CN103880890A - Novel antitumor drug-ruthenium (Ru) (II) complex and preparation method thereof - Google Patents
Novel antitumor drug-ruthenium (Ru) (II) complex and preparation method thereof Download PDFInfo
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- CN103880890A CN103880890A CN201410106706.6A CN201410106706A CN103880890A CN 103880890 A CN103880890 A CN 103880890A CN 201410106706 A CN201410106706 A CN 201410106706A CN 103880890 A CN103880890 A CN 103880890A
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Abstract
The invention relates to the technical field of ruthenium (Ru) complexes and provides a novel antitumor drug-Ru (II) complex and a preparation method thereof. The Ru (II) complex takes 2,3-bis-2-furyl quinoxaline as a main ligand and bipyridyl or phenanthroline as an auxiliary ligand. The chemical formula of the Ru (II) complex is [Ru(bpy)2dpq-df]*(PF6)2 or [Ru(phen)2dpq-df]*(PF6)2. The prepared substance is a novel Ru (II) anticancer drug, has better planarity and is expected to have better stabilizing effects with DNA (deoxyribonucleic acid) G-4 strobiles, thus becoming a potential anticancer drug. Meanwhile, the designed drug ligand structures can overcome the defects of side effects, narrow antitumor spectra and the like of platinum anticancer drugs.
Description
Technical field
The present invention relates to ruthenium class title complex technical field, refer more particularly to ruthenium (II) title complex of the concrete antitumour activity of a class potentiality and preparation method thereof.
Background technology
The methods for the treatment of of tumour mainly contains pharmacological agent (chemotherapy), operative treatment and radiotherapy, and wherein pharmacological agent remains the main method for the treatment of tumour.Therefore, development of new, can optionally act on tumour cell and not have virose antitumor drug to seem particularly urgent to normal cell.American scientist Rosenberg reported first in 1969 metal complexes of Pt (II) there is anti-tumor activity.The seventies, cis-platinum obtained developing very soon as Metal Anticancer Drug, had nowadays become and had treated clinically one of the most widely used medicine such as carcinoma of testis, ovarian cancer, neck tumour and bladder cancer.Cis-platinum, as cancer therapy drug application clinically, make metal inorganic medicine obtain confirmation, but its toxic side effect is also fairly obvious, the resistance producing as renal toxicity, bone marrow toxicity, ototoxicity, peripheral nerve toxicity, emetic property and life-time service etc.; And platinum complex has close antitumor spectrum, platinum medicine, to many tumours inoperative, is restricted its application in addition.This impels investigator's sight to turn to the non-Platinum Anti-tumor Drugs of exploitation.Transition metal ruthenium (II) class title complex has good electrochemistry, photochemistry, Photophysics and abundant fluorescent property, except this, also has unique DNA binding ability.Research shows, Several Kinds of Malignancy is as all closely related with the unconventionality expression of human body proto-oncogene promoter region c-myc gene in mammary cancer, cervical cancer and lung cancer etc., in this fragment gene, there is the sequence of one section of rich G, (in potassium ion buffered soln) forms G-tetra-chain body structures under certain condition, by ruthenium (II) class title complex induction or stablize the DNA G-tetra-chain body structures of oncogene, lower its transcription, just can suppress the expression of oncogene, cancer cell specific induction of apoptosis.Therefore find the ruthenium complexe that can stablize proto-oncogene promotor G-tetra-serobilas and can become potential cancer therapy drug.
Summary of the invention
The object of the invention is to design and synthesize a kind of New Ruthenium (II) kind anti-cancer drugs thing with better planarity, expect to there is better stabilization with DNA G-4 serobila, thereby become potential cancer therapy drug, meanwhile, the Drug Ligand structure of the present invention design can overcome platinum-containing anticancer drug side effect and the weak point such as antitumor spectrum is narrow.
The technical scheme that the present invention provides is:
A kind of serial ruthenium (II) title complex, is characterized in that, with 2,3-two-2-furyl quinoxaline is main part, ruthenium (II) title complex using dipyridyl or phenanthroline as assistant ligand, the chemical formula of this ruthenium (II) title complex be [Ru(bpy)
2dpq-df] × (PF
6)
2or [Ru(phen)
2dpq-df] × (PF
6)
2, (dpq-df is two pyridos [3,2-f:2 ', 3 '-h] quinoxaline-10,11-Coumarin, and bpy is for connecting pyridine, phen is phenanthroline)
[Ru(bpy)
2dpq-df] × (PF
6)
2following (1) formula of structural formula shown in,
[Ru(phen)
2dpq-df] × (PF
6)
2following (2) formula of structural formula shown in:
A kind of obtain described ruthenium (II) title complex [Ru(bpy)
2dpq-df] × (PF
6)
2preparation method, it is characterized in that: the method comprises the following steps:
(1) 5-nitro phenanthroline is synthetic
Taking a hydration phenanthroline as raw material,, under heating condition, reflux 3 hours with the vitriol oil, concentrated nitric acid, then regulate pH value to neutral, then suction filtration, obtain 5-nitro phenanthroline;
(2) synthesizing of the amino phenanthroline of 5-nitro-6-
By 5-nitro phenanthroline and oxammonium hydrochloride by volume 1:6 mix, drip gradually the ethanolic soln of KOH, until mixture gradually becomes brown color, again mixing solutions is poured in frozen water, leave standstill a night, suction filtration also washs mixing solutions, obtains the amino phenanthroline of product 5-nitro-6-;
Synthesizing of (3) 5,6-diamino phenanthrolines
Amino 5-nitro-6-phenanthroline is dissolved in dehydrated alcohol, under Pd/C catalyzer is used, drips hydrazine hydrate, reflux after 1 hour, filtered while hot is separated out yellow solid after filtrate adds excessive sherwood oil, is product 5,6-diamino phenanthroline;
(4) preparation of furoin (Furoin)
The furfural of getting VITMAIN B1 and new distillation is with thing amount than reacting under the ratio condition of ice bath of 1:1.5, and adjust pH to 10, leaves standstill suction filtration after 24 hours, and recrystallization after thick product washing, obtains white micro-crystals furoin;
(5) preparation of α,α'-difurfuroyl (Coumarin formyl)
Cupric sulfate pentahydrate is reacted with furoin 2 hours under 74 DEG C of water-baths, by reaction solution impouring frozen water, decompress filter, recrystallization after washing, can obtain yellow needle-like crystal α,α'-difurfuroyl;
(6) two pyridos [3,2-f:2 ', 3 '-h] quinoxaline-10,11-Coumarin (Dpq-df) synthetic
5,6-diaminostilbene, 10-phenanthroline and α,α'-difurfuroyl 1:1 are dissolved in DMF (dimethyl formamide), reflux 2 days under protection of inert gas, then cooling suction filtration, washing, recrystallization, obtains the two pyridos [3 of yellow needle crystal, 2-f:2 ', 3 '-h] quinoxaline-10,11-Coumarin;
(7) cis-[Ru (bpy)
2cl
2] 2H
2o's is synthetic
By RuCl
3, dipyridyl joins in DMF with mol ratio 1:2, and adds catalyzer lithium chloride, then reflux under protection of inert gas, joins mixing solutions in acetone after cooling, prepares cis-[Ru (bpy)
2cl
2) 2H
2o;
(8) [Ru (bpy)
2dpq-df] × (PF
6)
2synthetic
Cis-[Ru (bpy)
2cl
2] × 2H
2o and dpq-df with the mol ratio of 1:1.5 under the protection of rare gas element; reflux 6 hours; then suction filtration; to adding in filtrate 2g hexafluoro to close after ammonium phosphate suction filtration again; crude product is separated with 200-300 order neutral alumina column; in the middle of collecting, red zone elutriant, can obtain product [Ru (bpy)
2dpq-df] × (PF
6)
2.
A kind of obtain described ruthenium (II) title complex [Ru(phen)
2dpq-df] × (PF
6)
2preparation method, it is characterized in that: the method comprises the following steps:
(1) 5-nitro phenanthroline is synthetic
Taking a hydration phenanthroline as raw material,, under heating condition, reflux 3 hours with the vitriol oil, concentrated nitric acid, then regulate pH value to neutral, then suction filtration, obtain 5-nitro phenanthroline;
(2) synthesizing of the amino phenanthroline of 5-nitro-6-
By 5-nitro phenanthroline and oxammonium hydrochloride by volume 1:6 mix, drip gradually the ethanolic soln of KOH, until mixture gradually becomes brown color, again mixing solutions is poured in frozen water, leave standstill a night, suction filtration also washs mixing solutions, obtains the amino phenanthroline of product 5-nitro-6-;
Synthesizing of (3) 5,6-diamino phenanthrolines
Amino 5-nitro-6-phenanthroline is dissolved in dehydrated alcohol, under Pd/C catalyzer is used, drips hydrazine hydrate, reflux after 1 hour, filtered while hot is separated out yellow solid after filtrate adds excessive sherwood oil, is product 5,6-diamino phenanthroline;
(4) preparation of furoin (Furoin)
The furfural of getting VITMAIN B1 and new distillation is with thing amount than reacting under the ratio condition of ice bath of 1:1.5, and adjust pH to 10, leaves standstill suction filtration after 24 hours, and recrystallization after thick product washing, obtains white micro-crystals furoin;
(5) preparation of α,α'-difurfuroyl (Coumarin formyl)
Cupric sulfate pentahydrate is reacted with furoin 2 hours under 74 DEG C of water-baths, by reaction solution impouring frozen water, decompress filter, recrystallization after washing, can obtain yellow needle-like crystal α,α'-difurfuroyl;
(6) two pyridos [3,2-f:2 ', 3 '-h] quinoxaline-10,11-Coumarin (Dpq-df) synthetic
5,6-diaminostilbene, 10-phenanthroline and α,α'-difurfuroyl 1:1 are dissolved in DMF (dimethyl formamide), reflux 2 days under protection of inert gas, then cooling suction filtration, washing, recrystallization, obtains the two pyridos [3 of yellow needle crystal, 2-f:2 ', 3 '-h] quinoxaline-10,11-Coumarin;
(7) [cis-Ru (phen)
2cl
2] 2H
2o's is synthetic
By RuCl
3, phenanthroline joins in DMF with mol ratio 1:2, and adds catalyzer lithium chloride, then reflux under protection of inert gas, joins mixing solutions in acetone after cooling, prepares cis-[Ru (bpy)
2cl
2) 2H
2o;
Or [Ru (phen) (8)
2dpq-df] × (PF
6)
2synthetic
[cis-Ru (phen)
2cl
2] 2H
2o and dpq-df with the mol ratio of 1:1.5 under the protection of rare gas element; reflux 6 hours; then suction filtration; to adding in filtrate 2g hexafluoro to close after ammonium phosphate suction filtration again; crude product is separated with 200-300 order neutral alumina column; in the middle of collecting, red zone elutriant, can obtain product [Ru (phen)
2dpq-df] × (PF
6)
2.
Step 8) described in the reaction solvent aqueous solution that is ethylene glycol, eluent is formed by the volume ratio mixture of 1:3 by toluene and acetonitrile.
What preparation method of the present invention obtained obtains product [Ru (bpy)
2dpq-df] × (PF
6)
2(or [Ru (phen)
2dpq-df] × (PF
6)
2).Can be used as the stablizer of promoter region DNA G-tetra-serobilas.The promoter region G-tetra-serobila DNA that described promoter region DNA G-tetra-serobilas are behaved, the nucleotides sequence of described promoter region DNA is classified 5 '-TGAGGGTGGGTAGGGTGGGTAA-3 ' as.
New Ruthenium (II) title complex prepared by the present invention is expected to interact with promoter region DNA G-tetra-serobilas, stablizes better the structure of G-tetra-serobilas, thereby has more superior anti-tumor activity.
Brief description of the drawings
Fig. 1 be embodiment mono-[Ru(bpy)
2dpq-df] × (PF
6)
2] it
1hNMR spectrogram;
Fig. 2 be embodiment mono-[Ru(bpy)
2dpq-df] × (PF
6)
2] MALDI-MS spectrogram;
Fig. 3 be embodiment bis-[Ru(phen)
2dpq-df] × (PF
6)
2] it
1hNMR spectrogram;
Fig. 4 be embodiment bis-[Ru(phen)
2dpq-df] × (PF
6)
2] MALDI-MS spectrogram.
Fig. 5 be embodiment mono-G-tetra-serobila DNA with [Ru(bpy)
2dpq-df] × (PF
6)
2] effect fluorescence spectrum figure.
Fig. 6 be embodiment bis-G-tetra-serobila DNA with [Ru(phen)
2dpq-df] × (PF
6)
2] effect fluorescence radiation spectrogram.
Embodiment
Below in conjunction with drawings and Examples, technical solution of the present invention is done to supportive being described in further detail.
Embodiment mono-New Ruthenium (II) title complex a[Ru(bpy)
2dpq-df] × (PF
6)
2synthetic
Synthesizing of 1.5-nitro phenanthroline
Take a hydration phenanthroline 5g(25mmol) be placed in 100mL round-bottomed flask, add the 30mL vitriol oil, under magnetic agitation, be slowly warming up to 150 DEG C, dropwise add again 15mL concentrated nitric acid, stopped reaction after reactant continues to reflux 3 hours, be cooled to room temperature, containing in the beaker of 500g ice, regulate the pH value of reaction solution to approaching neutral (pH5～6) with the NaOH solution (50g NaOH is dissolved in 200mL left and right distilled water) preparing in advance reaction mixture impouring.Suction filtration obtains light yellow solid, washs more than three times with frozen water, and products therefrom is for subsequent use after dry at 50 DEG C.Output 5.12g, productive rate 91.0%.
Synthesizing of the amino phenanthroline of 2.5-nitro-6-
By 4g(17.8mmol) 5-nitro phenanthroline is dissolved in 100mL dehydrated alcohol reflux, the complete molten 8g(118.9mmol that adds afterwards of question response thing) oxammonium hydrochloride, now separate out light yellow suspended solids, and within 45 minutes, toward the ethanolic soln (9g KOH is dissolved in 100mL dehydrated alcohol) that drips KOH in above-mentioned mixed solution, reaction mixture gradually becomes brown color.Stopped reaction after continuing to reflux 30 minutes, is cooled to after room temperature, and reaction solution is poured in 300～600mL frozen water, suction filtration after the standing night, and filter cake respectively water, methyl alcohol and chloroform is dry after washing, and obtains product 1.6g, productive rate 37.5%.
Synthesizing of 3.5,6-diamino phenanthroline
By 0.4g(1.67mmol) the amino phenanthroline of 5-nitro-6-is dissolved in 400mL dehydrated alcohol, and reflux is to entirely molten, then adds 0.2g Pd/C catalyzer (10%Pd) and be uniformly mixed, and within 15min, dropwise adds 4mL hydrazine hydrate (80%).Stopped reaction after continuing to reflux 1 hour, filtered while hot, concentrated by rotary evaporation filtrate, then separate out yellow solid after adding excessive sherwood oil, after suction filtration, with the vacuum-drying of petroleum ether filter cake, can obtain yellow cotton-shaped product 0.24g, productive rate 68%.
4. the preparation of furoin (Furoin)
Get vitamin B12 .0g, distilled water 4mL, dehydrated alcohol 16mL in 100mL Erlenmeyer flask after mixed dissolution, is cooled to 0 DEG C with ice-water bath; The NaOH aqueous solution 4mL that separately gets 2M is cooled to 0 DEG C in beaker, adds gradually in Erlenmeyer flask maintaining under condition of ice bath, stirs.Add the furfural 8.2mL(0.1mol of new distillation), fully mixing rear adjustment pH value in reaction is 10, covers taper bottleneck, at room temperature leaves standstill 24 hours.The thick product of leaching, washs at twice with 40mL cold water, then with the ethanol/water washing of 8:2, suction filtration obtains light yellow solid.Crude product ethyl alcohol recrystallization, obtains white micro-crystals 6.8g, productive rate 70.8%.
5. the preparation of α,α'-difurfuroyl (Coumarin formyl)
In the 100mL three-necked bottle that magnetic stirring apparatus, reflux condensing tube and constant pressure funnel are housed, add 16g cupric sulfate pentahydrate, 22mL pyridine, and 9mL distilled water, stir heating in water bath to 74 DEG C.Think to add in reaction solution 5.8g furoin, solution becomes deep green by mazarine, keep 74 DEG C to continue heating after 2 hours, by in above-mentioned reaction solution impouring 100mL frozen water, decompress filter, is washed to filtrate bleach, wash with 50mL cold methanol, solid crude product recrystallizing methanol, can obtain the about 5.3g of yellow needle-like crystal, productive rate 92.3%.
6. pair pyrido [3,2-f:2 ', 3 '-h] quinoxaline-10,11-Coumarin (dpq-df) synthetic
5,6-diaminostilbene, 10-phenanthroline (0.25g, 1.2mmol), α,α'-difurfuroyl (0.23g, 1.2mmol), is dissolved in 20mL DMF and is placed in 100mL three-necked bottle, refluxes 2 days under nitrogen protection.After reaction finishes, cooling suction filtration, the warm methanol wash of gained solid, dry, the cotton-shaped solid of product yellow-green colour.Use DMF recrystallization, can obtain yellow needle crystal, net weight 0.25g, productive rate 57.6%.7.cis-[Ru(bpy)
2cl
2] × 2H
2o's is synthetic
In three-necked flask, add 1.56g(6mmol) ruthenium chloride (RuCl
3× 3H
2o), 1.68g(28mmol) a hydration lithium chloride, and 1.87g(12mmol) dipyridyl is dissolved in 10ml DMF, under argon shield in 140 DEG C of reflux 8 hours.Be cooled to room temperature, add 50ml acetone, shake up (making as far as possible the product of drag deposition spread out), put refrigerator freezing and spend the night.Suction filtration, obtains atropurpureus crystallite, is washed till closely colourless, dry with frozen water.Productive rate approximately 70%.
Ruthenium (II) title complex [Ru(bpy)
2dpq-df] × (PF
6)
2preparation
Accurately take 0.4mmol cis-[Ru(bpy)
2cl
2] × 2H
2o, 0.22g(0.6mmol) dpq-df, be dissolved in 35mL ethylene glycol+5mL H
2the mixed solvent of O, under argon shield, refluxes 6 hours in 120 DEG C.Reaction starts solution and is atropurpureus, gradually becomes red along with reaction is tending towards perfect solution color.After reaction finishes, be cooled to room temperature, add the dilution of 40mL water, suction filtration is removed unreacted part, obtains burgundy clear filtrate.In filtrate, add 2g hexafluoro to close ammonium phosphate, stir, obtain scarlet precipitation, leave standstill after the night, suction filtration, water and ether washing leaching cake several respectively, vacuum-drying.Crude product is crossed to 200～300 order neutral alumina columns and separate, with toluene/acetonitrile (3:1, v/v) wash-out, red zone elutriant in the middle of collecting, is placed on stink cupboard with preservative film sealing and makes solvent evaporates, can obtain product [Ru(bpy)
2dpq-df] × (PF
6)
2approximately 0.3～0.4g, productive rate approximately 60%.Fig. 1 i.e. the proton nmr spectra of this product, and Fig. 2 i.e. the mass spectrum of this product, and data characterization result is as follows:
1HNMR[(CD
3)
2SO]:δ9.52(2H,d),8.88(4H,dd),8.26(4H,m),8.14(2H,t),8.06(2H,s),8.01(2H,dd),7.84(2H,d),7.72(2H,d),7.61(2H,t),7.38(2H,t),7.23(2H,d),6.85(2H,dd).Anal.data?for?C
42H
28F
12N
8O
2P
2Ru:calcd.(%):C,47.25;H,2.64;N,10.49.found(%):C,47.16;H,2.55;N,10.52.MALDI-MS?for?C
42H
28N
8O
2Ru:calcd.777.79[M]
+,found777.0[M]
+.
Embodiment bis-
New Ruthenium (II) title complex b[Ru(phen)
2dpq-df] × (PF
6)
2synthetic
This part synthetic referring to embodiment mono-of the main ligand dpq-df of the present embodiment, identical with embodiment mono-.
1.cis-[Ru(phen)
2cl
2] × 2H
2o's is synthetic
In three-necked flask, add 1.56g(6mmol) ruthenium chloride (RuCl
3× 3H
2o), 1.68g(28mmol) a hydration lithium chloride, and 2.38g(12mmol) phenanthroline, be dissolved in 10ml DMF, under argon shield in 140 DEG C of reflux 8 hours.Be cooled to room temperature, add 50ml acetone, shake up (making as far as possible the product of drag deposition spread out), put refrigerator freezing and spend the night.Suction filtration, obtains atropurpureus crystallite, is washed till closely colourless, dry with frozen water.Productive rate approximately 70%.
2.[Ru(phen)
2dpq-df] × (PF
6)
2synthetic
Accurately take 0.4mmol cis-[Ru (phen)
2cl
2] × 2H
2o, 0.22g(0.6mmol) dpq-df, be dissolved in 35mL ethylene glycol+5mL H
2the mixed solvent of O, under argon shield, refluxes 6 hours in 120 DEG C.Reaction starts solution and is atropurpureus, gradually becomes red along with reaction is tending towards perfect solution color.After reaction finishes, be cooled to room temperature, add the dilution of 40mL water, suction filtration is removed unreacted part, obtains burgundy clear filtrate.In filtrate, add 2g hexafluoro to close ammonium phosphate, stir, obtain scarlet precipitation, leave standstill after the night, suction filtration, water and ether washing leaching cake several respectively, vacuum-drying.Crude product is crossed to 200～300 order neutral alumina columns and separate, with toluene/acetonitrile (3:1, v/v) wash-out, red zone elutriant in the middle of collecting, is placed on stink cupboard with preservative film sealing and makes solvent evaporates, can obtain red product [Ru(phen)
2dpq-df] × (PF
6)
2approximately 0.3～0.4g, productive rate approximately 60%.Fig. 3 i.e. the proton nmr spectra of this product, and Fig. 4 i.e. the mass spectrum of this product, and data characterization result is as follows:
1HNMR[(CD
3)
2SO]:δ9.49(2H,d),8.80(4H,t),8.41(4H,s),8.21(4H,dd),8.07(4H,t),7.89(2H,dd),7.79(4H,m),7.22(2H,d),6.85(2H,dd).Anal.data?for?C
46H
28F
12N
8O
2P
2Ru:calcd.(%):C,49.52;H,2.53;N,10.04.found(%):C,49.56;H,2.51;N,10.17.MALDI-MS?for?C
46H
28N
8O
2Ru:calcd.825.84[M]
+,found826.1[M]
+
Embodiment tri-
New Ruthenium (II) title complex a[Ru(bpy)
2dpq-df] × (PF
6)
2(or title complex b[Ru(phen)
2dpq-df] × (PF
6)
2) and the DNA effect of human body promoter region.
The preparation of buffered soln
Buffered soln is prepared with high purity water.
High purity water obtains with the automatic triple distillation water generator of SZ97.
Damping fluid: 100mM KCl, 10mM Tris, pH=7
Determining of title complex and DNA concentration
1. determining of title complex concentration
Take certain mass title complex a and (or b) with after damping fluid dissolving, be mixed with the solution that concentration is 200 μ M.
The processing of 2.DNA and concentration are determined
1) rich G single stranded DNA
Get the rich G single stranded DNA of certain mass, be dissolved in high purity water, put into 4 DEG C of refrigerators and keep 24h, for subsequent use.
Concentration is determined: the absorbance A with ultraviolet spectrophotometer measurement DNA at 260nm
260.Molar extinction coefficient is 2.285 × 105m
3cm
-1, DNA concentration [DNA]=K × A
260/ 2.285 × 10
5(k is extension rate), unit is mol L
-1.2) rich G-tetra-serobila DNA
Get the rich G single stranded DNA of certain mass, be dissolved in buffered soln 1, be heated to seal to 90 DEG C, and keep 5 minutes.Then naturally cool to room temperature, put into 4 DEG C of refrigerators and keep 24 hours, for subsequent use.
Concentration is determined: the absorbance A with ultraviolet spectrophotometer measurement DNA at 260nm
260.Molar extinction coefficient is 2.285 × 105m
3cm
-1, DNA concentration [DNA]=K × A
260/ 2.285 × 10
5(k is extension rate),
Unit is mol L
-1.
Title complex and the interactional fluorometric assay of G-tetra-serobila
Instrument: Hitachi FP7000 fluorophotometer
Instrument parameter: excitation wavelength: 460nm, slit width: (10,10), voltage: 500V
Sweep limit: 500-750nm
In sample pool, add the complex solution of 5 μ L with microsyringe, then add the buffered soln of 1995 μ L, with liquid-transfering gun repeatedly compressing mix, after 5 minutes, measure fluorescence curve.Continue to add the G-quadruplex DNA storing solution of 10 μ L in sample pool, observe fluorescence intensity and strengthening, continue titration, observe fluorescence and raising always, as accompanying drawing 5(or accompanying drawing 6) as shown in.Continuous 8 titration fluorescence intensities no longer raise, and stop adding G-quadruplex DNA storing solution, and title complex a result is (title complex b result is as accompanying drawing 6) as shown in Figure 5.
According to New Ruthenium (II) title complex a (or b) and the fluorescence spectrum of G-4 disjunctor keying action that forms of human body promoter region DNA, result shows: two kinds of title complexs this in buffered soln because quenching effect fluorescence is very weak, when adding after rich G-tetra-serobila DNA, fluorescence significantly strengthens, and the increase fluorescence with G-tetra-chain bulk concentrations strengthens, this is because title complex is inserted in rich G-tetra-serobila DNA structures, illustrate that title complex can be good at being combined with G-tetra-serobilas, there is the effect of stablizing G-tetra-serobilas, therefore, title complex prepared by the present invention is a kind of potential cancer therapy drug.
Claims (5)
1. serial ruthenium (II) title complex, is characterized in that, with 2,3-two-2-furyl quinoxaline is main part, ruthenium (II) title complex using dipyridyl or phenanthroline as assistant ligand, the chemical formula of this ruthenium (II) title complex be [Ru(bpy)
2dpq-df] × (PF
6)
2or [Ru(phen)
2dpq-df] × (PF
6)
2.
2. title complex as claimed in claim 1, is characterized in that, described [Ru(bpy)
2dpq-df] × (PF
6)
2following (1) formula of structural formula shown in,
3. title complex as claimed in claim 1, is characterized in that, described [Ru(phen)
2dpq-df] × (PF
6)
2following (2) formula of structural formula shown in:
Ruthenium (II) title complex described in an acquisition [Ru(bpy)
2dpq-df] × (PF
6)
2preparation method, it is characterized in that: the method comprises the following steps:
(1) 5-nitro phenanthroline is synthetic
Taking a hydration phenanthroline as raw material,, under heating condition, reflux 3 hours with the vitriol oil, concentrated nitric acid, then regulate pH value to neutral, then suction filtration, obtain 5-nitro phenanthroline;
(2) synthesizing of the amino phenanthroline of 5-nitro-6-
By 5-nitro phenanthroline and oxammonium hydrochloride by volume 1:6 mix, drip gradually the ethanolic soln of KOH, until mixture gradually becomes brown color, again mixing solutions is poured in frozen water, leave standstill a night, suction filtration also washs mixing solutions, obtains the amino phenanthroline of product 5-nitro-6-;
Synthesizing of (3) 5,6-diamino phenanthrolines
Amino 5-nitro-6-phenanthroline is dissolved in dehydrated alcohol, under Pd/C catalyzer is used, drips hydrazine hydrate, reflux after 1 hour, filtered while hot is separated out yellow solid after filtrate adds excessive sherwood oil, is product 5,6-diamino phenanthroline;
(4) preparation of furoin (Furoin)
Get VITMAIN B1 and react with under the ratio condition of ice bath of the new furfural distilling with mass ratio 1:1.5, adjust pH to 10, leaves standstill suction filtration after 24 hours, and recrystallization after thick product washing, obtains white micro-crystals furoin;
(5) preparation of α,α'-difurfuroyl (Coumarin formyl)
Cupric sulfate pentahydrate is reacted with furoin 2 hours under 74 DEG C of water-baths, by reaction solution impouring frozen water, decompress filter, recrystallization after washing, can obtain yellow needle-like crystal α,α'-difurfuroyl;
(6) two pyridos [3,2-f:2 ', 3 '-h] quinoxaline-10,11-Coumarin (Dpq-df) synthetic
5,6-diaminostilbene, 10-phenanthroline and α,α'-difurfuroyl 1:1 are dissolved in DMF (dimethyl formamide), reflux 2 days under protection of inert gas, then cooling suction filtration, washing, recrystallization, obtains the two pyridos [3 of yellow needle crystal, 2-f:2 ', 3 '-h] quinoxaline-10,11-Coumarin;
(7) cis-[Ru (bpy)
2cl
2] 2H
2o's is synthetic
By RuCl
3, dipyridyl joins in DMF with mol ratio 1:2, and adds catalyzer lithium chloride, then reflux under protection of inert gas, joins mixing solutions in acetone after cooling, prepares cis-[Ru (bpy)
2cl
2) 2H
2o;
(8) [Ru (bpy)
2dpq-df] × (PF
6)
2synthetic
Cis-[Ru (bpy)
2cl
2] × 2H
2o and dpq-df with the mol ratio of 1:1.5 under the protection of rare gas element; reflux 6 hours; then suction filtration; to adding in filtrate 2g hexafluoro to close after ammonium phosphate suction filtration again; crude product is separated with 200-300 order neutral alumina column; in the middle of collecting, red zone elutriant, can obtain product [Ru (bpy)
2dpq-df] × (PF
6)
2.
Ruthenium (II) title complex described in an acquisition [Ru(phen)
2dpq-df] × (PF
6)
2preparation method, it is characterized in that: the method comprises the following steps:
(1) 5-nitro phenanthroline is synthetic
Taking a hydration phenanthroline as raw material,, under heating condition, reflux 3 hours with the vitriol oil, concentrated nitric acid, then regulate pH value to neutral, then suction filtration, obtain 5-nitro phenanthroline;
(2) synthesizing of the amino phenanthroline of 5-nitro-6-
By 5-nitro phenanthroline and oxammonium hydrochloride by volume 1:6 mix, drip gradually the ethanolic soln of KOH, until mixture gradually becomes brown color, again mixing solutions is poured in frozen water, leave standstill a night, suction filtration also washs mixing solutions, obtains the amino phenanthroline of product 5-nitro-6-;
Synthesizing of (3) 5,6-diamino phenanthrolines
Amino 5-nitro-6-phenanthroline is dissolved in dehydrated alcohol, under Pd/C catalyzer is used, drips hydrazine hydrate, reflux after 1 hour, filtered while hot is separated out yellow solid after filtrate adds excessive sherwood oil, is product 5,6-diamino phenanthroline;
(4) preparation of furoin (Furoin)
The furfural of getting VITMAIN B1 and new distillation is with thing amount than reacting under the ratio condition of ice bath of 1:1.5, and adjust pH to 10, leaves standstill suction filtration after 24 hours, and recrystallization after thick product washing, obtains white micro-crystals furoin;
(5) preparation of α,α'-difurfuroyl (Coumarin formyl)
Cupric sulfate pentahydrate is reacted with furoin 2 hours under 74 DEG C of water-baths, by reaction solution impouring frozen water, decompress filter, recrystallization after washing, can obtain yellow needle-like crystal α,α'-difurfuroyl;
(6) two pyridos [3,2-f:2 ', 3 '-h] quinoxaline-10,11-Coumarin (Dp
q-df) synthetic
5,6-diaminostilbene, 10-phenanthroline and α,α'-difurfuroyl 1:1 are dissolved in DMF (dimethyl formamide), reflux 2 days under protection of inert gas, then cooling suction filtration, washing, recrystallization, obtains the two pyridos [3 of yellow needle crystal, 2-f:2 ', 3 '-h] quinoxaline-10,11-Coumarin;
(7) [cis-Ru (phen)
2cl
2] 2H
2o's is synthetic
By RuCl
3, phenanthroline joins in DMF with mol ratio 1:2, and adds catalyzer lithium chloride, then reflux under protection of inert gas, joins mixing solutions in acetone after cooling, prepares cis-[Ru (bpy)
2cl
2) 2H
2o;
Or [Ru (phen) (8)
2dpq-df] × (PF
6)
2synthetic
[cis-Ru (phen)
2cl
2] 2H
2o and dpq-df with the mol ratio of 1:1.5 under the protection of rare gas element; reflux 6 hours; then suction filtration; to adding in filtrate 2g hexafluoro to close after ammonium phosphate suction filtration again; crude product is separated with 200-300 order neutral alumina column; in the middle of collecting, red zone elutriant, can obtain product [Ru (phen)
2dpq-df] × (PF
6)
2.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105440085A (en) * | 2015-12-30 | 2016-03-30 | 广西师范大学 | 9-benzothianthrene hydrazine-ruthenium (II) complex as well as synthetic method and application thereof |
| CN106674221A (en) * | 2016-12-27 | 2017-05-17 | 广东工业大学 | Novel organic ligand, preparation method thereof, novel ruthenium complex and fluorescent probe |
| US10053480B1 (en) | 2017-10-11 | 2018-08-21 | King Saud University | Anti-quorum and DNA cleaving agent |
| CN110384799A (en) * | 2019-08-26 | 2019-10-29 | 同济大学 | PH responsiveness composite nano materials, preparation based on hollow copper sulfide and ruthenium complex and its application in treating cancer drug |
-
2014
- 2014-03-21 CN CN201410106706.6A patent/CN103880890A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| ZHEN Q. X. ET AL.: "Synthesis, characterization and DNA-binding properties of [Ru(phen)2taptp]2+ and [Ru(phen)2dptatp]2+", 《INORGANICA CHIMICA ACTA》 * |
| 张晟: "带杂环的钌（II）多吡啶配合物与DNA相互作用的研究", 《中国优秀硕士学位全文数据库 工程科技I辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105440085A (en) * | 2015-12-30 | 2016-03-30 | 广西师范大学 | 9-benzothianthrene hydrazine-ruthenium (II) complex as well as synthetic method and application thereof |
| CN106674221A (en) * | 2016-12-27 | 2017-05-17 | 广东工业大学 | Novel organic ligand, preparation method thereof, novel ruthenium complex and fluorescent probe |
| US10053480B1 (en) | 2017-10-11 | 2018-08-21 | King Saud University | Anti-quorum and DNA cleaving agent |
| CN110384799A (en) * | 2019-08-26 | 2019-10-29 | 同济大学 | PH responsiveness composite nano materials, preparation based on hollow copper sulfide and ruthenium complex and its application in treating cancer drug |
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