CN101723907A - O-dicyano-acenaphtho pyrazine compound and anti-tumor application thereof - Google Patents
O-dicyano-acenaphtho pyrazine compound and anti-tumor application thereof Download PDFInfo
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Abstract
The invention relates to a DNA-targeted o-dicyano-acenaphtho pyrazine compound in the field of application of antineoplastic medicaments. The compound is prepared by taking acenaphthene quinone as a raw material and performing bromination, cyclization and aromatic nucleophilic substitution reaction. The compound is characterized in that: one end takes an amino straight chain of a flexible side chain or an annular group as an electron-donating group, while the other end takes two cyanogen groups as electron-withdrawing groups; the two ends form an electron deficient large-plane conjugated system; and the structure accords with an ideal DNA intercalator. The compound shows obvious inhibitory activity to an in vitro test of MCF-7 (human mammary cancer cells).
Description
Technical field
The present invention relates to acenaphthene and the design of pyrazine compounds and the application that tumour cell is suppressed thereof in the biological chemical field.
Background technology
DNA is the important composition material of organism, is the carrier of genetic information and the basic substance of genetic expression, has a very important role in vital movements such as biological growth, growth and breeding.And malignant tumour be body under the effect of various tumorigenesis factor, the cellular abnormality hyperplasia of local organization and the true tumor that forms.The chemotherapeutics that with DNA is target spot can act on tumour cell DNA, thereby DNA is produced damage, triggers DNA-damage-repair mechanism and responds trigger cell Cycle Arrest or cell death inducing.
Since intercalator (intercalator) speech since proposing by Lennna in 1961, people have carried out a large amount of research to it.It is meant that the reversibility of polycyclic aromatic hydrocarbons small-molecule substance and DNA interacts.This quasi-molecule volume is little, is in the electron deficiency state, and has certain planar rigidity, can be inserted between the base pair of two accumulations of DNA.Various DNA intercalators as pyrido-carbazole class, anthraquinone class, Quinomycin A class, acridine, actinomycin class, benzoglyoxaline [1,2-C] quinoline etc., all is used as antitumor research, and has obtained some progress.Naphthalimide and acenaphthene and heterocycle two class pharmacophores only are discussed here.
The naphthalimide chromophoric group has good planarity, has good DNA embedded performance, has been studied widely to be used for the DNA intercalator, thereby has caused the photosensitive damage of DNA or have excellent anti-tumor activity.
1973, Hispanic Brana study group has reported a series of 3-nitro-naphthalene imide derivatives first, four 3-nitro-naphthalene imide analog compounds can strongly inhibited human hela Hela cell and the growth of KB cell, and can suppress the synthetic of DNA and RNA.QSAR studies show that, must contain nitrogen-atoms in the side chain of compound, and this point is most important to its cytotoxicity; Simultaneously, when the nitrogen-atoms on the side chain and two carbon atoms in imide ring nitrogen interval, the activity of compound is the highest.
Qian Xuhong group is that a series of acenaphthenes with antitumous effect and heterocyclic compound (formula A) (patent No.: 200410050449.5[P]) have been synthesized in substrate research with the acenaphthenequinone, they can be in low strength range with the tumour cell generation apoptosis of dose-dependent mode inducing culture, and retardance cell cycle.Be applied to obviously to suppress tumor growth by apoptosis-induced mode in the tumor model animal body.Be very high inducer of apoptosis and antineoplastic compound of a class activity.
The a series of compound of synthetic such as Liu Fengyu (formula B) (Bioorg.Med.Chem., 2006,14:6962), show the good anticancer activity.But both all exist yield low, and isomers is arranged, and separate difficulty, and instability, solubleness are not high, shortcomings such as test difficulty.
In general, for an ideal DNA intercalator, the parent of its molecule should have certain planar rigidity and (be chromophoric group, have at least
Surface-area, promptly the best is the size of 3～4 5 or 6 yuan of aromatic nucleus), have very strong electron-withdrawing group (can make chromophoric group be in the electron deficiency state) and have the electron-donating group of flexible side-chains.Such Polycyclic aromatic hydrocarbons small molecules can interact with the DNA reversibility, is inserted between the base pair of two accumulations among the DNA.
Summary of the invention
The objective of the invention is to design a synthetic class is the compound of parent with acenaphthene and pyrazine compound, be characterized in, one end is an electron-donating group with the amino straight chain or the cyclic group of flexible side-chains, the other end is an electron-withdrawing group with two cyano group, two ends form the big planar conjugate system of electron deficiency, make it have the purposes of treatment tumour.Prove that through in vitro tests these compounds show stronger inhibition ability to the MCF-7 growth of tumour cell.
The concrete technical scheme of the present invention is: adjacent dicyano acenaphthene of a class and pyrazine compound have following general structure:
In the general formula, X is:
1)
Wherein: n=0～5, R
1And R
2Be respectively H, C
1～C
5Straight-chain paraffin, Ph, thiophene, pyridine;
2)
Wherein: Y is O, S, NH, NMe, NEt, NC
3H
7
The synthetic method of acenaphthene of the present invention and pyrazine compounds is simple, and raw material is easy to get, and it is synthetic to be undertaken by following reaction formula:
Reaction reagent and condition: a. liquid bromine, 60-70 ℃, 2.0h; B. Diaminomaleonitrile, Glacial acetic acid refluxes 2.0h; C.HR, ethylene glycol mono-ether refluxes 1.0h.
Adjacent dicyano acenaphthene and the application of pyrazine dyestuff aspect antitumour drug comprise the test of compound and DNA binding mode and extracorporeal suppression tumor cell growth activity:
(1) test of target compound and DNA binding mode:
A. the test of ultra-violet absorption spectrum:
The ultraviolet titration experiments is carried out on the UV-3100 spectrophotometer, uses the quartzy cuvette of 1cm, and temperature is 25 ℃.At first use 30mM, pH is that 7.5 Tris-HCl buffered soln carries out baseline correction to instrument, measuring the interior concentration of 200-400nm scope is the ultraviolet absorption spectrum of the compound of 10 μ M, dripping calf thymus DNA in the solution then is CT-DNA, and itself and compound concentrations ratio were followed successively by 0.1: 1,0.3: 1,0.5: 1,1: 1 and 2: 1.Add DNA mixed number time at every turn,, place after 10 minutes, measure, the spectra re-recorded data so that DNA fully contacts, reacts with compound.
B. the test of fluorescence spectrum:
Accurately prepare the DMSO solution of compound, concentration is 10
-3-10
-4About M, get the DMSO solution 0.1mL of compound and 30mM, pH and be 7.5 Tris-HCl solution and be mixed in the volumetric flask of 10mL.The Tris-HCl-DMSO solution for preparing two groups of compounds, wherein one group is the Tris-HCl solution that adds CT-DNA, and another group then is the solution that does not contain the same concentrations compound of DNA, and compound concentrations remains on 10
-5-10
-6Between the M, the concentration of CT-DNA is 50 μ M, constant volume, and the room temperature lucifuge is placed a night.Obtain one group of sample liquid and one group of blank liquid like this, measure their fluorescent emission wavelength, fluorescence intensity.
By above-mentioned test, show that target compound and the combination of DNA are that intercalation combines.
(2) extracorporeal suppression tumor cell growth activity test:
(microculture tetrozolium, MTT) reduction method is carried out inhibition test to MCF-7 (breast cancer cell) with tetrazolium.
The concrete operations of tetrazolium (MTT) reduction method are: get and be in logarithmic phase, MCF-7 cell in good condition dispels into single cell suspension, behind the blood counting chamber counting, with 2 * 10
3Individual/hole is inoculated in 96 orifice plates.After cultivation 24h is adherent, add compound respectively, concentration gradient is 0.1,1,10 and 100 μ mol/L, and control group adds 0.1% DMSO, and each concentration is all established three multiple holes.Be 24h action time.After cultivating end, discard substratum, every hole replaces and contains the substratum that final concentration is 0.5mg/ml MTT, and 37 ℃ are continued to cultivate 4.0h.Discard nutrient solution, every hole adds 100 μ l DMSO dissolving bluish voilet first a ceremonial jade-ladle, used in libation particle, measures absorbance value (OD) with microplate reader under wavelength 570nm, and reference wavelength is 630nm.The cellular control unit survival rate is set at 100%, and other treatment group OD value is compared with control group, calculates the inhibiting rate of analyte to growth of tumour cell by following formula
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%,
Screening method: tetrazolium (microculture tetrozolium, MTT) reduction method,
Cell strain: the MCF-7 cell,
Action time: 24h,
Growth in vitro test result to compound is as follows:
Presentation of results compound 4a, 4b, growth has inhibition preferably to the MCF-7 cell for 4g, 4h.
Embodiment
Synthesizing of embodiment 1:5-bromine acenaphthenequinone (2)
In two mouthfuls of flasks of 500mL, add 20g (109.8mmol) acenaphthenequinone and 25.0mL liquid bromine (466.8mmol), begin to stir, in the oil bath temperature control 60-70 ℃, reaction solution is refluxed, behind the 2h, stopped reaction adds aqueous solution of sodium bisulfite, is colourless to reaction solution.Behind the thin up, decompress filter, and repeatedly wash making beating with water, to pH=7.0.Filter cake recrystallization in Glacial acetic acid gets 5-bromine acenaphthenequinone, pale brown look needle-like crystal, yield 90% four times.
1H?NMR(400MHz，DMSO)δ(ppm)8.39(d，1H)，8.21(d，1H)，8.15(d，1H)，8.04(t，1H)，7.96(d，1H).
Synthesizing of embodiment 2:3-bromo-acenaphthene and pyrazine-8,9 dintrile (3)
Add 200mg (0.77mmol) 5-bromine acenaphthenequinone and 110mg (1.07mmol) Diaminomaleonitrile in two mouthfuls of flasks of 15ml, then add the 10ml Glacial acetic acid, stirring heating backflow 2.0h during cooling is fallen back, filters, and uses CH after the drying
2Cl
2: the solution of sherwood oil=3: 1 (volume ratio) is that eluent separates purification on silicagel column, obtains aureus 3-bromo-acenaphthene and pyrazine-8,9 dintrile 192mg (0.58mmol), yield 67.7%.
1H?NMR(400MHz，CDCl
3)δ(ppm)8.03-8.06(t，1H)，8.18-8.19(d，1H)，8.34-8.35(d，1H)，8.48-8.50(d，1H)，8.56-8.57(d，1H).
Synthesizing of embodiment 3:3-(2-dimethyl) ethylamino--acenaphthene and pyrazine-8,9 dintrile (4a)
Get 100mg (0.3mmol) 3-bromo-acenaphthene and pyrazine-8,9 dintrile in the 10ml round-bottomed flask, add the 5ml ethylene glycol mono-ether, stir down, add 234 μ l (2.0mmol) ethylene glycol mono-ethers, N
2Protection is reflux 45min down; solution is by the light yellow scarlet that graduates into; after the cooling; pour in the water, filter, get red solid; dry back with methylene dichloride: methyl alcohol: triethylamine=100: 2.5: 1 (volume ratio) is that eluent separates purification on silicagel column; get red powder shape solid 3-(2-dimethyl) ethylamino--acenaphthene and pyrazine-8,9 dintrile 50mg (0.15mmol), yield 50.0%.
1H?NMR(400MHz?DMSO)δ(ppm)8.78-8.76(d，1H)，8.54-8.52(d，1H)，8.36(t，1H)，8.31-8.29(d，1H)，7.89-8.91(t，1H)，6.93-6.95(d，1H)，3.64-3.66(m，2H)，2.84(t，2H)，2.42(s，6H)；HRMS(EI)m/z(M+H)
+C
20H
16N
6calcd?for?340.1436，found：340.1444.
Synthesizing of embodiment 4:3-(2-diethyl) ethylamino--acenaphthene and pyrazine-8,9 dintrile (4b)
Synthetic method is with embodiment 3, reaction times 45min.Yield 40.0%, red solid.
1H?NMR(400MHz?DMSO)δ(ppm)8.73-8.75(d，1H)，8.54-8.55(d，1H)，8.38-8.40(t，1H)，8.30-8.32(d，1H)，7.87-7.91(t，1H)，6.91-6.93(d，1H)，3.56(m，2H)，2.78(t，2H)，2.59(m，4H)，0.99-1.02(t，6H)；HRMS(EI)m/z(M+H)
+C
22H
20N
6calcd?for?368.1749，found：368.1756.
Synthesizing of embodiment 5:3-(pyridine-2-methyl) amido-acenaphthene and pyrazine-8,9 dintrile (4c)
Synthetic method is with embodiment 3, reaction times 1.0h.Yield 50.0%, orange red solid.
1H?NMR(400MHz?DMSO)δ(ppm)9.17-9.20(t，1H)，8.86-8.88(d，1H)，8.59(d，1H)，8.58(d，1H)，8.24-8.26(d，1H)，7.92-7.96(t，1H)，7.76-7.80(t，1H)，7.46-7.48(d，1H)，7.30-7.33(t，1H)，6.78-6.80(d，1H)，4.83-3.84(d，2H)；HRMS(EI)m/z(M+H)
+C
22H
12N
6calcd?for?360.1123，found：360.1115.
Synthesizing of embodiment 6:3-(2-anilino ethylamino-)-acenaphthene and pyrazine-8,9 dintrile (4d)
Synthetic method is with embodiment 3, reaction times 2.5h.Yield 50.0%, dark red solid.
1H?NMR(400MHz?DMSO)δ(ppm)8.79-8.81(d，1H)，8.56-8.88(d，1H)，8.52(t，1H)，8.30-8.32(d，1H)，7.88-7.92(t，1H)，7.08-7.12(t，2H)，6.94-6.96(d，1H)，6.63-6.66(d，2H)，6.54-6.57(t，1H)，5.76-5.82(t，1H)，3.67-3.69(m，2H)，3.44-3.46(m，2H)；HRMS(EI)m/z(M+H)
+C
24H
16N
6calcd?for?388.1436，found：388.1445.
Synthesizing of embodiment 7:3-piperidyl-acenaphthene and pyrazine-8,9 dintrile (4e)
Synthetic method is with embodiment 3, reaction times 1.0h.Yield 70.0%, red solid.
1H?NMR(400MHz?CDCl
3)δ(ppm)8.52-8.54(d，1H)，8.49-8.51(d，1H)，8.38-8.40(d，1H)，8.87-8.91(t，1H)，7.36-7.38(d，1H)，3.57-3.60(t，4H)，2.037(m，4H)，1.81-1.83(m，2H)；HRMS(EI)m/z(M+H)
+C
21H
15N
5calcd?for?337.1327，found：337.1303.
Synthesizing of embodiment 8:3-parathiazan base-acenaphthene and pyrazine-8,9 dintrile (4f)
Synthetic method is with embodiment 3, reaction times 1.0h, yield 66.0%, red solid.
1H?NMR(400MHz，DMSO)δ(ppm)8.61-8.63(d，1H)，8.48-8.50(d，1H)，8.47-8.48(d，1H)，7.98-8.00(t，1H)，7.40-7.42(d，1H)，3.76(t，4H)，2.98(t，4H)；HRMS(EI)m/z(M+H)
+C
20H
13N
5Scalcd?for?355.0892，found：355.0898.
Synthesizing of embodiment 9:3-morpholinyl-acenaphthene and pyrazine-8,9 dintrile (4g)
Synthetic method is with embodiment 3, reaction times 1.0h.Yield 56.0%, orange red solid.
1H?NMR(400MHz，DMSO)δ(ppm)8.60-8.62(d，1H)，8.55-8.56(d，1H)，8.48-8.50(d，1H)，7.97-7.99(t，1H)，7.37-7.39(d，1H)，3.94(t，4H)，3.52(t，4H).IR(KBr?cm
-13435,2224)；HRMS(EI)m/z(M+H)
+C
20H
13N
5O?calcd?for?339.1120，found：339.1118.
Synthesizing of embodiment 10:3-N-methylpiperazine-acenaphthene and pyrazine-8,9 dintrile (4h)
Synthetic method is with embodiment 3, reaction times 1.0h, yield 50.0%, red solid.
1H?NMR(400MHz，DMSO)，δ(ppm)8.59-8.60(d，1H)，8.49-8.51(d，1H)，8.44-8.46(d，1H)，7.94-7.98(t，1H)，7.34-7.36(d，1H)，3.55(m，4H)，2.67(m，4H)，2.32(s，3H)；HRMS(EI)m/z(M+H)
+C
21H
16N
6calcd?for?352.1436，found：332.1432.
Embodiment 11: the research of target compound and DNA binding mode
A. the test of ultra-violet absorption spectrum:
The ultraviolet titration experiments is carried out on the UV-3100 spectrophotometer, uses the quartzy cuvette of 1cm, and temperature is 25 ℃.At first use 30mM, pH is that 7.5 Tris-HCl buffered soln carries out baseline correction to instrument, measuring the interior concentration of 200-400nm scope is the ultraviolet absorption spectrum of the compound of 10 μ M, dripping calf thymus DNA in the solution then is CT-DNA, and itself and compound concentrations ratio were followed successively by 0.1: 1,0.3: 1,0.5: 1,1: 1 and 2: 1.Add DNA mixed number time at every turn,, place after 10 minutes, measure, the spectra re-recorded data so that DNA fully contacts, reacts with compound.It is as shown in table 1 to calculate its intrinsic binding constant:
The intrinsic binding constant of table 1 compound
B. the research of fluorescence spectrum:
Accurately prepare the DMSO solution of compound, concentration is 10
-3-10
-4About M, get the DMSO solution 0.1mL of compound and 30mM, pH and be 7.5 Tris-HCl solution and be mixed in the volumetric flask of 10mL.The Tris-HCl-DMSO solution for preparing two groups of compounds, wherein one group is the Tris-HCl solution that adds CT-DNA, and another group then is the solution that does not contain the same concentrations compound of DNA, and compound concentrations remains on 10
-5-10
-6Between the M, the concentration of CT-DNA is 50 μ M, constant volume, and the room temperature lucifuge is placed a night.Obtain one group of sample liquid and one group of blank liquid like this, measure their fluorescent emission wavelength, fluorescence intensity.
Getting compound by spectrum test mainly is that intercalation combines with the combination of DNA.
Embodiment 12: the extracorporeal suppression tumor cell growth activity is measured
(microculture tetrozolium, MTT) reduction method is carried out inhibition test to MCF-7 (breast cancer cell) with tetrazolium.
The concrete operations of tetrazolium (MTT) reduction method are: get and be in logarithmic phase, MCF-7 cell in good condition dispels into single cell suspension, behind the blood counting chamber counting, with 2 * 10
3Individual/hole is inoculated in 96 orifice plates.After cultivation 24h is adherent, add compound respectively, concentration gradient is 0.1,1,10 and 100 μ mol/L, and control group adds 0.1% DMSO, and each concentration is all established three multiple holes.Be 24h action time.After cultivating end, discard substratum, every hole replaces and contains the substratum that final concentration is 0.5mg/ml MTT, and 37 ℃ are continued to cultivate 4.0h.Discard nutrient solution, every hole adds 100 μ l DMSO dissolving bluish voilet first a ceremonial jade-ladle, used in libation particle, measures absorbance value (OD) with microplate reader under wavelength 570nm, and reference wavelength is 630nm.The cellular control unit survival rate is set at 100%, and other treatment group OD value is compared with control group, calculates the inhibiting rate of analyte to growth of tumour cell by following formula
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%,
Screening method: tetrazolium (microculture tetrozolium, MTT) reduction method,
Cell strain: the MCF-7 cell,
Action time: 24h,
Growth in vitro test result to compound is as follows:
Table 2 compound is to the inhibiting rate % of MCF-7 cell growth
Above compound 4a, 4b, growth has inhibition preferably to the MCF-7 cell for 4g, 4h.
Claims (2)
1. adjacent dicyano acenaphthene of a class and pyrazine compound is characterized in that this compounds has following general structure:
In the general formula, X is:
1)
Wherein: n=0～5, R
1And R
2Be respectively H, C
1～C
5Straight-chain paraffin, Ph, thiophene, pyridine;
；
2)
Wherein: Y is O, S, NH, NMe, NEt, NC
3H
7
2. according to the purposes of described adjacent dicyano acenaphthene of claim 1 and pyrazine compound, it is characterized in that be that human breast cancer cell carry out inhibition test with the tetrazolium reduction method to MCF-7 with target compound:
The concrete operations of tetrazolium reduction method are: get and be in logarithmic phase, MCF-7 cell in good condition dispels into single cell suspension, behind the blood counting chamber counting, with 2 * 10
3Individual/hole is inoculated in 96 orifice plates, after cultivation 24h is adherent, add compound respectively, concentration gradient is 0.1,1,10 and 100 μ mol/L, control group adds 0.1% DMSO, each concentration is all established three multiple holes, be 24h action time, after cultivating end, discard substratum, every hole replaces and contains the substratum that final concentration is 0.5mg/mlMTT, 37 ℃ are continued to cultivate 4.0h, discard nutrient solution, every hole adds 100 μ l DMSO dissolving bluish voilet first a ceremonial jade-ladle, used in libation particle, measures absorbance value OD with microplate reader under wavelength 570nm, reference wavelength is 630nm, the cellular control unit survival rate is set at 100%, and other treatment group OD value is compared with control group, calculates the inhibiting rate of analyte to growth of tumour cell by following formula:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%,
Growth in vitro test result to compound is as follows:
Presentation of results compound 4a, 4b, growth has inhibition preferably to the MCF-7 cell for 4g, 4h.
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