CN102936241A - Homopiperony lamine pyridine-2-formaldehyde and synthetic method and application thereof - Google Patents
Homopiperony lamine pyridine-2-formaldehyde and synthetic method and application thereof Download PDFInfo
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- CN102936241A CN102936241A CN2012104553118A CN201210455311A CN102936241A CN 102936241 A CN102936241 A CN 102936241A CN 2012104553118 A CN2012104553118 A CN 2012104553118A CN 201210455311 A CN201210455311 A CN 201210455311A CN 102936241 A CN102936241 A CN 102936241A
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Abstract
The invention discloses a homopiperony lamine pyridine-2-formaldehyde and a synthetic method and an application thereof. The homopiperony lamine pyridine-2-formaldehyde is prepared by dissolving pyridine-2-formaldehyde and homopiperony lamine with the same amount of substance into organic solvent, performing condensation reaction within the temperature range of 40 DEG C to the boiling temperature of the organic solvents, cooling and crystallizing. The applicant further found that the homopiperony lamine pyridine-2-formaldehyde has remarkable inhibitory activity in human bladder cancer cells T-24, human hepatoma carcinoma cells HepG2, human osteosarcoma cells MG-63 and human ovarian cancer cis-platinum resisting cells SK-OV-3/DDP, has good latent medical values and is hopeful to be used in preparation of various antineoplastic drugs. The structural formula of the homopiperony lamine pyridine-2-formaldehyde is as follows.
Description
Technical field
The present invention relates to medical technical field, be specifically related to homopiperony lamine contracting pyridine-2-formaldehyde and synthetic method thereof and application.
Background technology
Since Schiff in 1864 since synthetic Schiff's base (Schiff base) is first, ten hundreds of New Schiff Base compounds are synthesized and characterize, and have developed into a class important branch in the organic compound based on the organic compound on schiff base structure basis.The function and application of Schiff's base also has been widely applied to the every field such as chemistry, biology, material, and wherein aspect its chemical research, the research of the relevant nature of Schiff's base is one of hot research field always.
Existing result of study shows that fully Schiff's base has widely biological activity and pharmacologically active, such as antitumor, antibiotic, antiviral, anti-malarial, diminish inflammation and analgesic etc.The peculiar imine group of Schiff's base or azomethine group are quite common in the compound of nature and growth and synthetic, and a lot of research shows that also the imine group in these compounds plays keying action in the biological activity performance of Schiff's base; The functional group that the imido grpup both sides connect then provides larger selection space for the diversity of Schiff's base activity.Show if any report, homopiperony lamine and derivative Schiff's base thereof have had certain anti-microbial activity when micro-molar concentration, can significantly suppress the growth (Pandeya S N, et al.1999) of trichophyton (MIC=820～980 μ M) and acrothesium floccosum (MIC=200～930 μ M).But have not yet to see the relevant report of the synthetic and activity research of the New Schiff Base take homopiperony lamine and pyridylaldehyde as architecture basics.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of new schiff base compounds, and homopiperony lamine contracting pyridine-2-formaldehyde and synthetic method and application take homopiperony lamine and pyridylaldehyde as architecture basics specifically are provided.
Homopiperony lamine contracting pyridine-2-formaldehyde of the present invention, its structural formula is shown below:
The synthetic method of above-mentioned homopiperony lamine contracting pyridine-2-formaldehyde is: take by weighing the pyridine-2-formaldehyde and the homopiperony lamine that equate amount of substance and be dissolved in the organic solvent, spend to the boiling temperature scope of organic solvent in 40 and to carry out condensation reaction, rear cooling reacts completely, leave standstill crystallization, isolate crystal, drying namely obtains homopiperony lamine contracting pyridine-2-formaldehyde.
In the above-mentioned synthetic method,
Described organic solvent can be any one or the two or more combination that is selected from methylene dichloride, ethanol, methyl alcohol and the chloroform.When organic solvent was above-mentioned two or more combination, the proportioning between them can be any proportioning.Organic solvent is preferably used first before use
Molecular sieve dewaters, thereby more is conducive to the carrying out that react.The consumption of organic solvent can be determined as required, being generally pyridine-2-formaldehyde and the homopiperony lamine that can dissolve the participation reaction gets final product, pyridine-2-formaldehyde and the 0.01mol homopiperony lamine that specifically can be 0.01mol dissolve with 20～300mL organic solvent, preferably dissolve with 30～100mL.When the input amount of organic solvent is larger, reacts completely and preferably remove the organic solvent that accounts for input amount 80～95% by underpressure distillation first and again reaction solution is cooled off afterwards.
Whether complete, extremely fully approximately need to 1～12h in the reaction of said temperature scope internal condensation if adopting thin-layer chromatography (TLC) to follow the tracks of the detection condensation reaction during condensation reaction.The temperature of carrying out condensation reaction is preferably 60～70 ° of C, and reaction is to fully about 3～6h under this condition.
Normally reaction solution is cooled to 10～25 ℃ after reacting completely and leaves standstill crystallization.The time of leaving standstill is generally 1～12h.Described drying adopts vacuum-drying usually, and the temperature general control is at 25～50 ° of C.
The homopiperony lamine contracting pyridine-2-formaldehyde that is made by aforesaid method can reach by the method for solvent recrystallization the purpose that is further purified, and described solvent can be identical with aforementioned organic solvent.
The present invention also comprises the application of above-mentioned homopiperony lamine contracting pyridine-2-formaldehyde in the preparation antitumor drug.
The present invention comprises that also above-mentioned homopiperony lamine contracting pyridine-2-formaldehyde is the antitumor drug of effective constituent preparation.
Compared with prior art, the present invention is take homopiperony lamine and pyridine-2-formaldehyde as architecture basics, direct reaction in organic solvent forms the two keys of Schiff's base C=N after two compounds are sloughed a part water by aldimine condensation, thereby directly obtains homopiperony lamine contracting pyridine-2-formaldehyde; Reaction conditions is gentle, step is simple.The applicant has also investigated the proliferation inhibition activity of homopiperony lamine contracting pyridine-2-formaldehyde to 7 kinds of human tumor cell lines, and the result shows that its anti tumor activity in vitro is remarkable, has preferably potential pharmaceutical use, is expected to the preparation for various antitumor drugs.
Description of drawings
Fig. 1 is the infrared spectra spectrogram of the product that makes of the embodiment of the invention 1;
Fig. 2 is the UV spectrum spectrogram of the product that makes of the embodiment of the invention 1;
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the product that makes of the embodiment of the invention 1;
Fig. 4 is the carbon-13 nmr spectra figure of the product that makes of the embodiment of the invention 1;
Fig. 5 is the electrospray ionization mass spectrum spectrogram of the product that makes of the embodiment of the invention 1.
Embodiment
The invention will be further described with specific embodiment for the below, but the present invention is not limited to these embodiment.
The homopiperony lamine of getting the pyridine-2-formaldehyde of 0.01mol and 0.01mol be dissolved in the methylene dichloride of 50mL (methylene dichloride use before with 6g's
Molecular sieve dehydration), gained solution stirring reaction under 40 ℃ of conditions is extremely complete, and (TLC follows the tracks of detection, about 12h), stopped reaction is cooled to 18 ℃ with reaction solution, leave standstill 3h, separate out white needle-like crystals, filter, the gained crystal is vacuum-drying 2h under room temperature condition, obtain white solid product, productive rate 68%.
To white solid product obtained above carry out respectively infrared spectra, UV spectrum,
1H and
13C nuclear magnetic resonance spectrum and electrospray ionization mass spectrum identify that shown in Fig. 1,2,3,4 and 5, concrete spectral characteristic is as follows respectively for their spectrogram:
Infrared spectra: (KBr, cm
-1) 3428 (ν
N-H), 2923,2852 (ν
Ar-H), 1649 (ν
C=N), 1500,1484,1437 (ν
C=C), 1246 (ν
C-O), 1047,1031 (ν
C-N);
UV spectrum (H
2O): ε
Max=1.070 * 10
4Lmol cm
-1(236nm);
Nuclear magnetic resonance spectrum (hydrogen spectrum):
1H NMR (500MHz, d-DMSO) δ 8.67 (d, J=31.6Hz, 1H, H-Ar), (8.33 d, J=34.8Hz, 1H, H-Ar), 8.00 (t, J=17.4Hz, 1H, H-Ar), 7.74 (t, J=7.4Hz, 1H, H-Ar), 7.32 (s, 1H, HC=N), 6.81 – 6.64 (m, 3H, H-Ar), 5.91 (s, 2H, CH
2), 3.88 (t, J=7.0Hz, 2H, CH
2), 2.96 (t, J=7.3Hz, 2H, CH
2);
Nuclear magnetic resonance spectrum (carbon spectrum):
13C NMR (125MHz, d-DMSO) δ 161.43,153.54,148.51,146.63,144.96,135.64,132.57,123.79,120.87,120.31,108.43,107.25,99.85,62.18,36.08.
Electrospray ionization mass spectrum: m/z 255.20[M+H]
+, 277.16[M+Na]
+.
Therefore, can determine that above-mentioned white solid product is homopiperony lamine contracting pyridine-2-formaldehyde, its chemical structural formula is as follows:
(dehydrated alcohol is used 5g's before using in the dehydrated alcohol of 20mL to get the pyridine-2-formaldehyde of 0.01mol and the homopiperony lamine mixed dissolution of 0.01mol
Molecular sieve dehydration), (TLC follows the tracks of detection to gained solution extremely fully in 78 ℃ of lower back flow reaction under agitation condition, about 6h), stopped reaction is cooled to 10 ℃ with reaction solution, leave standstill 1h, separate out white needle-like crystals, filter, the gained crystal is vacuum-drying 12h under room temperature condition, namely obtain homopiperony lamine contracting pyridine-2-formaldehyde, productive rate 90%.
(volume ratio of chloroform and methyl alcohol is 3:1, and chloroform and methyl alcohol are used respectively 15g's before using in the chloroform/methanol mixed solvent of 300mL to get the pyridine-2-formaldehyde of 0.01mol and the homopiperony lamine mixed dissolution of 0.01mol
Molecular sieve dehydration), gained solution is in 60 ℃ of lower stirring reactions to complete (TLC follows the tracks of detection, about 1h), stopped reaction, remove the 280mL solvent by vacuum distillation method, remaining reaction solution fully is cooled to 25 ℃ of room temperatures, leaves standstill 12h, separates out white needle-like crystals, filter, the gained crystal is vacuum-drying 24h under room temperature condition, obtains white solid product, productive rate 60%.
Above-mentioned white solid product is carried out Spectrum Analysis, and its spectral characteristic is identical with the product that embodiment 1 makes, and therefore, can determine that the white solid product that present embodiment makes is homopiperony lamine contracting pyridine-2-formaldehyde.
Embodiment 4
The homopiperony lamine of getting the pyridine-2-formaldehyde of 0.01mol and 0.01mol be dissolved in the anhydrous methanol of 150mL (anhydrous methanol use before with 10g's
Molecular sieve dehydration), gained solution is in 50 ℃ of lower stirring reactions to complete (TLC follows the tracks of detection, about 4h), stopped reaction, remove the 120mL solvent by vacuum distillation method, remaining reaction solution fully is cooled to 20 ℃, leaves standstill 4h, separates out white needle-like crystals, filter, the gained crystal is vacuum-drying 6h under room temperature condition, namely obtains homopiperony lamine contracting pyridine-2-formaldehyde, productive rate 72%.
In order to prove absolutely the purposes of homopiperony lamine contracting pyridine-2-formaldehyde of the present invention in pharmacy, the applicant has carried out the anti tumor activity in vitro experiment to homopiperony lamine contracting pyridine-2-formaldehyde.
One, homopiperony lamine contracting pyridine-2-formaldehyde is tested the proliferation inhibition activity of 7 kinds of human tumor cell lines:
1, cell strain and cell cultures
Human lung carcinoma cell NCI-H460, human liver cancer cell BEL-7402, HepG2, transitional cell bladder carcinoma cell line T-24, ovarian cancer cell SK-OV-3, the ovarian cancer cell of anti-cis-platinum SK-OV-3/DDP, human osteosarcoma cell MG-63 totally 7 kinds of tumor cell lines are selected in this experiment.
The all cells strain is all cultivated in the RPMI-1640 nutrient solution that contains the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate, puts 37 ℃ and contains volumetric concentration 5%CO
2Cultivate in the incubator.
2, the preparation of testing compound
Used homopiperony lamine contracting pyridine-2-formaldehyde is the product that the embodiment of the invention 1 makes, with 2 gained of methylene dichloride recrystallization, its purity 〉=95%, its DMSO liquid storage (concentration is 0.001mol/L) is diluted to five concentration gradients successively by the RMPI1640 substratum, be respectively 40,20,10,5,2.5 μ mol/L, wherein solubility promoter DMSO final concentration≤1%.At first test the target product of 20 μ mol/L for the inhibiting rate of tumor cell proliferation, be considered as the primary dcreening operation result; Test respectively again target product under the different gradient concentrations propagation of various tumour cells is suppressed degree, in order to the Fitting Calculation half-inhibition concentration, i.e. IC
50Value.
3, cell growth inhibition test (mtt assay)
The tumour cell of (1) taking the logarithm vegetative period, behind tryptic digestion, be mixed with the cell suspension that concentration is 5000/mL with the nutrient solution that contains 10% calf serum, be inoculated in 96 well culture plates with every hole 190 μ L, make cell density to 1000 to be measured～10000/hole (marginal pore is filled with aseptic PBS);
(2) 5%CO
2, hatch 24h for 37 ℃, be paved with the hole to cell monolayer at the bottom of, every hole adds the medicine 10 μ L of finite concentration gradient, each concentration gradient is established 4 multiple holes;
(3) 5%CO
2, hatched 48 hours, and observed under the inverted microscope for 37 ℃;
(4) every hole adds the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L, continues to cultivate 4h;
(5) stop cultivating, carefully suck nutrient solution in the hole, every hole adds 150 μ LDMSO and fully dissolves first a ceremonial jade-ladle, used in libation precipitation, behind the vibrator mixing, is 570nm at the microplate reader wavelength, and reference wavelength is the optical density value that 450nm measures each hole;
(6) zeroing hole (substratum, MTT, DMSO), control wells (the medicine dissolution medium of cell, same concentrations, nutrient solution, MTT, DMSO) are set simultaneously.
(7) according to the optical density value (OD value) that records, judge viable cell quantity, the OD value is larger, and cytoactive is stronger.
Utilize formula:
The computerized compound is to the inhibiting rate of growth of tumour cell.Its test result as shown in the following Table 1.
Table 1: homopiperony lamine contracting pyridine-2-formaldehyde when 20 μ mol/L to the growth inhibition ratio (%) of different tumor cell lines
Annotate: "-" represents without proliferation inhibition activity; " ND " represents undetermined.
Surpass or near 50% cell strain, further by SPSS software the inhibiting rate data of five concentration gradients are carried out match for inhibiting rate under primary dcreening operation concentration, obtain product to the half-inhibition concentration (IC of different tumor lines
50Value, the μ mol/L of unit), the result is as shown in table 2 below:
Table 2: homopiperony lamine contracting pyridine-2-formaldehyde when 20 μ mol/L to the IC of 4 kinds of human tumor cell lines
50Value (μ M)
From the anti tumor activity in vitro test result, homopiperony lamine contracting pyridine-2-formaldehyde all shows significant proliferation inhibition activity for human bladder cancer cell T-24, human liver cancer cell HepG2, human osteosarcoma cell MG-63 and four kinds of cell strains of the human ovarian cancer cell of anti-cis-platinum SK-OV-3/DDP, wherein the activity for human liver cancer cell HepG2 is the highest in three kinds of cell strains, IC
50Value reaches 12.13 ± 0.66 μ mol/L; And to the MG-63 cell, cis-platinum does not have proliferation inhibition activity, but homopiperony lamine contracting pyridine-2-formaldehyde shows certain inhibition activity, IC
50Value is 44.45 ± 1.65 μ mol/L.In addition, although compound does not suppress active to Proliferation of Human Ovarian Cell SK-OV-3, its cisplatin resistance strain SK-OV-3/DDP is shown suppress activity, inhibiting rate reaches IC
50Value is 27.28 ± 2.18 μ mol/L, and apparently higher than the line clinical chemotherapy medicine-cis-platinum for ovarian cancer, this shows that also it is different from the mechanism of anticancer action of cis-platinum, is conducive to it and effectively overcomes corresponding tumour cell to the resistance of cis-platinum.On the other hand, for NCI-H460, T-24, three kinds of cell strains of SK-OV-3, the proliferation inhibition activity of homopiperony lamine contracting pyridine-2-formaldehyde still is starkly lower than cis-platinum, but this toxicity that also shows homopiperony lamine contracting pyridine-2-formaldehyde normal tissue cell also may be lower.This shows that under the low concentration rank of micromoles per liter (μ mol/L), homopiperony lamine contracting pyridine-2-formaldehyde can carry out establishment to the uncontrolled proliferation of 4 kinds of cells in 7 kinds of typical human tumor cells of filler test.
In sum, compound involved in the present invention-homopiperony lamine contracting pyridine-2-formaldehyde aggregate performance has gone out suitable anti tumor activity in vitro, has preferably potential pharmaceutical use, is expected to the preparation for various antitumor drugs.
Claims (8)
1. homopiperony lamine contracting pyridine-2-formaldehyde, its structural formula is shown below:
2. the synthetic method of homopiperony lamine contracting pyridine-2-formaldehyde claimed in claim 1, it is characterized in that: take by weighing the pyridine-2-formaldehyde and the homopiperony lamine that equate amount of substance and be dissolved in the organic solvent, spend to the boiling temperature scope of organic solvent in 40 and to carry out condensation reaction, rear cooling reacts completely, leave standstill crystallization, isolate crystal, drying namely obtains homopiperony lamine contracting pyridine-2-formaldehyde.
3. the synthetic method of homopiperony lamine contracting pyridine-2-formaldehyde according to claim 2 is characterized in that: described organic solvent is selected from any one or the two or more combinations in methylene dichloride, ethanol, methyl alcohol and the chloroform.
4. the synthetic method of homopiperony lamine contracting pyridine-2-formaldehyde according to claim 2, it is characterized in that: the temperature of described condensation reaction is 60～70 ℃.
5. the synthetic method of homopiperony lamine contracting pyridine-2-formaldehyde according to claim 2 is characterized in that: after reacting completely reaction solution is cooled to 10～25 ℃.
6. the synthetic method of homopiperony lamine contracting pyridine-2-formaldehyde according to claim 2, it is characterized in that: the time of leaving standstill is 1～12h.
7. the application of homopiperony lamine contracting pyridine-2-formaldehyde claimed in claim 1 in the preparation antitumor drug.
8. the antitumor drug for preparing take homopiperony lamine contracting pyridine-2-formaldehyde claimed in claim 1 as effective constituent.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB191112550A (en) * | 1911-05-24 | 1912-02-08 | Philip Arthur Newton | Improvements in and relating to the Manufacture and Production of Homopiperonylamine. |
| CN1396160A (en) * | 2002-07-24 | 2003-02-12 | 广州市众为生物技术有限公司 | Process for preparing N-methyl piperethanamine salt |
| CN102977081A (en) * | 2012-10-22 | 2013-03-20 | 广西师范大学 | Homopiperony lamine pyridine -2- formaldehyde and synthetic method and application thereof |
-
2012
- 2012-11-14 CN CN2012104553118A patent/CN102936241A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB191112550A (en) * | 1911-05-24 | 1912-02-08 | Philip Arthur Newton | Improvements in and relating to the Manufacture and Production of Homopiperonylamine. |
| CN1396160A (en) * | 2002-07-24 | 2003-02-12 | 广州市众为生物技术有限公司 | Process for preparing N-methyl piperethanamine salt |
| CN102977081A (en) * | 2012-10-22 | 2013-03-20 | 广西师范大学 | Homopiperony lamine pyridine -2- formaldehyde and synthetic method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| XIAOLI BIAN，等: "Synthesis and antihyperglycemic evaluation of various protoberberine derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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Application publication date: 20130220 |