CN103193801B - A kind of copper (II) title complex and application thereof - Google Patents
A kind of copper (II) title complex and application thereof Download PDFInfo
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- CN103193801B CN103193801B CN201310112365.9A CN201310112365A CN103193801B CN 103193801 B CN103193801 B CN 103193801B CN 201310112365 A CN201310112365 A CN 201310112365A CN 103193801 B CN103193801 B CN 103193801B
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Abstract
The invention discloses a kind of copper (II) title complex and application thereof, is utilize derivative of phenanthroline part to form N
4coordination or N
2o
2the compound of the copper of coordination.Copper of the present invention (II) title complex has special characteristic electron, various chemical reactivity and special structure, these characteristics can be combined by way of non-covalent binding with DNA, are a kind of effective, cancer therapy drugs of combining in Non-covalent binding mode.
Description
Technical field
The invention belongs to field of bioanalysis, be specifically related to a kind of transition metal copper (II) title complex containing derivative of phenanthroline part and application thereof.
Background technology
DNA break reagent has caused in the application of their different field to be paid attention to widely, the application such as in the middle of molecular biology, biotechnology and medical science.Transition metal complex plays very important effect in nucleic acid chemistry, because transition metal complex has diversified purposes, as footprint reagent, sequence-specific combination, structure probe and treatment reagent.And clinical study shows, be combined by way of non-covalent binding with DNA as cancer therapy drug using cis-Platinum compound and with platinum class related drugs, there is severe side effect, general toxicity, and acquired resistance.Copper complex especially receives the concern of people and is studied widely, this is because they have the close redox potential of biology, and have the base of nucleic acid and compare high-affinity, these are all produce the essential condition that active oxygen radical (ROS) makes DNA break under reductive agent and molecular oxygen exist.
Summary of the invention
The object of the present invention is to provide a kind of phenanthroline copper (II) title complex and application thereof, this copper (II) title complex has special characteristic electron, various chemical reactivity and special structure, these characteristics can be combined by way of non-covalent binding with DNA, are a kind of effective, cancer therapy drugs of combining in Non-covalent binding mode.
For achieving the above object, the present invention adopts following technical scheme:
A kind of copper (II) title complex utilizes derivative of phenanthroline part to form N
4coordination or N
2o
2the compound of the copper of coordination; Shown in the structural formula as I of derivative of phenanthroline part:
I；
N
4coordination or N
2o
2shown in the structural formula as I I-IV of the compound of the copper of coordination:
II，
Ⅲ，
Ⅳ。
Described copper (II) title complex, as DNA break reagent, is applied to molecular biology, biotechnology and medical science.
Remarkable advantage of the present invention is: copper of the present invention (II) title complex has special characteristic electron, various chemical reactivity and special structure, these characteristics can be combined by way of non-covalent binding with DNA, are a kind of effective, cancer therapy drugs of combining in Non-covalent binding mode.
Of the present invention containing the metal copper complexes of derivative of phenanthroline part and the interaction of DNA; At H
2o
2deposit and have studied their cutting situations to pBR322 DNA in case; And have studied their cytotoxicity experiments to human cervical carcinoma cell (HeLa), show significant anti-tumor activity.
Accompanying drawing explanation
Fig. 1 be metal copper complexes 1-3 in 6.6%DMSO-TBS solution and the uv-absorbing spectrogram of ctDNA, a:[Cu (L
2)] (NO
3)
2; B:[Cu (acac) (L) (NO
3); C:[Cu (acac-Cl) (L) (MeOH)] (NO
3).
Fig. 2 is ligand L and the utilizing emitted light spectrogram of metal copper complexes 1-3 in DMSO-TBS (V/V, 1/14) solution in ctDNA-EB system, a:L; B:[Cu (L
2)] (NO
3)
2; C:[Cu (acac) (L) (NO
3)]; D:[Cu (acac-Cl) (L) (MeOH)] (NO
3); E: the relative intensity of fluorescence of ligand L metal copper complexes 1-3
vsthe comparison diagram (M:L, copper complex 1-3) of [DNA]/[M].
The melting-point diagram that Fig. 3 is ligand L, metal copper complexes 1-3 and ctDNA acts on.
Fig. 4 is the viscogram of ligand L, metal copper complexes 1-3 and EB and ctDNA effect.
Fig. 5 is the CD figure that ligand L and metal copper complexes 1-3 and ctDNA act on; A:L; B:[Cu (L
2)] (NO
3)
2; C:[Cu (acac) (L) (NO
3)]; D:[Cu (acac-Cl) (L) (MeOH)] (NO
3).
Fig. 6 is at H
2o
2under existence, the ligand L of different concns and metal copper complexes 1-3 are to the gel electrophoresis figure of pBR322 DNA effect.
a：1：DNA;2：DNA+H
2O
2;3-11：DNA+H
2O
2+L(5,10,15,20,25,30,35,40,45μM)；
b：1：DNA;2：DNA+H
2O
2;3-11：DNA+H
2O
2+1(1,2.5,5,7.5,10,12.5,15,17.5,20μM)；
c：1：DNA;2：DNA+H
2O
2;3-11：DNA+H
2O
2+2(5,10,15,20,25,30,35,40,45μM)；
d：1：DNA;2：DNA+H
2O
2;3-11：DNA+H
2O
2+3(1,2.5,5,7.5,10,12.5,15,17.5,20μM)；
e：1：DNA;2：DNA+H
2O
2;3：DNA+CuNO
3·3H
2O(45μM)；4：DNA+H
2O
2+CuNO
3·3H
2O（45μM）。
For there is different ROS trapping agent (DMSO, KI, NaN in Fig. 7
3) in situation, ligand L and metal copper complexes 1-3 are to the gel electrophoresis figure of pBR322 DNA effect.
a：l：DNA；2:DNA+H
2O
2；3:DNA+H
2O
2+DMSO；4:DNA+H
2O
2+KI；5:DNA+H
2O
2+NaN
3；6:DNA+H
2O
2+1；7:DNA+H
2O
2+1+DMSO；8:DNA+H
2O
2+1+KI；9：DNA+H
2O
2+1+NaN
3；
b：1:DNA+H
2O
2+2；2:DNA+H
2O
2+2+DMSO；3:DNA+H
2O
2+2+KI；4:DNA+H
2O
2+2+NaN
3；5:DNA+H
2O
2+3；6:DNA+H
2O
2+3+DMSO；7:DNA+H
2O
2+3+KI；8：DNA+H
2O
2+3+NaN
3；
c：1:DNA+H
2O
2+L；2:DNA+H
2O
2+L+DMSO；3:DNA+H
2O
2+L+KI；4:DNA+H
2O
2+L+NaN
3。
Fig. 8 is that ligand L and metal copper complexes 1-3 are to the cytoactive figure of HeLa cell.
Embodiment
The synthesis of many pyridines plane ligand L:
(1) in 250mL there-necked flask, the 28mL vitriol oil is added, solution remains on less than 5 DEG C, and add 2.0g(10.0mmol successively) 1,10-phenanthroline, 4.6g(44.6mmol) Potassium Bromide and 14mL concentrated nitric acid, solution to continue to stir at normal temperatures after 30 minutes backflow 3 hours, and brown liquid cooling is poured in the frozen water of 120g to room temperature, by the pH value of sodium hydroxide solution regulator solution to 6-7, obtain muddy solution to filter, solid with hot wash several times, merging filtrate CHCl
3(8 × 30mL) extracts, anhydrous sodium sulfate drying, and drying also obtains orange needle-like solid by recrystallizing methanol, is 1,10-phenanthroline-5,6-diketone;
(2) by 212mg(1.0mmol) 1; 10-phenanthroline-5; 6-diketone and 1.552g(20.0mmol) ammonium acetate; 4-pyridylaldehyde 133mg(1.4mmol) joins in 25mL Glacial acetic acid; reflux 6 hours under nitrogen protection; with the dilution of 200mL redistilled water after cooling, be added dropwise to ammoniacal liquor regulator solution to neutral, use CHCl
3(3 × 30mL) extracts, rear anhydrous magnesium sulfate drying, filters outstanding steaming and obtains yellow solid.Crude product purified by silica gel column chromatography for separation (CH
2cl
2: CH
3oH=80:1), obtain white solid, be part 2-(4-pyridine)-1H-[9,10-f] phenanthro-imidazoles L.
The synthesis of copper complex is as follows:
(1) [Cu (L
2)] (NO
3)
2(1) synthesis: by 50mg(0.168mmol) absolute methanol solution of L and 20mg(0.083mmol) Gerhardite join in 20mL anhydrous methanol, reflux 6 hours under nitrogen protection, have light green solid to generate.Be cooled to room temperature, filter, a small amount of methyl alcohol/trichloromethane of solid part washes three times, then uses washed with diethylether, finally solid vacuum-drying, obtains light green solid 42mg, and productive rate is 65%.
Positive ion scanning electrospray ionization mass spectrum ESI-MS (DMF)):
m/z=720.9 ({ [M-NO
3]
+); 659.5 ({ [M-2NO
3+ H]
+) .IR (KBrpellet, cm
-1): 1618,1515,1380 (C=C, C=N), 552 (Cu-N), 512 (Cu-O). ultimate analysis: C
36h
22n
12o
6cu × 2CHCl
3× 3H
2o:C, 42.45; H, 2.81; N, 15.64; Found:C, 42.60; H, 2.83; N, 15.87.
(2) [Cu (acac) (L) (NO
3)] synthesis of (2): by 50mg(0.168mmol) absolute methanol solution of L and methyl ethyl diketone (18L; 175mmol) and 47mg(0.168mmol) Gerhardite join in 20mL anhydrous methanol, under nitrogen protection reflux 6 hours.Reaction end is cooled to room temperature, is placed in the inferior solution evaporation of room temperature, after several days, has the crystal of bright green to separate out, repeatedly use methanol solution recrystallization repeatedly.Obtain bright green green solid 65mg, productive rate is 74%.
Positive ion scanning electrospray ionization mass spectrum ESI-MS (DMF): m/z=460.9 ({ [M-NO
3]
+) .IR (KBrpellet, cm
-1): 3068 (ArH), 1579,1512,1377 (C=C, C=N), 546 (Cu-N), 512 (Cu-O). ultimate analysis: C
23h
18n
6o
5cu × 2H
2o:C, 46.82; H, 5.89; N, 11.70; Found:C, 46.93; H, 5.52; N, 11.65.(3) [Cu (acac-Cl) (L) (MeOH)] (NO
3) synthesis of (3): by 50mg(0.168mmol) absolute methanol solution of L and 3-chloracetyl acetone (0.023mg; 0.171mmol) and 47mg(0.168mmol) Gerhardite join in 20mL anhydrous methanol, under nitrogen protection reflux 6 hours.Reaction end is cooled to room temperature, is placed in the inferior solution evaporation of room temperature, after several days, has tiny serpentinous crystal to separate out, and with the crystallization of methanol-acetonitrile solution weight repeatedly.Obtain sap green green solid 74mg, productive rate is 79%.
Positive ion scanning electrospray ionization mass spectrum ESI-MS (DMF): m/z=496.1 ({ [M-NO
3]
+) .IR (KBrpellet, cm
-1): ν=3060 (ArH), 1578,1513,1451 (C=C, C=N), 552 (Cu-N), 512 (Cu-O). ultimate analysis C
25h
22.50N
7.5o
9clCu:C, 44.75; H, 3.38; N, 15.66; Found:C, 44.38; H, 3.29; N, 15.91.
The use procedure of product or mode:
Embodiment 1
In UV spectrum research, CT-DNA is used for the different compound of bonding.CT-DNA is dissolved in TBS damping fluid (5mMTris-HCl/50mMNaCl, pH7.2), and preserves in the environment of 4 DEG C.Its absorbancy at 260nm place of the concentration of CT-DNA, and use 6600M
-1cm
-1determine as molar absorptivity.Be (2.0 × 10 in concentration
-5mol/L) ligand L and metal copper complexes [Cu (L
2)] (NO
3)
2, [Cu (acac) (L) (NO
3) and [Cu (acac-Cl) (L) (MeOH)] (NO
3) in solution (6.6%DMSO-TBS) add the CT-DNA of a series of difference amount (0-80 μM) respectively, and measure the change of their ultraviolet-visible absorption spectroscopy, as shown in Figure 1, the absorbancy of metal copper complexes 1-3 at 326nm place reduces along with the increase of the concentration of ctDNA.
Embodiment 2
Fluorescence spectrum experiments research be that the competitiveness of compound and ethidium bromide is tested.Concentration is (2.0 × 10
-6mol/L) ethidium bromide and concentration are (4.0 × 10
-6mol/L) in CT-DNA solution (DMSO-TBS, V/V=1/14)) in add a series of difference amount ligand L of (0-60 μM) and metal copper complexes [Cu (L respectively
2)] (NO
3)
2, [Cu (acac) (L) (NO
3) and [Cu (acac-Cl) (L) (MeOH)] (NO
3), and their emmission spectrum change (Fig. 2) is measured with spectrophotofluorometer.Excitation wavelength is 520nm.And binding constants calculates according to formula 1:
K EtBr[EtBr]=
K app[complex](1)
K
etBrbe 1 × 10
7m
-1; The concentration of ethidium bromide is 2 μMs; The concentration of compound is the compound concentration of the emissive porwer of ethidium bromide when reducing 50%.As shown in Figure 3, along with the increase of ligand L and metal copper complexes 1-3 concentration, the fluorescence intensity in ctDNA-EB system has quencher in various degree (being respectively 43%, 78%, 70%and80%).According to formula (1), the binding constants of ligand L and metal copper complexes 1-3 is respectively 2.0 × 10
5, 4.0 × 10
6, 2.0 × 10
6, 2.7 × 10
6m
-1.
Embodiment 3
The experiment of DNA fusing point is that monitoring of DNA is in the change of the ultraviolet-visible absorption spectroscopy at 266nm place by changing temperature.Be (5.0 × 10 in concentration
-5mol/L) CT-DNA solution (1.6%DMSO-TBS, pH7.2) adds ligand L and metal copper complexes [Cu (L
2)] (NO
3)
2, [Cu (acac) (L) (NO
3) and [Cu (acac-Cl) (L) (MeOH)] (NO
3) ([M]/[CT-DNA=1/10], M represent ligand L, copper complex [Cu (L respectively
2)] (NO
3)
2, [Cu (acac) (L) (NO
3) and [Cu (acac-Cl) (L) (MeOH)] (NO
3) after the change of ultraviolet-visible absorption spectroscopy.As shown in Figure 3, the fusing point of ligand L and metal copper complexes 1-3 and ctDNA exceeds 5-10 DEG C than the fusing point of ctDNA self.
Embodiment 4
In constant water bath temperature (27.2 DEG C), viscosity test is carried out with Ubbelohde viscometer.Concentration is (2.0 × 10
-4mol/L) CT-DNA solution (DMSO/TBS, V/V=1/13, pH7.2) and add ligand L and metal copper complexes [Cu (L respectively
2)] (NO
3)
2, [Cu (acac) (L) (NO
3) and [Cu (acac-Cl) (L) (MeOH)] (NO
3) (C
m/ C
dNA=0.01-0.12, M represent ligand L and metal copper complexes [Cu (L
2)] (NO
3)
2, [Cu (acac) (L) (NO
3) and [Cu (acac-Cl) (L) (MeOH)] (NO
3) change of writing time afterwards, survey three times for one group, calculate its mean value.Final data η/η
0[complex]/[DNA] represents, (η represents viscosity when there is compound; η
0represent the viscosity of DNA), but η=(t-t
0)/t
0(t is the mean time of testing after DNA adds compound; t
0mean time for DNA single is solely tested).As shown in Figure 4, in ctDNA, along with ligand L metal copper complexes 1-3 concentration increase, its viscosity also increases.
Embodiment 5
Circular dichroism spectrum U.S. AVIVModel420 circular dichroism spectrometer is measured.Spectral scan uses 1mm quartz colorimetric utensil; Instrument parameter: wavelength region 200-350nm, bandwidth (bandwith) 1nm, step-length (stepsize) 2.5nm, the data point readings time is 0.5s.Buffering baseline is also measured and is obtained in same colorimetric pool, places balance before all samples test in room temperature, and the specific rotation numerical value of institute's test sample product all deducts the background value that damping fluid self causes.The multiple scanning of each test sample is averaged at least three times.Concentration is (4.0 × 10
-6mol/L) CT-DNA solution (TBS damping fluid, pH7.2) and dropwise add respectively a series of difference amount ligand L and metal copper complexes [Cu (L
2)] (NO
3)
2, [Cu (acac) (L) (NO
3) and [Cu (acac-Cl) (L) (MeOH)] (NO
3) (C
m/ C
dNA=10:0.5-10:5, M represent ligand L and metal copper complexes Cu [Cu (L
2)] (NO
3)
2, [Cu (acac) (L) (NO
3) and [Cu (acac-Cl) (L) (MeOH)] (NO
3), and their spectrum change is measured with circular dichroism spectrometer.As shown in Figure 5, along with ligand L metal copper complexes 1-3 concentration increase, the conformation of its ctDNA has different changes.
Embodiment 6
PBR322 DNA is used as the substrate of cutting experiment, DNA cutting experiment is carried out by agarose gel electrophoresis, reaction is the dimethyl formamide of 5% and the Tris damping fluid (10mMTris-HCl of 95% at solution, pH7.6, and1mMEDTA) carry out in, the cumulative volume of reaction solution is 15 μ L, is the pBR322 DNA of (100ng/ μ L) and the L of respective concentration, [Cu (L containing concentration
2)] (NO
3)
2, [Cu (acac) (L) (NO
3) and [Cu (acac-Cl) (L) (MeOH)] (NO
3), or be the pBR322 DNA of (100ng/ μ L) and the L of respective concentration, [Cu (L containing concentration
2)] (NO
3)
2, [Cu (acac) (L) (NO
3) and [Cu (acac-Cl) (L) (MeOH)] (NO
3) and H
2o
2.Sample 37 DEG C constant temperature and place after 30 minutes in the environment of dark, add 3 μ L sample-loading buffers (containing 0.25% tetrabromophenol sulfonphthalein, the blue or green FF of 0.25% dimethylbenzene, 60% glycerine).Sample is added in the sepharose sample well of 1%, with TBE(Tris-boricacid-EDTA (TBE) buffer, pH=8.2) electrophoretic buffer is done, electrophoresis about 3 hours under 60V constant voltage, after electrophoresis terminates, gel is put into EB dilute solution dyeing 5 minutes, after taking out gel, at ultraviolet transillumination instrument photographs DNA gel photo, to observe the cutting situation of compound to DNA.As shown in Figure 6, along with ligand L metal copper complexes 1-3 concentration increase, it has cutting in various degree to pBR322 DNA.
Embodiment 7
The cutting mode of researching DNA is carried out by free radical quenching experiments.Containing pBR322DNA(100ng/ μ L) add different free radical scavengers respectively, as hydroxyl radical free radical trapping agent DMSO(4.3 μ L, 4mM in Tris damping fluid), hydrogen peroxide trapping agent KI(4.3 μ L, 4mM), singlet oxygen trapping agent NaN
3(4.3 μ L, 4mM), the volume of mixing solutions is 15 μ L, carries out according to the step of DNA cutting experiment.As shown in Figure 7, the trapping agent of DMSO(hydroxyl radical free radical) and KI(H
2o
2trapping agent) pBR322 DNA is had to the effect suppressing its fracture, and NaN
3(singlet oxygen trapping agent) does not show the effect of any suppression.
Embodiment 8
The research of cytotoxicity experiment is carried out to HeLa cell, has detected the viability of cell with mtt assay.Cell is placed in and is supplemented with 10% fetal bovine serum (FBS), penicillin (100 units/mL), in Streptomycin sulphate (100 mg/ml) RPMI1640 nutrient solution, and in 5% carbonic acid gas and 95% air, 37 DEG C can cultivate in humidified incubator.HeLa cell is inoculated in 96 porocyte culture plates, and makes cell adhesion after the part and metal copper complexes 1-3 growth of the different concns added, and puts in 37 DEG C of CO2gas incubator and continues to cultivate 24h.According to a series of program, carry out the activity of test cell with mtt assay.Relative cytotoxicity formula [OD
sample-OD
blank]/[OD
control-OD
blank] * 100 calculate percentage ratio and represent, and each experiment is in triplicate.As shown in Figure 8, metal copper complexes 1-3 shows significant anti-tumor activity.Obtain the inhibiting rate of medicine to cell according to the survival rate that mtt assay records, with the concentration of medicine for X-coordinate, inhibiting rate is ordinate zou mapping, then obtains drug concentration when 50% inhibiting rate, obtains IC50.The IC50 value of ligand L and title complex 1-3 is respectively: 21.17,3.56,3.88,4.23 μMs.
(calf thymus DNA (CT-DNA) (Sigma-Aldrich); Ethidium bromide (EB) (Aladdin reagent); The raw work biological reagent of super spirial plasmid pBR322DNA()).
The foregoing is only preferred embodiment of the present invention, all equalizations done according to the present patent application the scope of the claims change and modify, and all should belong to covering scope of the present invention.
Claims (1)
1. an application for copper (II) title complex, is characterized in that: utilize derivative of phenanthroline part to form N
4coordination or N
2o
2the compound of the copper of coordination; Shown in the structural formula as I of derivative of phenanthroline part:
I；
N
4coordination or N
2o
2shown in the structural formula as I I-III of the compound of the copper of coordination:
II，
Ⅲ；
Described copper (II) title complex, as DNA break reagent, is applied to molecular biology, biotechnology and medical science.
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