CN103980177A - Acetylene compound as well as preparation method and application thereof - Google Patents
Acetylene compound as well as preparation method and application thereof Download PDFInfo
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- CN103980177A CN103980177A CN201410211924.6A CN201410211924A CN103980177A CN 103980177 A CN103980177 A CN 103980177A CN 201410211924 A CN201410211924 A CN 201410211924A CN 103980177 A CN103980177 A CN 103980177A
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- C07—ORGANIC CHEMISTRY
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
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Abstract
The invention relates to a novel acetylene compound applied to an anti-cancer drug as well as a preparation method and application thereof. The invention provides an acetylene compound of which the structural formula is as shown in the specification, wherein R represents a functional group; R=R, CR1R2R3, (CR1R2)nX or NR1R2; R, R1, R2 and R3 are hydrogen, halogen, C1-C24 alkyl chains, an aromatic group and a heterocyclic group; n is 1-6; X is amino, an ether group, an amidogent, sulfydryl, phosphino, halogen or an ester group; the aromatic group is phenyl, naphthyl, pyrenyl, anthryl, alkyl or halogen; the heterocyclic group is pyrrole, thiophene, pyridine, piperazine, pyran, furfuran, imidazole, parazole or morpholine. The experiment proves that the acetylene can lead obvious chain interruption of DNA and apoptosis of tumor cells. The acetylene compound proves that the synthetic acetylene has high biological activity.
Description
Technical field
The present invention relates to a kind of novel enediyne compound that can be used for cancer therapy drug and its preparation method and application.
Background technology
Cancer is one of major disease causing mankind's death, and the method that is used for the treatment of clinically cancer has operative treatment, radiation and chemotherapy etc., and to kill malignant cell, wherein chemotherapy is Main Means.Conventional medicine is mainly microbiotic and so on, such as Zorubicin, and Dx, taxol, carboplatin etc.These antibiotics itself also bring very large toxic side effect in treatment cancer.Therefore, find low toxicity, efficient, the new type anticancer medicine of highly selective is the huge challenge that scientist faces always.
Enediyne compound, as a kind of antitumor antibiotics of novelty, has unique molecular structure and antitumor mechanism and efficiently killer cell effect, is the strongest active antitumor antibiotics so far.This compounds can generate phenyl diradical by Bergman Cyclization reaction, and the free radical of formation is captured the H atom on DNA chain, thereby causes strand or the double-strand break of DNA.Some natural enediyne antitumor antibiotics are as Dynemicins, Calicheamicins, and Esperamcins, C1027 etc., its antitumour activity is higher more than 1000 times than Zorubicin.These natural enediynes are mostly separated obtaining from the metabolism of microorganism.The enediyne of synthetic is harsher because its condition that Bergman Cyclization reaction occurs is compared natural enediyne, has limited the application biologically.In addition, some natural cancer therapy drugs also have very strong secondary toxicity, and the selectivity that how to improve cancer therapy drug reduces with this problem that side effect is also a needs solution.
Above-mentioned is Enediyne Antitumor Antibiotics anticancer mechanism.
About the synthetic work that can be used for the enediyne of cancer therapy drug aspect, from 1992, just possess some special knowledge.Except the antibiotic homologue of synthesis of natural enediyne, an enediyne part for synthetic concentrates on photic initiation reaction, the irradiation of these reaction needed UV-light; A part is main forms metal complexes, but limitation is larger.Although part enediyne can react under mild conditions, do not have tumour cell and Normocellular selectivity, these have all limited the application of enediyne at biological anti-tumor aspect.
In human body, the cellular environment of healthy tissues, in pH=7.4 left and right, occurs after canceration, and its singularity causes the obvious slant acidity of cell tissue environment of living in, and some cellular environments even can reach pH=4.5-5.5.Utilizing tumour cell different from Normocellular this, can be the synthetic enediyne drug provision favourable condition with better cell selective.
Summary of the invention
Thereby the object of the invention is synthetic a kind of novel reacting and there is the enediyne compound of antitumor action under acidic conditions.Utilize the sour environment of tumour cell to bring out the anti-tumor activity of enediyne compound.
Concrete technical scheme of the present invention is: a kind of enediyne compound.
Wherein, R represents functional group;
R=R, CR
1r
2r
3, (CR
1r
2)
nx or NR
1r
2; R wherein, R
1, R
2, R
3for hydrogen, halogen, C1-C24 alkyl chain, aromatic group, heterocyclic group; N is 1 ~ 6; X is amino, ether, amide group, sulfydryl, phosphino-, halogen or ester group.
Described aromatic group is phenyl, naphthyl, pyrenyl, anthryl, alkyl or halogen; Described heterocyclic group is pyrroles, thiophene, pyridine, piperazine, pyrans, furans, imidazoles, pyrazoles or morpholine.
Said structure formula be take maleimide as main framing structure.
Said structure formula contains the end 3,3 that can be hydrolyzed under acidic conditions, 3-triethoxy functional group.
Another object of the present invention is by hydrolysis reaction, to generate the bioactive another kind of enediyne that has that Bergman Cyclization reaction easily occurs under acidic conditions:
The enediyne compound that the present invention proposes can be used as the application of cancer therapy drug.Described enediyne is based on 1-benzyl-3,4-bis-(3,3,3-triethoxy-1-proyl)-1H-pyrroles-2, the compound of 5-diketone.This compound can be derived and be synthesized the homologous compound with different new functions by structure regulating.Research shows, this compounds can be hydrolyzed and generate highly active enediyne under acidic conditions, and reacts by spontaneous Bergman Cyclization, causes the chain cracking of DNA and the death of tumour cell.This new enediyne compound is expected to bring into play latent effect in tumor suppression and cancer therapy.
The present invention also provides a kind of preparation method of enediyne compound, uses palladium and cesium carbonate for main catalyzer, and the mixed solvent of toluene and tetrahydrofuran (THF) carries out a Yuan coupled reaction (Sonogashira reaction); Step is:
Under nitrogen atmosphere, by cuprous iodide, palladium, triphenylphosphine, cesium carbonate and 3,4-bis-iodo-N-benzyl maleimides add in bottle successively, after the tetrahydrofuran (THF) that adding dewaters heavily steamed and toluene, stir, add 3,3,3-triethoxy-1-propine completes reaction after stirring reaction 5h at 45 ℃; Reacted mixed system is directly done to carrier with florisil, and cyclohexane/ethyl acetate is made eluent and is directly carried out column chromatography for separation, by vacuumizing except after desolventizing, obtains light yellow thickness product enediyne a, and structure is as follows:
。
Synthetic enediyne a is hydrolyzed to react and generates enediyne b; Step is:
At 0 ℃, the enediyne a of fresh preparation is dissolved in trichloromethane, add after two trifluoroacetic acids and stir 30 seconds rapidly, then add the potassium carbonate powder of grinding with trifluoroacetic acid excessive in neutralization reaction; Cross and filter out solid, vacuum is removed solvent at 0 ℃, obtains yellow sticky solid enediyne b, and structure is:
。
The anti-tumor biological experiment of enediyne provided by the invention, comprising:
Enediyne causes the splitting of chain experiment of superhelix double-stranded DNA, mainly with super spirial plasmid Φ X174 RF1DNA, evaluates enediyne a and the activity of enediyne b to DNA.Two kinds of different enediynes are dissolved in respectively in DMSO and acetone, are added in the TE damping fluid of DNA, at 37 ℃, cultivate laggard row agarose gel electrophoresis of for some time, carry out the cracking situation of analyzing DNA.
Enediyne causes the toxicity of apoptosis of tumor cells to show.With tumor cells of hepatocellular carcinoma HepG2 cell, evaluate the antitumor action of enediyne a.Enediyne a is dissolved in acetone and is joined in cultured tumour cell, after cultivation for some time, by MTT method, cytoactive is evaluated.
Effect of the present invention, finds through experimental result, enediyne a can cause the obvious chain cracking of DNA under acidic conditions; Active enediyne b after hydrolysis also can cause the obvious chain cracking of DNA under neutrallty condition.Meanwhile, enediyne a also shows cells apoptosis clearly to tumour cell.
The invention has the advantages that, synthesize the enediyne that Bergman Cyclization can occur under acidic conditions.Utilize the sour environment of people's interior tumor cell, the apoptosis that this class enediyne can cause the obvious splitting of chain of DNA and cause tumour cell, illustrates that synthetic enediyne has higher biological activity.
Accompanying drawing explanation
Fig. 1-enediyne a causes the splitting of chain of DNA.
Wherein: DMSO solution+PPTS of-1-DNA+ enediyne a, pH=6
—2—DNA+?DMSO+?PPTS，pH=6
DMSO solution+PPTS of-3-DNA+ enediyne a, pH=5
—4—DNA+?DMSO+?PPTS，pH=5
DMSO solution+PPTS of-5-DNA+ enediyne a, pH=4
—6—DNA+?DMSO+?PPTS，pH=4。
Fig. 2-enediyne b causes the splitting of chain of DNA.
Wherein :-1-DNA
-2-DNA+ acetone
-3-DNA+ enediyne b, 100 mM/L
-4-DNA+ enediyne a, 100 mM/L
-5-DNA+ enediyne b, 50 mM/L
-6-DNA+ enediyne a, 50 mM/L.
Fig. 3-enediyne a causes the apoptotic effect of HepG2 tumour cell.
Wherein: the DMSO solution of--HepG2+ enediyne a (concentration is respectively 0,0.15 mM/L, 0.3 mM/L, 0.6 mM/L, 1.3 mM/L, 2.5 mM/L, 5 mM/L, 10 mM/L, 20 mM/L and 40 mM/L) the 24 hours reaction times
The DMSO solution of-zero-HepG2+ enediyne a (concentration is respectively 0,0.15 mM/L, 0.3 mM/L, 0.6 mM/L, 1.3 mM/L, 2.5 mM/L, 5 mM/L, 10 mM/L, 20 mM/L and 40 mM/L) the 48 hours reaction times
The DMSO solution of-▽-HepG2+ enediyne a (concentration is respectively 0,0.15 mM/L, 0.3 mM/L, 0.6 mM/L, 1.3 mM/L, 2.5 mM/L, 5 mM/L, 10 mM/L, 20 mM/L and 40 mM/L) the 72 hours reaction times.
Embodiment
< example 1> enediyne a's is synthetic
Two kinds of raw material 3,4-bis-iodo-N-benzyl maleimides that synthetic enediyne a is used and 3,3,3-triethoxy-1-propine is respectively according to document Tetrahedron
2005, 61,4585 and Organic letters
2008, described in 10,4915, method is synthetic.
Under nitrogen, by cuprous iodide (98.5mg, 40mmol%), palladium (29.2mg, 10mmol%), triphenylphosphine (68.2mg, 20mmol%), cesium carbonate (1.27g, 3.9mmol) and 3,4-bis-iodo-N-benzyl maleimides (0.57g, 1.3mmol) be added to successively in the Schlenk bottle being dried, the tetrahydrofuran (THF) (4ml) and the rear stirring of toluene (10ml) that add heavily steaming to dewater, add 3,3,3-triethoxy-1-propine (0.68g, 3.9mmol), at 45 ℃, after stirring reaction 5h, complete reaction.The thick solution of reaction system is carried out to the column chromatography for separation of florisil with the eluent of cyclohexane/ethyl acetate=40:1, after solvent removed in vacuo, obtain light yellow thickness product enediyne a(0.405g, productive rate 59.6%).
1H?NMR(?500MHz,?CDCl
3):δ（ppm）?7.28-7.34?(m,?5H,?Bn),?4.69?(s,?2H,?CH
2),?3.73?(q,12H,?CH
2,?J=7.0MHz),?1.25(t,?18H,CH
3,?J=7.0MHz)。
13C?NMR(?500MHz,?CDCl
3,?ppm):?δ165.6,?135.3,?128.9,?128.8,?128.6,?128.2,?109.1,?103.7,?72.9,?59.5,?42.7,?14.9。HRMS (ESI): m/z C
29h
37nO
8(M+Na)
+, calculated value 550.2417; Measured value 550.2419.Structural formula is:
< example 2> enediyne b's is synthetic
Reaction is carried out at 0 ℃.By the enediyne a(20mg of fresh preparation) be dissolved in trichloromethane (10ml), add two trifluoroacetic acids (TFA).Rapid stirring 30 seconds, then adds the potassium carbonate powder (2g) of grinding, with acid excessive in neutralization reaction.Solids removed by filtration, collects filtrate, and vacuum is removed solvent, obtains yellow enediyne b.
1H?NMR(?500MHz,?CDCl
3):?δ（ppm）7.30-7.35(m,5H,Bn),?4.72(s,2H,CH
2),4.33(q,4H,CH
2,J=7.0MHz),1.36(t,6H,CH
3,J=7.0MHz).
13C?NMR?(?500MHz,?CDCl
3):?δ（ppm）164.4,?152.0,?134.9,?129.4,?128.9,?128.7,?128.4,?98.5,?72.6,?63.1,?43.0,?13.9。HRMS (ESI): m/z C
21h
17nO
6(M+Na)
+, calculated value 402.0954; Measured value 402.0958.Structural formula is:
The cracking ability of < example 3> enediyne a to superhelix double-stranded DNA
Select super spirial plasmid Φ X174 RF1DNA to test.The DMSO solution of enediyne a is added in the TE damping fluid of Φ X174, adds the aqueous solution regulation system pH of para-methylbenzenepyridinsulfonate sulfonate (PPTS) respectively at pH=4, pH=5, pH=6 left and right.Mixture is placed on to constant temperature at 37 ℃ and, after 40 hours, takes out solution and carry out agarose gel electrophoresis, by ultraviolet imagery system, carry out scanning imagery analysis.
Φ X174 RF1DNA is a kind of superhelix double-stranded DNA, and it 95% exists with Form I form, if DNA is cleaved, can be converted into Form II by Form I, is called strand cracking, or changes into Form III by Form I, is called double-stranded cracking.
Result shows, when pH=6, DNA is without obvious variation, and when pH=5, DNA starts to change to some extent, and adds the DNA of enediyne a to change slightly obviously than the DNA that does not add enediyne a.When pH=4, add the DNA after enediyne a to occur significantly to change, show that enediyne a has caused the strand cracking of DNA, DNA is converted into Form II form by Form I form.As shown in Figure 1.
The cracking ability of < example 4> enediyne b to superhelix double-stranded DNA
The acetone soln of enediyne b is added in the TE damping fluid of Φ X174, mixture is placed on to isothermal reaction at 37 ℃ and, after 48 hours, gets solution and carry out agarose gel electrophoresis, by ultraviolet imagery system, carry out scanning imagery analysis.
Result shows, when enediyne a is hydrolyzed into after active higher enediyne b, under neutrallty condition, the enediyne b that concentration is 100mM/L just can cause the obvious cracking of DNA, even if concentration is reduced to 50mM/L, DNA also has obvious splitting of chain.As shown in Figure 2.
The apoptotic effect of < example 5> enediyne a inducing tumor cell
Use MTT analytical procedure to characterize cytoactive, concrete grammar is:
1) at 37 ℃, contain 5%CO
2atmosphere under, culturing cell 24h in the DMEM substratum that is supplemented with 10 % foetal calf serums;
2) with the buffer salt solution containing 0.25% trypsinase and 0.03% EDTA, cell trypsinized is processed, until reach 70 %, merged in tissue culture flasks;
3) cell is seeded on 96 porocyte culture plates, and makes its adherent culture 24 hours;
4) treated with medicaments cell, is dissolved in enediyne in acetone and is added in cell culture medium; Continue to cultivate 24h, 48h, 72h;
5) will be dissolved with MTT(3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt) PBS solution (pH=7.4) join in each orifice plate, cell is cultivated 4 hours again, make yellow dyes become blue colored crystal;
6) by suction, remove unreacted dyestuff, in orifice plate, add DMSO to carry out crystalline substance and separate;
7) cytoactive detects: with enzyme-linked immunosorbent assay instrument, at 490nm wavelength place, measure OD value, indirectly reflect the activity of cell.
Result shows, with enediyne a, processes after tumour cell, after cultivation 24h, can cause the obvious apoptosis of tumour cell, and incubation time is to 48h, and after 72h, cytoactive has obvious reduction, as shown in Figure 3.
Claims (10)
1. an enediyne compound, its chemical structural formula is:
Wherein, R represents functional group;
R=R, CR
1r
2r
3, (CR
1r
2)
nx or NR
1r
2; R wherein, R
1, R
2, R
3for hydrogen, halogen, C1-C24 alkyl chain, aromatic group, heterocyclic group; N is 1 ~ 6; X is amino, ether, amide group, sulfydryl, phosphino-, halogen or ester group.
2. enediyne compound according to claim 1, is characterized in that, described aromatic group is phenyl, naphthyl, pyrenyl, anthryl, alkyl or halogen; Described heterocyclic group is pyrroles, thiophene, pyridine, piperazine, pyrans, furans, imidazoles, pyrazoles or morpholine.
3. enediyne compound according to claim 1 and 2, is characterized in that take that maleimide is as main framing structure.
4. according to the enediyne compound described in claim 1 goods 2, it is characterized in that containing the end 3,3 that can be hydrolyzed, 3-triethoxy functional group under acidic conditions.
5. a preparation method for enediyne compound, its reaction is as follows:
。
6. enediyne compound according to claim 1, its structural formula is:
。
7. a preparation method for enediyne compound, uses palladium and cesium carbonate for main catalyzer, the Yuan that the mixed solvent of toluene and tetrahydrofuran (THF) a carries out coupled reaction; Step is:
Under nitrogen atmosphere, by cuprous iodide, palladium, triphenylphosphine, cesium carbonate and 3,4-bis-iodo-N-benzyl maleimides add in bottle successively, after the tetrahydrofuran (THF) that adding dewaters heavily steamed and toluene, stir, add 3,3,3-triethoxy-1-propine completes reaction after stirring reaction 5h at 45 ℃; Reacted mixed system is directly done to carrier with florisil, and cyclohexane/ethyl acetate is made eluent and is directly carried out column chromatography for separation, by vacuumizing except after desolventizing, obtains light yellow thickness product enediyne a, and structure is as follows:
。
8. the preparation method of enediyne according to claim 5, is characterized in that synthetic enediyne a to be hydrolyzed and to react generation enediyne b; Step is:
At 0 ℃, the enediyne a of fresh preparation is dissolved in trichloromethane, add after two trifluoroacetic acids and stir 30 seconds rapidly, then add the potassium carbonate powder of grinding with trifluoroacetic acid excessive in neutralization reaction; Cross and filter out solid, vacuum is removed solvent at 0 ℃, obtains yellow sticky solid enediyne b, and structure is:
。
9. an enediyne as claimed in claim 1 is for the application of antitumor drug.
10. an enediyne as claimed in claim 6 (a) is for the application of antitumor drug.
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