CN101337980B - Ruthenium complexes for restraining DNA from topologizing isomerase , preparation method and application thereof - Google Patents
Ruthenium complexes for restraining DNA from topologizing isomerase , preparation method and application thereof Download PDFInfo
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- CN101337980B CN101337980B CN2008100301963A CN200810030196A CN101337980B CN 101337980 B CN101337980 B CN 101337980B CN 2008100301963 A CN2008100301963 A CN 2008100301963A CN 200810030196 A CN200810030196 A CN 200810030196A CN 101337980 B CN101337980 B CN 101337980B
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Abstract
The invention discloses a ruthenium complex for inhibiting DNA topoisomerase, which has a molecular formula of [RuL2(PZPP)]Cl2, wherein L is 2,2-bipyridine or 1,10-o-phenanthroline, and PZPP is 3-(2-pyrazinyl)-1,2,4-triazolo[4,5-e]pyrene. The invention also provides the preparation method of the ruthenium complex. The invention further provides a compound 3-(2-pyrazinyl)-1,2,4-triazolo[4,5-e]pyrene obtained in the preparation process of the ruthenium complex. The invention also discloses the application of the ruthenium complex for inhibiting DNA topoisomerase in the preparation of anticancer drugs. The ruthenium complex for inhibiting DNA topoisomerase has good water solubility and has double effects on inhibiting type-I DNA topoisomerase and type-II DNA topoisomerase, and both of the IC50 values are less than 1 [mu]m. The ruthenium complex has wide application prospect.
Description
Technical field
The present invention relates to a kind of topoisomerase enzyme inhibitor and preparation method thereof, especially a kind of ruthenium complexe that suppresses the DNA topoisomerase and preparation method thereof.
Background technology
In the whole vital process of organism, the eubolism of cell DNA plays a part very important.In the DNA of complexity metabolism, comprise the transmission of dna replication dna, reorganization and genetic information, all relate to the dynamic change of DNA sterie configuration.DNA topoisomerase (Topoisomerase is called for short Topo) then is a key ribozyme of regulating this reaction
[1]According to the difference of topoisomerase inducing DNA fracture mechanism, mainly it is divided into two classes: I type DNA topoisomerase (Topo I) and II type DNA topoisomerase (Topo II).
The DNA topoisomerase is a popular target spot of present antitumor drug research.Studies confirm that, different with normal cell, topoisomerase shows the high level expression that is not affected by other factors in tumour cell, the activity that therefore suppresses the DNA topoisomerase just can play and stop the tumour cell fast breeding, and then the effect of kill tumor cell.Be the cancer therapy drug of target spot such as Zorubicin, pidorubicin, VP in recent years with the topoisomerase
16, VM
26, camptothecine and derivative thereof etc., become most important medicine in the clinical chemotherapy scheme.But still have many problems to wait further investigation and discussion at present, have shortcomings such as complex structure, specificity are not high, poorly soluble, toxicity is bigger such as most topoisomerase organic inhibitors, the Topo I/II double inhibitor that has good inhibition ability simultaneously at present report also seldom.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiency of prior art, and a kind of Stability Analysis of Structures is provided, the ruthenium complexe of the inhibition DNA topoisomerase of good water solubility.
Another object of the present invention provides the simple preparation method of above-mentioned ruthenium complexe synthetic method.
Another object of the present invention provides the compound that produces among the preparation method of above-mentioned ruthenium complexe.
A further object of the invention provides the application of above-mentioned ruthenium complexe.
The present invention is achieved through the following technical solutions the foregoing invention purpose.
The ruthenium complexe useful molecules formula [RuL of inhibition DNA topoisomerase provided by the invention
2(PZPP)] Cl
2Represent that wherein L is 2,2-dipyridyl (bpy) or phenanthroline (Phen), PZPP are 3-(2-pyrazinyl)-1,2, and the 4-triazine is [5,6-e] pyrene also.
When L is 2, during 2-dipyridyl (bpy), the molecular structural formula of described ruthenium complexe (having omitted anionicsite) is as (I):
When L was phenanthroline (Phen), the molecular structural formula of described ruthenium complexe was as (II):
Inhibition DNA topoisomerase ruthenium complexe [RuL of the present invention
2(PZPP)] Cl
2, play suppress the effect of DNA topoisomerase be the cationic moiety of this compound, negatively charged ion can be other ions that do not influence this compound water soluble, as NO
3 2-, Br
-Deng.
The preparation method of above-mentioned ruthenium complexe comprises the steps:
(1) preparation part 3-(2-pyrazinyl)-1,2, the 4-triazine is [5,6-e] pyrenes (PZPP) also: with 2-pyrazine miaow buttocks and pyrene diketone reflux in ethanol of stoichiometry mol ratio, cooling, collecting precipitation, the dry PZPP that gets;
(2) preparation title complex: two (2,2 '-dipyridyl)-two chloro-two hydration rutheniums (II) of stoichiometry mol ratio or two (phenanthroline)-two chloro-, two hydration rutheniums (II) and PZPP are refluxed in ethylene glycol, add NaClO then
4The aqueous solution is separated out precipitation, after filtration, drying, the purification, is dissolved in acetone again, adds tetrabutylammonium chloride, separates out solid, filters, is drying to obtain.
The preparation method's of above-mentioned ruthenium complexe chemical reaction can be expressed with following chemical equation:
Step (1) is
Step (2) is
The ruthenium complexe of inhibition DNA topoisomerase provided by the invention can be applicable to prepare cancer therapy drug.
Compared with prior art, the present invention has following beneficial effect:
(1) ruthenium complexe of inhibition DNA topoisomerase of the present invention comprises metal coordination ion, itself is electrically charged, increased the water-soluble of compound, and the metal complexes molecular structure has bigger plasticity-, on part, introduce other molecular activity group easily, can carry out corresponding structure at different substrate combining environmentals and modify.
(2) experimental result show ruthenium provided by the invention (II) title complex show to I type and II type DNA topoisomerase stronger the double inhibition effect, title complex [RuL
2PZPP]
2+Inhibition IC to Topo I and Topo II
50All less than 1 μ M, being better than common organic topoisomerase enzyme inhibitor, is the metal complexes that the first has the effect of efficient Topo I/II double inhibition, has good application and development and is worth.
(3) preparation method of above-mentioned ruthenium provided by the invention (II) title complex is simple, the reaction conditions temperature is closed, implement easily, industrially be easy to a large amount of preparations, intermediate product in the preparation process and target product Stability Analysis of Structures, and compared with corresponding organic molecule large increase has been arranged on water-soluble, good dissolving is all arranged in water, greatly reduce the difficulty of production, saved production cost.
Description of drawings
Fig. 1 is the [Ru (bpy) of title complex among the embodiment 3
2PZPP]
2+The gel electrophoresis lab diagram that suppresses I type DNA topoisomerase.
Fig. 2 is the [Ru (bpy) of title complex among the embodiment 3
2PZPP]
2+The gel electrophoresis lab diagram that suppresses II type DNA topoisomerase.
Embodiment
Embodiment 1
(1) preparation part 3-(2-pyrazinyl)-1,2, the 4-triazine is [5,6-e] pyrenes (PZPP) also:
With 2-pyrazine miaow buttocks (1.1g, 8mmol) and pyrene diketone (1.8g, 8mmol) reflux 4 hours in ethanol.Cool to room temperature obtains yellow mercury oxide.Collecting precipitation, vacuum drying yellow solid, productive rate 76%.
Ultimate analysis C
21H
11N
5(molecular weight 333), experimental value: C 75.69, H 3.28, and N 21.03%; Theoretical value: C 75.68, H 3.30, and N 21.02%.FAB-MS：m/z＝334(C
21H
11N
5?333)。
(2) preparation [Ru (bpy)
2(PZPP)] Cl
2: (2,2 '-dipyridyl)-two chloro-two hydration rutheniums (II) with two (1.0g, 2mmol) and PZPP (0.6g, 2mmol) back flow reaction added NaClO after 10 hours in ethylene glycol
4The aqueous solution is separated out red solid.The thick product of suction filtration exsiccant is dissolved in acetone after separating purification through aluminum oxide column chromatography again, adds tetrabutylammonium chloride, separates out red solid, obtains target product [Ru (bpy) after the suction filtration drying
2(PZPP)] Cl
2, productive rate 78%.
Ultimate analysis C
41H
27Cl
2N
9Ru (molecular weight 817.1), experimental value: C 60.12, H 3.36, and N 15.38%; Theoretical value: C 60.21, H 3.30, and N 15.42%.ES-MS：[CH
3CN，m/z]＝374([M-2Cl]
2+)。
(1) preparation part 3-(2-pyrazinyl)-1,2, the 4-triazine is [5,6-e] pyrenes (PZPP) also:
With 2-pyrazine miaow buttocks (1.1g, 8mmol) and pyrene diketone (1.8g, 8mmol) reflux 4 hours in ethanol.Cool to room temperature obtains yellow mercury oxide.Collecting precipitation, vacuum drying yellow solid, productive rate 76%.
Ultimate analysis C
21H
11N
5(molecular weight 333), experimental value: C 75.69, H 3.28, and N 21.03%; Theoretical value: C 75.68, H 3.30, and N 21.02%.FAB-MS：m/z＝334(C
21H
11N
5?333)。
(2) preparation [Ru (phen)
2(PZPP)] Cl
2: with two (phenanthroline)-two chloro-, two hydration rutheniums (II) (1.1g, 2mmol) and PZPP (0.6g, 2mmol) back flow reaction after 10 hours in ethylene glycol adds NaClO
4The aqueous solution is separated out red solid.The thick product of suction filtration exsiccant is dissolved in acetone after separating purification through aluminum oxide column chromatography again, adds tetrabutylammonium chloride, separates out red solid, obtains target product [Ru (phen) after the suction filtration drying
2(PZPP)] Cl
2, productive rate 83%.
Ultimate analysis C
45H
27Cl
2N
9Ru (molecular weight 865.1), experimental value: C 62.33, H 3.15, and N 14.53%; Theoretical value: C 62.42, H 3.12, and N 14.56%.ES-MS：[CH
3CN，m/z]＝398([M-2Cl]
2+)。
The topoisomerase of embodiment 3 Ru (II) title complex suppresses experiment
Suppress the untwist method of experiment of topoisomerase according to medicine and suppress the judgement of ability, this compounds and pBR322DNA and topoisomerase are reacted in suitable damping fluid, reaction mixture adds the reaction terminating liquid termination reaction behind 37 ℃ of incubation certain hours.Agar 0.9% is warded off on (TBE) gel, electrophoresis under the constant-pressure conditions of 75V.Gel is with the EB solution-dyed of 1 μ g/mL, and takes pictures under UV-light.The Topo I or the active title complex concentration of Topo II that suppress 50% are defined as IC
50Experimental result shows that title complex is the double inhibitor of Topo I and Topo II, shows extraordinary inhibition ability, IC
50Value is seen Fig. 1 and Fig. 2 less than 1 μ M, and among the figure, plasmid DNA shows with the supercoiled Form I of closed loop band; In DNA, add a certain amount of Topo I/II, make the superhelix degree of DNA lax, show as Form II band, and along with the continuous adding of title complex, be that add-on is 0.4,0.6,0.8,1.0,1.2 μ M, the enzymic activity of Topo I/II is suppressed, and the dna content that shows as Form II type in electrophorogram reduces gradually, and the dna content of Form I type increases successively.Simultaneously, the organic molecule inhibitor that ruthenium complexe of the present invention is better than having reported aspect water-soluble, good stability.
Claims (4)
1. ruthenium complexe that suppresses the DNA topoisomerase, its molecular formula is [RuL
2(PZPP)] Cl
2, wherein L is 2, and 2-dipyridyl or phenanthroline, PZPP are 3-(2-pyrazinyl)-1,2, and the 4-triazine is [5,6-e] pyrene also; Described L is 2, and the molecular structure of ruthenium complexe cationic moiety is suc as formula I during the 2-dipyridyl; The molecular structure of ruthenium complexe cationic moiety was suc as formula II when described L was phenanthroline:
2. the preparation method of the described ruthenium complexe of claim 1 is characterized in that comprising the steps:
(1) preparation part: with 2-pyrazine miaow buttocks and pyrene diketone reflux in ethanol of stoichiometry mol ratio, cooling, collecting precipitation, the dry part 3-(2-pyrazinyl)-1,2 that gets, the 4-triazine is [5,6-e] pyrene also, and reaction formula is as follows:
(2) preparation title complex: two (2,2 '-dipyridyl)-two chloro-two hydration rutheniums (II) of stoichiometry mol ratio or two (phenanthroline)-two chloro-, two hydration rutheniums (II) and part are refluxed in ethylene glycol, add NaClO then
4The aqueous solution is separated out precipitation, after filtration, drying, the purification, is dissolved in acetone again, adds tetrabutylammonium chloride, separates out solid, filters, is drying to obtain, and reaction formula is as follows:
3. the compound 3-(2-pyrazinyl)-1,2 that produces in the preparation method's of the described ruthenium complexe of claim 2 the step (1), the 4-triazine is [5,6-e] pyrene also, its chemical structural formula such as III:
。
4. the application in the preparation cancer therapy drug of the described ruthenium complexe of claim 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101555253B (en) * | 2009-05-08 | 2011-05-04 | 中山大学 | Ruthenium polypyridyl complex inducing DNA to condense, preparation method and application thereof |
| CN101845060B (en) * | 2010-05-05 | 2013-06-05 | 中山大学 | Beta-carboline ruthenium compound as well as preparation method and application thereof |
| CN102942595B (en) * | 2012-11-22 | 2015-12-02 | 中山大学 | One class ruthenium complexe and its preparation method and application |
| US10727423B2 (en) | 2016-06-20 | 2020-07-28 | Universal Display Corporation | Organic electroluminescent materials and devices |
| US10686140B2 (en) | 2016-06-20 | 2020-06-16 | Universal Display Corporation | Organic electroluminescent materials and devices |
| US11279722B2 (en) | 2018-03-12 | 2022-03-22 | Universal Display Corporation | Organic electroluminescent materials and devices |
| US11165028B2 (en) * | 2018-03-12 | 2021-11-02 | Universal Display Corporation | Organic electroluminescent materials and devices |
| CN113321687B (en) * | 2021-05-27 | 2022-08-26 | 广西医科大学 | Preparation method of ruthenium-based photosensitizer and application of ruthenium-based photosensitizer in photodynamic therapy of breast cancer |
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