CN101037423A - High spermidine conjugates, preparation and application thereof - Google Patents
High spermidine conjugates, preparation and application thereof Download PDFInfo
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- CN101037423A CN101037423A CN 200710054232 CN200710054232A CN101037423A CN 101037423 A CN101037423 A CN 101037423A CN 200710054232 CN200710054232 CN 200710054232 CN 200710054232 A CN200710054232 A CN 200710054232A CN 101037423 A CN101037423 A CN 101037423A
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Abstract
The invention discloses a high spermidine conjugate which is described by follow general formula: R' is H, halogen atom, alkyl, alkoxy or amido. The inventive high spermidine conjugate is a new composition which is used for anti-tumor medicine and has a good target-oriented drug delivery capacity. The inventive material is cheap. The reaction condition is gentle and the yield is high.
Description
Technical field
The invention belongs to medical compounds, preparation and applied technical field thereof, relate to a kind of high spermidine conjugates, preparation method and application thereof.
Background technology
Polyamines is the nitrogenous organic molecule material of a class that has physiologically active in the animal and plant body.In recent years, development along with molecular biology and cytobiology, many biological functions of polyamines constantly are familiar with, polyamines mainly is to combine by ionic linkage and hydrogen bond and protein (mainly referring to various enzymes), nucleic acid (mainly being meant DNA, RNA) and electronegative biomacromolecules such as phosphatide in vivo, and by biosynthetic pathway that influences them and the conformation that changes them, and then in vegeto-animal growing, bring into play the important physical function.For many years correlative study finds, natural polyamines, polyamines homologue and polyamines conjugate are in hypotensive, anti-HIV, diarrhea, treatment parasite, transgenosis, all demonstrate Application Prospect as aspects such as metal chelator and microbiotic.Particularly importantly, and the polyamines positive effect that especially anticancer aspect showed aspect the treatment central nervous system disease (referring to: Pieter smid, Hein K.A.C., et al.J.Med.Chem., 2005,48:6855-6899).One of important method of treatment cancer is a chemotherapy at present, but used antitumor drug in the chemotherapy process also exists serious toxic side effect in process of clinical application, and one of its major defect is exactly that drug molecule lacks selectivity to sick cell.In order to realize the target of cancer therapy drug effect, to the highly selective or the high identity of tumour cell, for a long time, scientist developed different drug delivery systems when promptly medicine was had an effect, and pharmaceutically-active selectivity is increased.Simultaneously, along with going deep into of oncological pathology research, the novel targets of antitumor cell effect is found in succession, with liposome, monoclonal antibody carrier be sign the 4th generation targeting drug delivery system, become the research focus of pharmaceutical field gradually.We also find under study for action, high spermidine also have good target administration ability (referring to ChaojieWang, Jean-Guy Delcros, et al.J.Med.Chem., 2003,46:2663-2671).Therefore the synthesizing new high spermidine conjugates will be widened research, the Application Areas of polyamines, and the high spermidine compounds is promoted the well-being of mankind better.
Summary of the invention
The object of the invention provides a kind of new high spermidine conjugates;
Another purpose of the present invention provides the preparation method of a kind of easy and simple to handle, mild condition, high spermidine conjugates that reaction yield is high;
Further aim of the present invention is the application of high spermidine conjugates on the preparation antitumor drug.
For realizing the object of the invention, adopt following technical scheme: a kind of high spermidine conjugates is following general formula compound:
R` is H, halogen atom, alkyl, alkoxyl group or amino.
R` is preferably H, fluorine atom, chlorine atom, bromine atoms, iodine atom, C
1-4Alkyl, C
1-4Alkoxyl group or amino.
High spermidine conjugates most preferably is following general formula compound:
Wherein,
Perhaps
Wherein,
The method for preparing high spermidine conjugates: the high spermidine compound is dissolved in solvent,-10～60 ℃ add aromatic formaldehyde or arone reaction, after reaction finishes, add the reductive agent reaction down at-10～20 ℃,-10～60 ℃ were reacted 4～18 hours down, the reaction back is steamed and is desolventized, residuum is dissolved in the halohydrocarbon, and washing and dry organic layer steam and remove halohydrocarbon, be dissolved in the alcohol after separating purification, at-10～30 ℃ of alcoholic solution or reactant aqueous solutions that add hydrochloric acid down ,-10～50 ℃ were reacted 4～18 hours down, filter, washing leaching cake, the dry high spermidine conjugates that gets; Described aromatic formaldehyde is to contain α-naphthaldehyde, β-naphthaldehyde, biphenylcarboxaldehyde, the anthraldehyde that substituting group is H, halogen atom, alkyl, alkoxyl group or amino on the aromatic ring; Arone is to contain the Tetralone an intermediate of Sertraline that substituting group is H, halogen atom, alkyl, alkoxyl group or amino on the aromatic ring; Described solvent is the mixed solution of Fatty Alcohol(C12-C14 and C12-C18) and halohydrocarbon.
The preferred method of preparation high spermidine conjugates: the high spermidine compound is dissolved in solvent, 10～30 ℃ add aromatic formaldehyde or arone reaction, react the raw material point that detects aromatic formaldehyde or arone to TLC stopped reaction when weakening, add the reductive agent reaction down at-5～10 ℃, 10～30 ℃ were reacted 8～13 hours down, the reaction back is steamed and is desolventized, residuum is dissolved in the halohydrocarbon, and washing and dry organic layer steam and remove halohydrocarbon, be dissolved in the alcohol after separating purification, at-5～10 ℃ of alcoholic solution or reactant aqueous solutions that add hydrochloric acid down, 10～30 ℃ were reacted 8～13 hours, filtered, washing leaching cake, the dry high spermidine conjugates that gets; Described aromatic formaldehyde is that to contain substituting group on the aromatic ring be H, fluorine atom, chlorine atom, bromine atoms, iodine atom, C
1-4Alkyl, C
1-4Alkoxyl group or amino α-naphthaldehyde, β-naphthaldehyde, biphenylcarboxaldehyde, anthraldehyde; Arone is that to contain substituting group on the aromatic ring be H, fluorine atom, chlorine atom, bromine atoms, iodine atom, C
1-4Alkyl, C
1-4Alkoxyl group or amino Tetralone an intermediate of Sertraline; Described solvent is the mixed solution of the pure and mild halohydrocarbon of saturated fatty, and wherein saturated fatty alcohol is C
1-4Saturated fatty alcohol, halohydrocarbon is alkyl chloride, bromoalkane.
The high spermidine compound: the mol ratio of aromatic formaldehyde or arone is 1: 0.1～3.
Solvent for use is methyl alcohol, ethanol, Virahol and 1, and each gets a kind of arbitrary proportion mixture in 2-ethylene dichloride, trichloroethane, methylene dichloride, the chloroform; Used reductive agent is Pd/C, Raney's nickel or NaBH
4
The preparation of the high spermidine compound (intermediate) of tertbutyloxycarbonyl (BOC) protection: with N-tertbutyloxycarbonyl-1; 4-butanediamine or 4-(4-tertbutyloxycarbonyl) piperazinyl butylamine is dissolved in the solvent; stir 10～20min after adding catalyzer; add N-(4-brombutyl) phthalic imidine, reaction is spent the night.Remove solvent under reduced pressure, resistates extracts with halogenated hydrocarbon solvent, the alkaline aqueous solution washing, and collected organic layer is also dry, removes solvent under reduced pressure, gets faint yellow oily thing, and this oily matter is dissolved in the alcoholic solution, adds BOC
2O and catalyzer, stirring reaction spends the night.Remove solvent under reduced pressure, resistates extracts with halogenated hydrocarbon solvent, water washing, collected organic layer is also dry, removes solvent under reduced pressure, separate purify faint yellow oily compound.
Wherein, solvent for use is acetonitrile, ethanol, methyl alcohol, Virahol, 1, a kind of in 2-ethylene dichloride, trichloroethane, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, triethylamine, the pyridine; The reaction catalyst system therefor is a kind of in sodium methylate, sodium hydroxide, potassium hydroxide, Potassium monofluoride, triethylamine, diethylamine, pyridine, the salt of wormwood.
This intermediate product structural formula is as follows:
R＝NHBOC，
High spermidine conjugates is the conjugate that high spermidine and polyamines are connected to form, it is a kind of new compound, has good target administration ability, because synthetic conjugate contains active amino, the relevant chemical reaction of warp can synthesize and contain other substituent compounds on Schiff's base, acid amides and the phenyl ring, so can be used as the intermediate use of the intermediate and the synthetic polyamine class pharmaceuticals of organic synthesis; Utilize the high carrying capacity of high spermidine, will have Cytotoxic aromatic group and be transported into cell interior, and then kill quick outgrowth cancer cells, use so can be used as antitumor drug; Utilize amino Electron Affinities, can generate metal ligand, be applied in the building-up reactions of metal complexes so can be used as part with the metallic cation effect.Preparation method's cost of material of the present invention is cheap, reaction conditions gentleness, productive rate height.
Description of drawings
Fig. 1 is the compound of embodiment 2
13C NMR figure;
Fig. 2 is the compound of embodiment 2
1H NMR figure;
Fig. 3 is the compound of embodiment 3
13C NMR figure;
Fig. 4 is the compound of embodiment 3
1H NMR figure;
Fig. 5 is the compound of embodiment 4
13C NMR figure;
Fig. 6 is the compound of embodiment 4
1H NMR figure;
Fig. 7 is the compound of embodiment 5
13C NMR figure;
Fig. 8 is the compound of embodiment 5
1H NMR figure;
Fig. 9 is the compound of embodiment 6
13C NMR figure;
Figure 10 is the compound of embodiment 6
1H NMR figure;
Figure 11 is the compound of embodiment 7
13C NMR figure;
Figure 12 is the compound of embodiment 7
1H NMR figure;
Figure 13 is the compound of embodiment 8
13C NMR figure;
Figure 14 is the compound of embodiment 8
1H NMR figure;
Figure 15 is the compound of embodiment 9
13C NMR figure;
Figure 16 is the compound of embodiment 9
1H NMR figure;
Figure 17 is the compound of embodiment 10
13C NMR figure;
Figure 18 is the compound of embodiment 10
1H NMR figure;
Figure 19 is the compound of embodiment 11
13C NMR figure;
Figure 20 is the compound of embodiment 11
1H NMR figure;
Used laboratory apparatus title and model: Bruker AV-400 type nuclear magnetic resonance analyser (D
2O makees solvent, TMS or D
2O is interior mark);
Vario EL III type elemental analyser (Germany).
Esquire 3000 type LC-MS mass spectrographs.
Embodiment
For the present invention is illustrated better, as follows for embodiment:
The high spermidine intermediate that embodiment 1 preparation one end and middle amido are protected by BOC
With 8.99g N-tertbutyloxycarbonyl-1, the 4-butanediamine is dissolved in the 180mL acetonitrile, adds Anhydrous potassium carbonate 9g, and stirring at room 15min is warmed up to 45 ℃, adds N-(4-brombutyl) phthalic imidine 11.5g altogether in four batches, 45 ℃ of temperature controls, and reaction is spent the night.Remove acetonitrile under reduced pressure, resistates 30mL chloroform extraction, 10% Na
2CO
3Solution washing three times is used 40mL at every turn, collected organic layer, and the organic layer anhydrous sodium sulfate drying removes chloroform under reduced pressure, gets faint yellow oily thing (impure).This oily matter is dissolved among the methanol solution 100mL, adds BOC acid anhydrides 10.42g, stirred overnight at room temperature is to there being a large amount of white insoluble solids to generate.Remove solvent under reduced pressure, resistates 40mL chloroform extraction, 3 * 40mL water washing, collected organic layer, the organic layer anhydrous sodium sulfate drying removes chloroform under reduced pressure, silicagel column separate purify faint yellow oily compound.This compound of 8.47g (17.3mmoL) is dissolved in the 50mL ethanol, adds hydrazine hydrate 10.2g, stirred overnight at room temperature removes solvent under reduced pressure to there being a large amount of white insoluble solids to occur, and residue is dissolved in the 35mL chloroform, 3 * 30mL w (Na
2CO
3The solution washing of)=10%, collected organic layer, the organic layer anhydrous sodium sulfate drying removes chloroform under reduced pressure, silicagel column separate purify faint yellow oily high spermidine intermediate.Overall yield 46.7%,
Experimental data is as follows:
1H NMR(CDCl
3，400MHz)
H：4.37(brs，1H)，2.89～2.93(t，J＝19.0Hz，6H)，2.48～2.51(t，J＝13.5Hz，2H)，1.37(s，4H)，1.26～1.31(m，22H).ESI-MS m/z：360.3(M+1)
+.
Ar is betanaphthyl, R shown in the embodiment 2 preparation general formulas 1
1Be NH
2.3HCl the high spermidine conjugates the time:
Preparing Ar according to the method for embodiment 1 is betanaphthyl, R
1High spermidine compound (intermediate) during for H is got the above-mentioned high spermidine intermediate of 0.09g and is dissolved among the dichloromethane solution 15mL of 25% methyl alcohol, stirs to add 0.14g β-naphthaldehyde down; Stopped reaction when the raw material point that-10 ℃ of following stirring reactions detect β-naphthaldehyde to TLC weakens removes solvent under reduced pressure, residuum is dissolved among the dichloromethane solution 12mL of 50% methyl alcohol, and reaction mixture stirs 15min down at-10 ℃, divides adding NaBH three times
4Be total to 0.1g ,-10 ℃ are reacted 4h down, remove solvent under reduced pressure, and residuum is dissolved in the 20mL chloroform, 10% Na
2CO
3Solution washing three times is used 30mL at every turn, and collected organic layer is used anhydrous sodium sulfate drying.Remove chloroform under reduced pressure, silicagel column separate purify faint yellow oily compound.The compound that obtains is dissolved in the 10mL dehydrated alcohol, is cooled to-10 ℃, the ethanolic soln 6mL of the hydrochloric acid of adding 4N ,-10 ℃ are stirred 4h down, to there being solid to generate, filter, with heavily steaming absolute ethanol washing three times, dry white solid compound, the yield 23.6% of getting.
As Fig. 1, Fig. 2 is the compound of embodiment 2
13C NMR figure,
1H NMR figure, experimental data is as follows:
1H NMR(D
2O，400MHz)
H：7.89～7.96(m，4H)，7.54～7.57(m，2H)，7.49(d，J＝1.9Hz，1H)，4.33(s，2H)，3.05～3.09(t，J＝15.2Hz，2H)，2.92～3.00(m，6H)，1.65～1.70(m，8H).
13C NMR(D
2O)
C：133.18，132.84，129.64，129.09，128.22，128.04，127.78，127.39，127.10，126.57，51.15，46.87，46.81，46.24，38.78，23.91，22.82，22.76，22.72.ESI-MS m/z：300.2(M+H-3HCl)
+；Anal.calcd.forC
19H
32N
3Cl
3·0.2H
2O：C 55.33，H 7.92，N 10.19，found：C 55.33，H 7.82，N 10.13.
Ar is 6-methoxyl group naphthyl, R shown in the embodiment 3 preparation general formulas 1
1Be NH
2.3HCl the high spermidine conjugates the time:
Preparing Ar according to the method for embodiment 1 is 6-methoxyl group naphthyl, R
1High spermidine intermediate during for H is dissolved in the above-mentioned high spermidine intermediate of 0.3g among the dichloromethane solution 15mL of 25% methyl alcohol, stirs to add 6-methoxynaphthalene formaldehyde 0.02g down; 60 ℃ are stirred 18h, stopped reaction when TLC detects the raw material point disappearance of 6-methoxynaphthalene formaldehyde.Remove solvent under reduced pressure, residuum is dissolved among the dichloromethane solution 12mL of 50% methyl alcohol, reaction mixture stirs 15min down at 20 ℃, divides adding NaBH three times
4Be total to 0.09g, 60 ℃ are reacted 18h down, remove solvent under reduced pressure, and residuum is dissolved in the 20mL chloroform, 10% Na
2CO
3Solution washing three times is used 40mL at every turn, and collected organic layer is used anhydrous sodium sulfate drying.Remove chloroform under reduced pressure, silicagel column separate purify faint yellow oily compound.The compound that obtains is dissolved in the 7.3mL dehydrated alcohol, 30 ℃ of aqueous solution of hydrochloric acid 9.5mL that add down 4N, 50 ℃ are stirred 18h down to there being a large amount of solids to generate, and filter, with heavily steaming absolute ethanol washing three times, dry white solid compound, the yield 69.3% of getting.
As Fig. 3, Fig. 4 is the compound of embodiment 3
13C NMR figure,
1H NMR figure, experimental data is as follows:
1H NMR(D
2O，400MHz)
H：7.89～7.96(m，3H)，7.53～7.56(t，J＝9.8Hz，1H)，7.38(d，J＝2.2Hz，1H)，7.28(d，J＝2.4Hz，1H)，7.25～7.26(d，J＝2.4Hz，1H)，4.39(s，2H)，3.96(s，3H)，3.06～3.19(m，8H)，1.78～1.94(m，8H).
13C NMR(D
2O)
C：157.78，134.52，129.76，129.51，128.40，127.91，127.24，125.89，119.14，106.21，55.42，51.10，46.88，46.82，46.13，38.79，23.91，22.81，22.75，22.73.ESI-MS m/z：330.3(M+H-3HCl)
+；Anal.calcd.for C
20H
34N
3Cl
3O·0.1H
2O：C 54.51，H 7.82，N9.54，found：C 54.48，H 7.75，N 9.46.
Ar is 4-xenyl, R shown in the embodiment 4 preparation general formulas 1
1Be NH
2.3HCl the aromatic base conjugate the time:
The high spermidine intermediate 0.26g that one end and middle amido are protected by BOC is dissolved among the dichloromethane solution 15mL of 25% methyl alcohol, stirs to add 4-biphenylcarboxaldehyde 0.16g down; 30 ℃ are stirred 9h, stopped reaction when TLC detects the raw material point disappearance of 4-biphenylcarboxaldehyde.Remove solvent under reduced pressure, residuum is dissolved among the dichloromethane solution 16mL of 50% methyl alcohol, reaction mixture stirs 15min down at 10 ℃, divides adding NaBH three times
4Be total to 0.1g, 30 ℃ are reacted 9h down, remove solvent under reduced pressure, and residuum is dissolved in the 20mL chloroform, 10% Na
2CO
3Solution washing three times is used 40mL at every turn, and collected organic layer is used anhydrous sodium sulfate drying.Remove chloroform under reduced pressure, silicagel column separate purify faint yellow oily compound.The compound that obtains is dissolved in the 7.2mL dehydrated alcohol, is cooled to 10 ℃, add the ethanolic soln 9.3mL of the hydrochloric acid of 4N, 30 ℃ are stirred 9h down to there being a large amount of solids to generate, filter, with heavily steaming absolute ethanol washing three times, dry beige solid chemical compound, the yield 78.6% of getting.
As Fig. 5, Fig. 6 is the compound of embodiment 4
13C NMR figure,
1H NMR figure, experimental data is as follows:
1H NMR(D
2O，400MHz)
H：7.72～7.79(q，4H)，7.47～7.58(m，5H)，4.30(s，2H)，3.01～3.16(m，8H)，1.74～1.79(m，8H).
13C NMR(D
2O)
C：141.81，139.64，130.45(2C)，129.76，129.21(2C)，128.16，127.63(2C)，127.00(2C)，50.68，46.88，46.81，46.20，38.76，23.90，22.80，22.73(2C).ESI-MS m/z：326.3(M+H-3HCl)
+；Anal.calcd.for C
21H
34N
3Cl
3·0.1H
2O：C 57.76，H 7.89，N 9.62，found：C 57.68，H7.83.N 9.43.
Ar is that tetralyl, R are NH shown in the embodiment 5 preparation general formulas 1
2.3HCl the aromatic base conjugate the time:
The high spermidine intermediate 0.67g that one end and middle amido are protected by BOC is dissolved among the dichloromethane solution 30mL of 25% methyl alcohol, stirs to add Tetralone an intermediate of Sertraline 0.28g down; 10 ℃ are stirred down 13h, stopped reaction when TLC detects the raw material point disappearance of Tetralone an intermediate of Sertraline.Remove solvent under reduced pressure, residuum is dissolved among the dichloromethane solution 40mL of 50% methyl alcohol, reaction mixture stirs 15min down at-5 ℃, divides adding NaBH five times
4Be total to 0.33g, 10 ℃ are reacted 13h down, remove solvent under reduced pressure, and residuum is dissolved in the 50mL chloroform, 10% Na
2CO
3Solution washing three times is used 40mL at every turn, and collected organic layer is used anhydrous sodium sulfate drying.Remove chloroform under reduced pressure, silicagel column separate purify faint yellow oily compound.The compound that obtains is dissolved in the 3.15mL dehydrated alcohol, be cooled to-5 ℃, the ethanolic soln 4.11mL that adds the hydrochloric acid of 4N, 10 ℃ are stirred 13h, pressure reducing and steaming solvent down, remaining solid is dissolved among the redistilled water 10mL, heavily steam the chloroform washing with 15mL, separatory is removed organic layer, the pressure reducing and steaming water layer, dry sorrel solid chemical compound, the yield 45.7% of getting.
As Fig. 7, Fig. 8 is the compound of embodiment 5
13C NMR figure,
1H NMR figure, experimental data is as follows:
1H NMR(D
2O，400MHz)
H：7.36～7.40(t，J＝12.5Hz，2H)，7.27～7.30(t，J＝14.0Hz，2H)，4.49～4.52(t，J＝8.8Hz，1H)，3.16～3.18(d，J＝8.0Hz，2H)，3.00～3.09(m，6H)，2.82～2.89(m，2H)，2.11～2.19(m，2H)，1.88～1.90(t，J＝9.7Hz，2H)，1.74～1.78(m，8H).
13C NMR(D
2O)
C：138.65，130.03，129.53(2C)，129.39，126.25，56.11，46.88，46.83，44.42，38.76，27.59，24.75，24.03，23.89，22.90，22.72，17.20.ESI-MS m/z：290.2(M+H-3HCl)
+；Anal.calcd.forC
18H
34N
3Cl
3·0.7H
2O：C 52.54，H 8.33，N 10.21，found：C 52.28，H 8.31，N 10.45.
Ar is the 9-anthryl shown in the embodiment 6 preparation general formulas 1, and R is
The time the aromatic base conjugate:
The high spermidine derivative 0.1g (0.7mmoL) that one end is replaced by piperazine is dissolved among the dichloromethane solution 15mL of 25% methyl alcohol,-10 ℃ are stirred adding 9-anthraldehyde 0.15g down, rise to stirring at room 4h, the stopped reaction when point that detects the 9-anthraldehyde to TLC weakens.Remove solvent under reduced pressure, residuum is dissolved among the dichloromethane solution 20mL of 50% methyl alcohol, reaction mixture stirs 15min down at-10 ℃, adds NaBH at twice
40.1g rises to room temperature reaction 4h altogether, removes solvent under reduced pressure, and residuum is dissolved in the 15mL chloroform, 10% Na
2CO
3Solution washing three times is used 20mL at every turn, and collected organic layer is used anhydrous sodium sulfate drying.Remove chloroform under reduced pressure, silicagel column separate purify reddish-brown thickness oily compound.The compound that obtains is dissolved in the 12mL dehydrated alcohol, is cooled under-10 ℃, add the ethanolic soln 8mL of the hydrochloric acid of 4N, rise to stirring at room 4h, to there being a large amount of solids to generate; Filter, with heavily steaming absolute ethanol washing three times, the dry white solid compound that gets.Productive rate 33.1%.
As Fig. 9, Figure 10 is the compound of embodiment 6
13C NMR figure,
1H NMR figure, experimental data is as follows:
1H NMR(D
2O，400MHz)
H：8.44(s，1H)，8.05～8.07(d，J＝8.9Hz，2H)，7.97～7.99(d，J＝8.5Hz，2H)，7.58～7.62(q，2H)，7.84～7.52(t，J＝15.0Hz，2H)，3.56(s，8H)，(m，4H)，2.95～3.02(m，4H)，1.64～1.78(m，8H).
13C NMR(D
2O)
C：130.98，130.62，130.40，129.61，127.91，125.69，122.64，120.77，56.43，48.60，47.13，46.90，46.83，42.93，40.91，22.93，22.82，22.72，20.76.ESI-MS m/z：419.5(M+H-4HCl)
+.Anal.calcd.for C
27H
42N
4Cl
4·1.9H
2O：C 54.17，H 7.71，N 9.36，found C 54.12，H7.70，N 9.33.
Ar is an Alpha-Naphthyl shown in the embodiment 7 preparation general formulas 5, and R is
The time the aromatic base conjugate:
The high spermidine derivative 0.34g that one end is replaced by piperazine is dissolved among the dichloromethane solution 15mL of 25% methyl alcohol, and 60 ℃ are stirred down and add α-naphthaldehyde 0.01g, stirring at room 18h, the stopped reaction when point that detects α-naphthaldehyde to TLC disappears.Remove solvent under reduced pressure, residuum is dissolved among the dichloromethane solution 18mL of 50% methyl alcohol, reaction mixture stirs 15min down at 10 ℃, adds NaBH at twice
40.12g rises to room temperature reaction 18h altogether, removes solvent under reduced pressure, and residuum is dissolved in the 15mL chloroform, 10% Na
2CO
3Solution washing three times is used 20mL at every turn, and collected organic layer is used anhydrous sodium sulfate drying.Remove chloroform under reduced pressure, silicagel column separate purify faint yellow oily compound.The compound that obtains is dissolved in the 8.2mL dehydrated alcohol, and 30 ℃ of aqueous solution of hydrochloric acid 6.7mL that add 4N down rise to stirring at room 18h, to there being a large amount of solids to generate, filter, with heavily steaming absolute ethanol washing three times, the dry white solid compound that gets.Productive rate 73.3%.
As Figure 11, Figure 12 is the compound of embodiment 7
13C NMR figure,
1H NMR figure, experimental data is as follows:
1H NMR(D
2O，400MHz)
H：8.01～8.08(m，3H)，7.54～7.69(m，4H)，4.72(s，2H)，3.58(s，8H)，3.16～3.27(m，4H)，3.01～3.07(q，4H)，1.72～1.81(m，8H).
13CNMR(D
2O)
C：133.72，130.98，130.65，129.55，127.61，126.83，126.65，125.75，122.57，56.44，48.61，48.00，46.94，46.83，40.93，22.93，22.81，22.73，20.78.ESI-MS m/z：369.4(M+H-4HCl)
+.Anal.calcd.for C
23H
40N
4Cl
4·0.8H
2O：C 52.24，H7.93，N 10.60，found C 52.31，H 7.87，N 10.49.
Ar is the 4-xenyl shown in the embodiment 8 preparation general formulas 6, and R is
The time the aromatic base conjugate:
The high spermidine derivative 0.3g that one end is replaced by piperazine is dissolved among the dichloromethane solution 15mL of 25% methyl alcohol, stirs to add 4-biphenylcarboxaldehyde 0.15g down, and 10 ℃ are stirred 9h down, the stopped reaction when point that detects the 4-biphenylcarboxaldehyde to TLC weakens.Remove solvent under reduced pressure, residuum is dissolved among the dichloromethane solution 20mL of 50% methyl alcohol, reaction mixture stirs 15min down at-5 ℃, adds NaBH at twice
4Be total to 0.1g, 10 ℃ are reacted 9h down, remove solvent under reduced pressure, and residuum is dissolved in the 15mL chloroform, 10% Na
2CO
3Solution washing three times is used 20mL at every turn, and collected organic layer is used anhydrous sodium sulfate drying.Remove chloroform under reduced pressure, silicagel column separate purify faint yellow oily compound.The compound that obtains is dissolved in the 3.93mL dehydrated alcohol, is cooled to-5 ℃, add the ethanolic soln 5.1mL of the hydrochloric acid of 4N, 10 ℃ of following stirring reaction 9h to there being solid to generate, filter, with heavily steaming absolute ethanol washing three times, the dry white solid compound that gets.Productive rate 84.1%.
As Figure 13, Figure 14 is the compound of embodiment 8
13C NMR figure,
1H NMR figure, experimental data is as follows:
1H NMR(D
2O，400MHz)
H：7.74～7.80(q，4H)，7.55～7.60(q，4H)，7.49～7.51(d，J＝6.5Hz，1H)，4.31(s，2H)，3.69(s，8H)，3.36～3.40(t，J＝14.9Hz，2H)，3.12～3.16(t，J＝15.8Hz，6H)，1.82～1.91(m，8H).
13C NMR(D
2O)
C：141.73，139.64，130.50(2C)，129.78，129.24(2C)，128.17，127.63(2C)，127.02(2C)，56.35，50.69，48.49，46.88(2C)，46.74，46.25，40.73(2C)，22.84，22.77，22.62，20.62.ESI-MS m/z：395.4(M+H-4HCl)
+.Anal.calcd.for C
25H
42N
4Cl
4·1.5H
2O：C 52.91，H7.99，N 9.87，found C 53.12，H 8.26，N 9.67.
Ar is a 6-methoxyl group naphthyl shown in the embodiment 9 preparation general formulas 7, and R is
The time the aromatic base conjugate:
The high spermidine derivative 0.36g that one end is replaced by piperazine is dissolved among the dichloromethane solution 20mL of 25% methyl alcohol, stirs to add 6-methoxynaphthalene formaldehyde 0.17g down, and 30 ℃ are stirred 13h down, the stopped reaction when point that detects 6-methoxynaphthalene formaldehyde to TLC disappears.Remove solvent under reduced pressure, residuum is dissolved among the dichloromethane solution 22mL of 50% methyl alcohol, reaction mixture stirs 15min down at 10 ℃, adds NaBH at twice
4Be total to 0.11g, 30 ℃ are reacted 13h down, remove solvent under reduced pressure, and residuum is dissolved in the 20mL chloroform, 10% Na
2CO
3Solution washing three times is used 20mL at every turn, and collected organic layer is used anhydrous sodium sulfate drying.Remove chloroform under reduced pressure, silicagel column separate purify faint yellow oily compound.The compound that obtains is dissolved in the 6.5mL dehydrated alcohol, is cooled to 10 ℃, add the ethanolic soln 8.4mL of the hydrochloric acid of 4N, 30 ℃ of following stirring reaction 13h to there being a large amount of solids to generate, filter, with heavily steaming absolute ethanol washing three times, the dry white solid compound that gets.Productive rate 84.0%.
As Figure 15, Figure 16 is the compound of embodiment 9
13C NMR figure,
1H NMR figure, experimental data is as follows:
1H NMR(D
2O，400MHz)
H：7.90～8.29(m，3H)，7.54～7.56(q，1H)，7.40～7.41(d，J＝2.3Hz，1H)，7.27～7.30(q，1H)，4.40(s，2H)，3.97(s，3H)，3.69(s，8H)，3.35～3.39(t，J＝16.0Hz，2H)，3.09～3.19(m，6H)，1.77～1.93(m，8H).
13C NMR(D
2O)
C：157.77，134.49，129.74，129.49，128.37，127.89，127.22，125.87，119.13，106.17，56.29，55.39，51.08，48.44(2C)，46.82，46.69，46.11，40.70(2C)，22.80，22.72，22.58，20.59.ESI-MS m/z：399.4(M+H-4HCl)
+.Anal.calcd.for C
24H
42N
4Cl
4O·1.3H
2O：C50.76，H 7.92，N 9.87，found C 50.77，H 7.89，N 9.66.
Ar is a betanaphthyl shown in the embodiment 10 preparation general formulas 7, and R is
The time the aromatic base conjugate:
The high spermidine intermediate 0.3g that one end and middle amido are protected by BOC is dissolved among the dichloromethane solution 15mL of 25% methyl alcohol, stirs to add β-naphthaldehyde 0.11g down; Stirred overnight at room temperature, stopped reaction when TLC detects the raw material point disappearance of β-naphthaldehyde.Remove solvent under reduced pressure, residuum is dissolved among the dichloromethane solution 18mL of 50% methyl alcohol, reaction mixture stirs 15min in ice-water bath, divides three times and adds NaBH
40.1g rises to room temperature reaction and spends the night altogether, removes solvent under reduced pressure, and residuum is dissolved in the 15mL chloroform, 10% Na
2CO
3Solution washing three times is used 20mL at every turn, and collected organic layer is used anhydrous sodium sulfate drying.Remove chloroform under reduced pressure, silicagel column separate purify faint yellow oily compound.The compound that obtains is dissolved in the 4.56mL dehydrated alcohol, is cooled to 0 ℃, add the ethanolic soln 7.4mL of the hydrochloric acid of 4N, rise to stirred overnight at room temperature,, filter, with heavily steaming absolute ethanol washing three times, the dry white solid compound that gets to there being a large amount of solids to generate.Yield 85.4%.
As Figure 17, Figure 18 is the compound of embodiment 10
13C NMR figure,
1H NMR figure, experimental data is as follows:
1H NMR(D
2O，400MHz)
H：7.92～7.97(m，4H)，7.49～7.58(m，3H)，4.35(s，2H)，3.56(s，8H)，3.24(s，2H)，2.99～3.11(q，6H)，1.68～1.79(m，8H).
13C NMR(D
2O)
C：133.21，132.86，129.68，129.12，128.19，128.07，127.81，127.42，127.12，126.60，56.35，51.17，48.51(2C)，46.87，46.75，46.28，40.81(2C)，22.84，22.76，22.65，20.68.ESI-MS m/z：369.4(M+H-4HCl)
+.Anal.calcd.for C
23H
40N
4Cl
4·0.3H
2O：C 53.14，H7.87，N 10.78，found C 53.15，H 7.89，N 10.59.
Ar shown in the embodiment 11 preparation general formulas 1 is for being NH to fluorophenyl, R
2.3HCl the aromatic base conjugate the time:
The high spermidine intermediate 0.67g that one end and middle amido are protected by BOC is dissolved among the dichloromethane solution 30mL of 25% methyl alcohol, stirs to add Tetralone an intermediate of Sertraline 0.28g down; Stirred overnight at room temperature, stopped reaction when TLC detects the raw material point disappearance of Tetralone an intermediate of Sertraline.Remove solvent under reduced pressure, residuum is dissolved among the dichloromethane solution 40mL of 50% methyl alcohol, reaction mixture stirs 15min in ice-water bath, divides five times and adds NaBH
40.33g rises to room temperature reaction and spends the night altogether, removes solvent under reduced pressure, and residuum is dissolved in the 50mL chloroform, 10% Na
2CO
3Solution washing three times is used 40mL at every turn, and collected organic layer is used anhydrous sodium sulfate drying.Remove chloroform under reduced pressure, silicagel column separate purify faint yellow oily compound.The compound that obtains is dissolved in the 3.15mL dehydrated alcohol, be cooled to 0 ℃, add the ethanolic soln 4.11mL of the hydrochloric acid of 4N, rise to stirred overnight at room temperature, the pressure reducing and steaming solvent, remaining solid is dissolved among the redistilled water 10mL, heavily steam the chloroform washing with 15mL, separatory is removed organic layer, the pressure reducing and steaming water layer, dry white solid compound, the yield 81.9% of getting.
As Figure 19, Figure 20 is the compound of embodiment 11
13C NMR figure,
1H NMR figure, experimental data is as follows:
1H NMR(D
2O，400MHz)
H：7.59～7.61(t，J＝5.5Hz，2H)，7.32～7.34(d，J＝8.8Hz，2H)，4.33(s，2H)，3.14～3.99(t，J＝21.6Hz，8H)，1.86～1.87(d，J＝2.3Hz，8H).
13CNMR(D
2O)
C：162.01～164.46(1C)，132.04～132.13(1C)，126.70～126.73(1C)，116.04□116.26(1C)，50.40，46.97，46.90，46.29，38.89，23.98，22.87(2C)，22.79.ESI-MS m/z：268.1(M+H-3HCl)
+.Anal.calcd.for C
15H
29N
3Cl
3F·0.2H
2O：C 47.37，H 7.79，N 11.05，found C 47.51，H 7.96，N 10.8.
The application of The compounds of this invention on the preparation antitumor drug:
Adopt the high spermidine conjugates of a series of novel textures of the inventive method synthetic, they all are new compounds of not seeing bibliographical information.Tested their growth in vitro inhibiting rate to the L1210 tumour cell, and the synergistic effect of they and ornithine decarboxylase (ODC) inhibitor Er Fujiajiniaoansuan (DFMO).
Test condition and experimental technique are referring to Chaojie Wang, Jean-Guy Delcros, et al.J.Med.Chem., 2003,46:2663-2671.
The anti tumor activity in vitro compound of having reported with foreign literature simultaneously is standard substance, has contrasted their extracorporeal anti-tumor effects, and test result sees the following form:
The external physiologically active of table 1 high spermidine conjugates
| compds. | L-1210 IC 50(μmol/L) | L-1210+DMFO IC 50(μmol/L) | (L-1210/L-1210+DMFO) IC 50 Ratio |
| Embodiment 2 | 16.94 15.06 9.98 14.77 8.04 | 8.13 5.60 4.86 9.08 5.08 | 2.08 2.69 2.05 1.63 1.58 |
L-1210: leukaemia cancer cell
Table 2 contains the external physiologically active of piperazine ring high spermidine conjugates
| compds. | L-1210 IC 50(μmol/L) | L-1210+DMFO IC 50(μmol/L) | (L-1210/L-1210+DMFO) IC 50 Ratio |
| Embodiment 10 embodiment 9 embodiment 8 | 35.77 15.09 20.26 | 23.35 8.57 7.48 | 1.53 1.76 2.71 |
| Embodiment 6 embodiment 7 standard substance | 57.89 92.61 8.04 | 17.89 37.88 5.08 | 3.24 2.44 1.58 |
L-1210: leukaemia cancer cell
The external physiologically active of table 3 high spermidine conjugates
| compds. | B16 | B16+SPD | B16+DMFO | B16/(B16+DMFO) |
| Embodiment 11 | IC 50(μmol/L) 18.39 | IC 50(μmol/L) 40.53 | IC 50(μmol/L) 9.38 | IC 50 Ratio 1.961 |
B16: melanoma cell
More than three tables show: institute's synthetic high spermidine class fragrance conjugate has the good in-vitro anti-tumor activity, can be used for preparing antitumor drug; And when adding ODC inhibitor DFMO, the anti-tumor activity of compound is significantly increased, it is the generation that ODC has suppressed endogenous polyamines, make cell have to deliver more external source polyamines by the polyamines transport passage, so just make more to have Cytotoxic compound molecule and enter model cell, thereby improved the anti-tumor activity of drug molecule, this explanation gained compound and DFMO have synergistic effect preferably, so when The combined is used, its anti-tumor activity will significantly strengthen.
Claims (9)
1, a kind of high spermidine conjugates is characterized in that, is following general formula compound:
R` is H, halogen atom, alkyl, alkoxyl group or amino.
2, high spermidine conjugates as claimed in claim 1 is characterized in that, R` is H, fluorine atom, chlorine atom, bromine atoms, iodine atom, C
1-4Alkyl, C
1-4Alkoxyl group or amino.
3, high spermidine conjugates as claimed in claim 2 is characterized in that, is following general formula compound:
Wherein,
4, high spermidine conjugates as claimed in claim 2 is characterized in that, is following general formula compound:
Wherein,
5, the method for preparing high spermidine conjugates, it is characterized in that, the high spermidine compound is dissolved in solvent,-10～60 ℃ add aromatic formaldehyde or arone reaction, after the reaction end, add the reductive agent reaction down at-10～20 ℃ ,-10～60 ℃ were reacted 4～18 hours down, the reaction back is steamed and is desolventized, residuum is dissolved in the halohydrocarbon, and washing and dry organic layer steam and remove halohydrocarbon, be dissolved in the alcohol after separating purification, at-10～30 ℃ of alcoholic solution or reactant aqueous solutions that add hydrochloric acid down ,-10～50 ℃ were reacted 4～18 hours down, filter, washing leaching cake, the dry high spermidine conjugates that gets; Described aromatic formaldehyde is to contain α-naphthaldehyde, β-naphthaldehyde, biphenylcarboxaldehyde, the anthraldehyde that substituting group is H, halogen atom, alkyl, alkoxyl group or amino on the aromatic ring; Arone is to contain the Tetralone an intermediate of Sertraline that substituting group is H, halogen atom, alkyl, alkoxyl group or amino on the aromatic ring; Described solvent is the mixed solution of Fatty Alcohol(C12-C14 and C12-C18) and halohydrocarbon.
6, the method for preparing high spermidine conjugates as claimed in claim 5, it is characterized in that, the high spermidine compound is dissolved in solvent, 10～30 ℃ add aromatic formaldehyde or arone reaction, react the raw material point that detects aromatic formaldehyde or arone to TLC stopped reaction when weakening, add the reductive agent reaction down, 10～30 ℃ of reactions 8～13 hours down at-5～10 ℃, the reaction back is steamed and is desolventized, residuum is dissolved in the halohydrocarbon, and washing and dry organic layer steam and remove halohydrocarbon, be dissolved in the alcohol after separating purification, at-5～10 ℃ of alcoholic solution or reactant aqueous solutions that add hydrochloric acid down, 10～30 ℃ were reacted 8～13 hours, filtered, washing leaching cake, the dry high spermidine conjugates that gets; Described aromatic formaldehyde is that to contain substituting group on the aromatic ring be H, fluorine atom, chlorine atom, bromine atoms, iodine atom, C
1-4Alkyl, C
1-4Alkoxyl group or amino α-naphthaldehyde, β-naphthaldehyde, biphenylcarboxaldehyde, anthraldehyde; Arone is that to contain substituting group on the aromatic ring be H, fluorine atom, chlorine atom, bromine atoms, iodine atom, C
1-4Alkyl, C
1-4Alkoxyl group or amino Tetralone an intermediate of Sertraline; Described solvent is the mixed solution of the pure and mild halohydrocarbon of saturated fatty, and wherein saturated fatty alcohol is C
1-4Saturated fatty alcohol, halohydrocarbon is alkyl chloride, bromoalkane.
7, as claim 5 or the 6 described methods that prepare high spermidine conjugates, it is characterized in that the high spermidine compound: the mol ratio of aromatic formaldehyde or arone is 1: 0.1～3.
8, the method for preparing high spermidine conjugates as claimed in claim 7 is characterized in that, solvent for use is methyl alcohol, ethanol, Virahol and 1, and each gets a kind of arbitrary proportion mixture in 2-ethylene dichloride, trichloroethane, methylene dichloride, the chloroform; Used reductive agent is Pd/C, Raney's nickel or NaBH
4
9, the application of high spermidine conjugates on the preparation antitumor drug.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830848A (en) * | 2010-04-22 | 2010-09-15 | 河南大学 | Polyamine derivative as well as preparation method and application thereof |
| CN103435586A (en) * | 2013-08-06 | 2013-12-11 | 河南大学 | Polyamine derivative containing flavone structure, and preparation method and application of polyamine derivative |
| WO2018192323A1 (en) * | 2017-04-20 | 2018-10-25 | 广州君赫生物科技有限公司 | Applications of spermidine and its derivative |
| WO2018192293A1 (en) * | 2017-04-20 | 2018-10-25 | 广州君赫生物科技有限公司 | Applications of spermine and its derivative in preparation of antitumor drug |
| US11766412B2 (en) | 2016-09-29 | 2023-09-26 | Geneheal Biotechnology Co., Ltd. | Methods of treating or alleviating adenylosuccinatelyase (ADSL) deficiency using spermidine or a pharmaceutically acceptable salt of spermidine |
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2007
- 2007-04-16 CN CN 200710054232 patent/CN101037423A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830848A (en) * | 2010-04-22 | 2010-09-15 | 河南大学 | Polyamine derivative as well as preparation method and application thereof |
| CN103435586A (en) * | 2013-08-06 | 2013-12-11 | 河南大学 | Polyamine derivative containing flavone structure, and preparation method and application of polyamine derivative |
| CN103435586B (en) * | 2013-08-06 | 2015-08-12 | 河南大学 | Containing the polyamine derivative and its preparation method and application of flavones structure |
| US11766412B2 (en) | 2016-09-29 | 2023-09-26 | Geneheal Biotechnology Co., Ltd. | Methods of treating or alleviating adenylosuccinatelyase (ADSL) deficiency using spermidine or a pharmaceutically acceptable salt of spermidine |
| WO2018192323A1 (en) * | 2017-04-20 | 2018-10-25 | 广州君赫生物科技有限公司 | Applications of spermidine and its derivative |
| WO2018192293A1 (en) * | 2017-04-20 | 2018-10-25 | 广州君赫生物科技有限公司 | Applications of spermine and its derivative in preparation of antitumor drug |
| CN110678452A (en) * | 2017-04-20 | 2020-01-10 | 广州君赫生物科技有限公司 | Application of spermidine and derivatives thereof |
| US11517541B2 (en) | 2017-04-20 | 2022-12-06 | Geneheal Biotechnology Co., Ltd. | Applications of spermidine and its derivatives |
| CN110678452B (en) * | 2017-04-20 | 2023-02-28 | 广州君赫生物科技有限公司 | Application of spermidine and derivatives thereof |
| US11684593B2 (en) | 2017-04-20 | 2023-06-27 | Geneheal Biotechnology Co., Ltd. | Applications of spermine and its derivative in preparation of antitumor drug |
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