905, US5122368, EP0398305 has antiinflammatory, sterilization, convulsion, antitumor, antiviral pharmacologically active.But, in acylhydrazone chemical constitution is introduced, pyrazole compound forms (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-the methoxyphenyl)-1H-pyrazoles-5-carbohydrazide compound of new synthesis, and studies this compound preparing the application in drugs against colon cancer and have not been reported.
Summary of the invention
For the deficiencies in the prior art, the problem to be solved in the present invention is to provide one (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide and is preparing the application in drugs against colon cancer.
The chemical structural formula of (E) of the present invention-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide is:
(E) of the present invention-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide is preparing the application in drugs against colon cancer.
Above-mentioned (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide effectively can suppress human colon carcinoma HCT-116 Growth of Cells, its half growth inhibitory concentration (GI 50) be 1.11 μMs.
Below in conjunction with concrete pharmacodynamic action and its mechanism of action discussing (E) of the present invention-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide of test.
Cultivate human colon carcinoma HCT-116 cell in conventional manner, and collect the good and cell being in logarithmic (log) phase of growth conditions for experimentation.Adopt Celluar and Molecular Biology method to test as follows, observe (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide to the apoptotic impact of human colon carcinoma HCT-116.
1. (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide is on the morphology of colon cancer cell and number impact
Collect logarithmic (log) phase human colon carcinoma HCT-116 cell, 1 μM or 5 μMs of compounds of the present invention are added respectively in containing the culture medium of this cell, process 48h, using DMSO as solvent control, examine under a microscope the change of cancerous cell morphology and number, found that the cell after this compound treatment 48h tails off compared with the cell number of solvent control group and there occurs obvious morphological change (see Fig. 1).
2. (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide measures the half growth inhibitory concentration of colon cancer cell
Logarithmic (log) phase human colon carcinoma HCT-116 cell is inoculated in 96 orifice plates, after (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-the methoxyphenyl)-1H-pyrazoles-5-carbohydrazide process 48h of variable concentrations (50,10,1,0.5,0.25,0.1,0.05,0.01 μMs), detect the number of living cells respectively by SRB method, calculate survival rate.
Survival rate=(during experimental group absorbance-dosing 0h absorbance) ÷ (during matched group OD value-dosing 0h absorbance) (with not celliferous culture fluid for absorbance measurement blank background).
Experimental result: (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide acts on human colon carcinoma HCT-116 cell, half growth inhibitory concentration GI 50be 1.11 μMs (see Fig. 2).
3. (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide affects the cell cycle arrest of colon cancer cell
To take the logarithm phase human colon carcinoma HCT-116 cell, add (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-the methoxyphenyl)-1H-pyrazoles-5-carbohydrazide of 5.0 μMs, after effect 24h, dye with PI, with flow cytometry, found that described compound effects human colon carcinoma HCT-116 cell is arrested in G in 24h 2/ M the phase (see Fig. 3).
4. (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide affects colon cancer cell inducing apoptosis
To take the logarithm phase human colon carcinoma HCT-116 cell, add (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-the methoxyphenyl)-1H-pyrazoles-5-carbohydrazide of 5.0 μMs, Annexin V-FITC/PI dyeing is carried out after effect 6h, 12h, 24h, 48h, by flow cytometry, found that this compound has the apoptosis-induced effect (see Fig. 4) of time dependence to human colon carcinoma HCT-116 cell.
(E) disclosed by the invention-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide can cause the growth inhibitory effect of human colon carcinoma HCT-116 cell 50% at 1.11 μMs, namely 5.0 μMs cause the cell cycle arrest of colon cancer cell and apoptosis-induced.Indicate that (E) of the present invention-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide has good development prospect preparing in drugs against colon cancer, be expected to become the effective antitumor medicine for colon cancer.
Accompanying drawing explanation
After Fig. 1 (E) of the present invention-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide effect human colon carcinoma HCT-116 cell, the cellular morphology change shown under microscope and number change situation.
Wherein, the compound treatment time is 48 hours, and concentration used is 0 μM (DMSO), 1 μM, 5 μMs.
Fig. 2 SRB methods analyst (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide acts on the dosage-cell survival rate relation after human colon carcinoma HCT-116 cell 48h.
Wherein, abscissa is the negative logarithm of concentration (unit: mol/L), and vertical coordinate is cell survival rate.
Fig. 3 Flow cytometry (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide is to the cell cycle arrest situation of human colon carcinoma HCT-116 cell.
Wherein, compound used therefor concentration 5.0 μMs, abscissa is 24h action time, and abscissa is cell DNA content, and vertical coordinate is cell number.Line segment 1,2 and 3 denotes G respectively 1, S and G 2/ M period.
The two dye method of Fig. 4 Annexin V-FITC/PI detects (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide induction human colon carcinoma HCT-116 cell undergoes apoptosis phenomenon.
Wherein, compound concentration used is 5.0 μMs, and abscissa is action time 6h, 12h, 24h, 48h, and vertical coordinate is the ratio of apoptotic cell in tested cell mass.
Detailed description of the invention
Embodiment 1:
(E) preparation of-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide
1) in the round-bottomed flask of 100 milliliters, add 0.690 gram of potassium carbonate (0.005 mole), 1.230 grams of 3-(4-methoxyphenyl)-1H-pyrazole-5-ethyl formate (0.005 mole), 0.810 gram of CCMP (0.005 mole) and acetonitrile (25 milliliters), device reflux condenser, top connects drying tube.Reflux 4 hours, reacts to raw material and consumes completely, with TLC detection reaction terminal.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make eluant silica gel column chromatography with ethyl acetate-light petrol (V/V=1/2) and be separated residue (100 ~ 200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 92%.
2) in methanol (5 milliliters) solution of 0.371 gram of (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl) pyrazoles-5-carboxylic acid, ethyl ester, add the hydrazine hydrate of 1.2 milliliter 80%, stirring and refluxing reacts 1 hour, reaction to raw material consumes, completely with TLC detection reaction terminal.Hold over night, separates out solid, and filter, decompress filter obtains crude product; Obtain high-purity 1-(3-(6-chloropyridine) methyl)-3-methoxyphenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
3) obtain 0.361 gram of (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide and 0.096 gram of (0.001 mole) piperonal are joined in 10 milliliters of ethanol, back flow reaction 3 hours, reaction to raw material consumes, completely with TLC detection reaction terminal; Hold over night, separates out white solid, and filter, decompress filter obtains crude product; Obtain high-purity (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 92%.
Structural formula is as follows:
Molecular formula: C 25h 20clN 5o 4
Molecular weight: 489.91
Character: yellow solid
Fusing point: 208-209 DEG C
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,DMSO)δ:3.79(s,3H,OCH 3),5.79(s,2H,CH 2),6.10(s,2H,O-CH 2),7.00(d,J＝8.0Hz,1H,ArH),7.02(d,J＝8.4Hz,2H,ArH),7.19(d,J＝8.0Hz,1H,ArH),7.30(s,1H,4-H),7.37(s,1H,ArH),7.50(d,J＝8.0Hz,1H,PyH),7.72(dd,J＝2.2Hz,8.4Hz,1H,PyH),7.73(d,J＝8.4Hz,2H,ArH),8.32(s,1H,＝CH),8.36(d,J＝2.2Hz,1H,PyH),11.87(s,1H,NH).
Ir data is as follows:
IR(KBr)ν:3176-2957(NH),1652(C＝O),1260(O-C)cm –1.
Mass spectrometric data is as follows:
MS(EI):m/z 490.4(M) +。
Embodiment 2:
SRB method measures (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide to Growth of Colon Cancer Cells half-inhibition concentration
At 37 DEG C and containing 5%CO 2environment under, with DMEM/10% hyclone culture medium culturing human colon carcinoma HCT-116 cell.Collect logarithmic (log) phase human colon carcinoma HCT-116 cell, be inoculated in 96 orifice plates, hatch 24h.After (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-the methoxyphenyl)-1H-pyrazoles-5-carbohydrazide adding variable concentrations (20,10,5,1,0.1,0.05,0.01 μMs) hatches 48h, add 50 μ L solution of trichloroacetic acid (30%), fix one hour for 4 DEG C.Get rid of solution, high purity water rinses five times, adds 100 μ L Sulforhodamine B and dye 30 minutes after drying, and rinses five times after drying with 1% acetum.Add Tris solution 100 μ L after drying fully to dissolve, microplate reader measures absorbance under 540nm wavelength.Survival rate is calculated, survival rate=(during experimental group absorbance-dosing 0h absorbance) ÷ (during matched group OD value-dosing 0h absorbance) (with not celliferous culture fluid for absorbance measurement blank background) according to absorbance.
Experimental result: (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide acts on human colon carcinoma HCT-116 cell, half growth inhibitory concentration GI 50be 1.11 μMs (the results are shown in Figure 2).
Embodiment 3:
PI staining for flow cytometry measures (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide to the impact of Cell Cycle of Colon Carcinoma
To take the logarithm the human colon carcinoma HCT-116 cell of trophophase, be inoculated in 6cm culture dish by every 3mL culture volume respectively containing the amount of 200,000 cell number, inoculate 8 culture dishs altogether.After 24 hours, 8 culture dishs are divided into two groups.In the culture dish often organized, two culture dishs add DMSO, and two culture dishs add 5.0 μMs of compound (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazides.After continuing to hatch 24h respectively, at peptic cell on ice, collecting cell suspension, centrifugal rear PBS washs 2 times.Add 70% ice ethanol, 10 milliliters of suspendibles, spend the night at-20 DEG C.Centrifuge cell suspension, rinses 2 times with PBS, dyes half an hour at cell adds 500 μ LPI/5 μ LRNAaseA lucifuge 4 DEG C.With DMSO group for negative control flow cytometer detects cell cycle with standardization program.
Result shows: (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide effect human colon carcinoma HCT-116 cell is arrested in G in 24h 2/ M the phase, (the results are shown in Figure 3, abscissa was cell DNA content, and vertical coordinate is cell number; Line segment 1,2 and 3 denotes G successively respectively 1, S and G 2/ M period).
Embodiment 4:
The two dye method of Annexin V-FITC/PI detects (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide induction colon cancer cell generation phenomena of apoptosis
To take the logarithm the human colon carcinoma HCT-116 cell of trophophase, be inoculated in 6cm culture dish by every 3mL culture volume respectively containing the amount of 200,000 cell number, inoculate 16 culture dishs altogether.After 24 hours, 16 culture dishs are divided into four groups.In four culture dishs often organized, two culture dishs add DMSO, and two culture dishs add 5.0 μMs of compound (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazides.Four groups hatch 6h, 12h, 24h, 48h respectively.Then at peptic cell on ice, collecting cell suspension, centrifugal rear PBS washs 2 times.Add Annexin V buffer 400 μ L to cell, add 4 μ L Annexin V-FITC/4 μ L PI after suspendible is even, lucifuge room temperature dyes 10 minutes.With DMSO group for negative control flow cytometry, determine whether described compound induces colon cancer cell generation phenomena of apoptosis.
Found that (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-the methoxyphenyl)-1H-pyrazoles-5-carbohydrazide of 5.0 μMs has the apoptosis-inducing effect (the results are shown in Figure 4) of time dependence to human colon carcinoma HCT-116 cell.

Claims (2)

1. (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide is preparing the application in drugs against colon cancer.
2. apply as claimed in claim 1, it is characterized in that: the half growth inhibitory concentration of described (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-methoxyphenyl)-1H-pyrazoles-5-carbohydrazide to human colon carcinoma HCT-116 cell is 1.11 μMs.
CN201510044974.4A 2015-01-28 2015-01-28 Application of (E)-N-piperonyl-1-(3-(6-chloropyridine)methyl)-3-(4-methoxyphenyl)-1H-pyrazole-5-carbohydrazide Pending CN104546844A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101121711A (en) * 2007-09-19 2008-02-13 山东大学 Pyrazolcarbazone derivatives and application thereof
CN102060757A (en) * 2010-12-14 2011-05-18 聊城大学 Acylhydrazone Schiff alkali compound and preparation method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101121711A (en) * 2007-09-19 2008-02-13 山东大学 Pyrazolcarbazone derivatives and application thereof
CN102060757A (en) * 2010-12-14 2011-05-18 聊城大学 Acylhydrazone Schiff alkali compound and preparation method and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
YONG XIA,ET AL.: "Synthesis and structure–activity relationships of novel 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide derivatives as potential agents against A549 lung cancer cells", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
YONG XIA,ET AL.: "Synthesis and structureeactivity relationships of novel 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide hydrazone derivatives as potential agents against A549 lung cancer cells", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

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Application publication date: 20150429