CN103788134B - A kind of preparation method and applications of microwave-assisted alkynyl-modified ruthenium (II) complex - Google Patents
A kind of preparation method and applications of microwave-assisted alkynyl-modified ruthenium (II) complex Download PDFInfo
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Abstract
The invention discloses a kind of (II) complex of ruthenium containing alkynyl and its synthetic method and applications.The present invention is shown using the general structure such as (I) that ruthenium containing alkynyl (II) complex is prepared in Microwave Assisted Process.There are good results in terms of inhibiting tumour cell effect for present invention ruthenium containing alkynyl (II) complex.Present invention ruthenium containing alkynyl (II) complex has stronger fluorescent emission, and the change in fluorescence to interact with DNA is obvious, binding force is strong, has potential application value in terms of DNA fluorescence diagnostic probe and solar cell material.Therefore, present invention ruthenium containing alkynyl (II) complex can be used for preparing the drug of prevention or treating cancer, in addition, can be used for DNA fluorescence diagnostic probe and for solar battery and photosensitizer.
Description
Technical field
The present invention relates to pharmaceutical chemistry, molecular biology and molecular material fields, and in particular to a kind of alkynyl-modified
The preparation method of ruthenium (II) complex and its as a kind of advantage of new complexes in terms of inhibiting tumour cell effect, DNA
Application in terms of fluorescence diagnostic probe, solar cell material.
Background technique
Ruthenium complex becomes pharmaceutical chemistry research in recent years, chemical biology, biological nothing as the research of anti-tumor drug
One of research hotspots in fields such as chemical machine.For example, Clarke et al. reviews the anticancer activity of ruthenium complex, especially anti-rotation
Move active (Chem.Rev., 1999,99,2511)；Sava is in " Metal Compounds in Cancer Therapy (cancer
Metallic compound in treating) " it reviews in (Chapman and Hall write, and S P Fricker is edited, London, 1994,65-91)
The antimetastatic activity of ruthenium complex.As the not isoplastic ligand of various bands that gos deep into studied ruthenium complex is also synthesized characterization
Out, we synthesize considered factor, design synthesis with regard to the other anti-tumor drug designs of angle reference of Pharmaceutical Analysis screening
It is a series of to contain alkynyl-modified ruthenium complex.
There is lot of documents to be reported in drug molecule design and synthesis and introduce alkynyl to enhance its activity, research finds to draw
Enter the advantage that this kind of group has oneself in terms of activity and combination power.Common drug have estradiol, BrdU, Tretinoin,
It can be seen that alkynyl-modified design in antimycotic furanone derivatives and various Pyrmidine nucleoside derivatives class drugs.
Zhang Yingchun et al. once reported the research containing dilute two acetylenics high efficiency anti-tumor antibiotic, was exactly because having alkene
This kind of drug of this unique texture of diine ring just has very strong antitumor action, and the result that this may be special with this is entering
It is obtained caused by advantage on cell.(World Notes on Antibiotics, 2008, Vol.29, No.l)
When studying ruthenium complex as semiconductor material, design synthesizes and characterizes 7 kinds of bands S.Ramachandra et al.
Alkynyl-modified Ru-polypyridine compound, this is also further doing in field of medicaments research application for alkynyl-modified ruthenium complex
The theoretical research and exploration on basis, it was demonstrated that this kind of compound is in synthesis a possibility that, especially Ru (bpy)2-EPIP、Ru
(bpy)2The synthesis of-TMS-EPIP has good directive significance with the characterization compound to be synthesized to us.
(Inorg.Chem.2011,50,1581-1591) and emerging spring of bear etc. are to the research of Pd catalyzed coupling reaction also drawing for alkynyl
Enter and proposes good direction.(Huaqiao University's journal, 2011, Vol.32, No.2) Jin Xuanye et al. is in research palladium chtalyst synthesis
A kind of method for being completely applicable in universal alkynyl group and introducing is proposed when Pyrmidine nucleoside derivatives, is alkynyl in ruthenium complex
Introduction is laid a good foundation.(Chin.J.Org.Chem., VOl, 29,2009, NO.1,44~54)
In metal complex with anti-tumor activity, ruthenium complex is had received widespread attention, and is generally recognized in the world
For, ruthenium and ruthenium complex belong to hypotoxicity, be easy absorb and drain quickly in vivo, will as most promising anticancer drug it
One.Ruthenium complex and cis-platinum ruthenium complex are as the application developmental research for the preparing anti-tumor drug some time, one
The perfect or even existing some drugs molecule that also reaches its maturity in terms of a little fields enters clinical stage, as one such more
Pyridine and phenanthroline ruthenium complex also have oneself in the advantage and application of antitumor application thereof.
We, which design, has synthesized alkynyl-modified [Ru(bpy)2(dppzi), mainly there is following innovation: first is that alkynyl
It introduces, this is a new class of ruthenium complex, the further development using new synthetic method to research propulsion ruthenium complex
There are very big directive significance, and effect, the increasing drug entrance that the introducing of alkynyl may promote drug molecule cross-film to absorb
The probability of cell has biggish researching value and research significance in terms of reducing poisonous side effect of medicine to increase drug effect；Second is that molecule
Comprehensive and systematic design, this time for alkynyl-modified [Ru(bpy)2(dppzi) study we in addition to apply three classes alkynyl group
Be investigated the influence of different isomer outside, to the premise of complex used respectively racemic compound, levo-compound with
And dextro-compound, to study the selectivity and drug heterogeneity of various configuration.In addition to this for the type of ruthenium complex
Also having carried out expansion, we also studied ferrosin class in addition to more pyridines, enrich the research base of alkynyl-modified ruthenium complex
Plinth.There are also the experiment that the important point is exactly our current upper alkynyls be with Songashira reaction in carbon carbon coupling reaction by
Microwave synthesizer completes, this preparation method and technology are current at home or completely new.
Highly sensitive in terms of clinical diagnosis and treatment, highly selective, quickly and low cost detects amino in organism
Acid is very important.In recent years, metal nano material has been widely used in biology with its unique physical and chemical performance
Molecular Detection field, ruthenium complex have become a kind of ideal sensing hair with its good stability and photoelectric effect
Luminescent material, it is believed that the complex of ruthenium is examined by being prepared into Optochemical sensor in conjunction with gold nano preparing clinical fluorescence
Disconnected probe, which facilitates, may big advantage and potentiality leaved for development.
Ruthenium complex luminous efficiency is high, and the service life is long, and its emission wavelength is conducive to biological inspection in visible region
It surveys, method is simple, can develop into a kind of new bio probe sensor.
The country, which has been reported, utilizes bipyridyl ruthenium complex ([Ru (II) (bpy)3]2+·6H2O carries out the system of fluorescence probe
It is standby, DNA molecular light switch ruthenium complex [Ru (phen)2(dppz)]2+Report just again be a ruthenium complex probe greatness
Using.Ruthenium (II) multi-pyridine ligand has excellent chemical stability, oxidation-reduction quality, excited state reaction activity, non-radioactive
Property and lifetime of excited state appropriate, but the ruthenium compound phase of DNA detection probe can be able to carry out as nucleic acid molecules photoswitch
When limited.Ruthenium (II) complex DNA identification, the detection of DNA mismatch, DNA quantitative analysis, the bonding of DNA protein label and
Novel Optoelectronic Device etc. has very important application prospect.
Traditional energy, the reserves such as petroleum, natural gas and coal are limited, therefore Renewable Energy Development becomes World Focusing
One of focus.Solar-energy photo-voltaic cell can directly convert the solar into electric energy for the regeneration of the energy provide it is direct and
Clean approach, and the different novel MOLECULE DESIGNs that can be used as solar battery are also at urgent problem instantly.
Alkynyl-modified [Ru(bpy)2(dppzi) is a kind of heterocyclic compound containing 2 nitrogen-atoms, unique electronics knot
Structure and photoelectric properties make such compound have good photoluminescent property and electric conductivity.In recent years, this is being utilized both at home and abroad
Class molecule also achieves major progress when being designed and synthesize the research of photoelectric functional material and photoelectric device.To being at present
Only Polypyridine ruthenium complex with wide visible absorption, good stability and suitable oxidizing potential due to being acknowledged as
It is best photosensitizer, it is more than 10% that sunlight can be made, which to switch to the gross efficiency of electric energy,.In addition, alkynyl-modified [Ru(bpy)2(dppzi)
One of the development emphasis for becoming high temperature resistant luminous organic material with its good thermal stability, leads in organic solar batteries etc.
The research in domain is exactly a good example.
Other than it may be used as solar cell design, alkynyl-modified [Ru(bpy)2(dppzi), which is also used as photosensitizer, to be made
With.Large quantities of novel dyestuffs has been emerged in recent years, including ruthenium complex dyestuff, pure organic dye and metalloporphyrin dyestuff
Deng.Among these dyestuffs, [Ru(bpy)2(dppzi) is since its thermodynamic stability is good, photochemical light physical message is abundant, sharp
The characteristics such as state reactivity is high and the service life is long and luminescent properties are good are sent out, have become most promising sensitizer at present.
Summary of the invention
Present invention aims at the development according to existing ruthenium complex, provide a kind of alkynyl-modified ruthenium (II) compound and
Its synthetic method and application.According to existing literature report and alkynyl group to the high affinity interaction of tumour cell, we are foretold
The advantage that alkynyl-modified [Ru(bpy)2(dppzi) may have its special in anti-tumor aspect, therefore design and synthesize a series of chemical combination
Object.Preparation-obtained target compound preparation for treat and/or the drug of pre- anti-cancer in application；It is glimmering as DNA
Photodynamic diagnosis probe and as the application in solar battery and photosensitizer；Comprising target compound and it is one or more can medicine
With the pharmaceutical composition of excipient preparation for treat and/or the drug of pre- anti-cancer in application.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
One kind ruthenium (II) complex alkynyl-modified as shown in following formula (I) and its optical isomer:
Wherein, R is optionally from following group, hydrogen, trimethyl silicon substrate, the alkyl or carbon atom that carbon atom number is 1~6 in formula
For 1~6 substitution alkyl, phenyl or substituted-phenyl, pyridyl group or substituted pyridinyl, furyl or substituted furan base, pyrrole radicals
Or substituted azole base, thiazole or substituted thiazolyl；L in formula optionally from it is various can be coordinated with metal Ru for the miscellaneous of nitrogen-atoms
Cycle compound and poly-heterocyclic compounds, racemic modification and optical isomer including the compound, preferably bipyridyl and neighbour are luxuriant and rich with fragrance
Sieve quinoline and their optical isomer；The acetylene base location that R replaces in formula can be located at ortho position, meta position or the contraposition of phenyl ring,
It is preferred that the contraposition of phenyl ring；Y is acid ion, preferably perchlorate, chlorate anions, hexafluoro-phosphate radical in formula；N is to make ruthenium (II) in formula
Complex and its optical isomer are integrally in the number of the acid ion of electroneutral, for positive integer, such as 1,2,3,4,5,6,7
Deng.
Abovementioned alkyl, phenyl, pyridyl group, furyl, thiazole, pyrroles substituent group optionally from hydroxyl, nitro, halogen, ammonia
Base, carboxyl, cyano, sulfydryl, the naphthenic base that carbon atom number is 3~8, SO3H, carbon atom number is 1~6 alkyl, carbon atom number are
2~6 alkenyl, the alkynyl group that carbon atom is 2~6, hydroxyl (C1-C6) alkyl, amino (C1-C6) alkyl, CO2R’、CONR’
R’、COR’、SO2R’R’、(C1-C6) alkoxy, (C1-C6) alkylthio group ,-N=NR ', NR ' R ' or trifluoro (C1-C6) alkyl；Its
In, the R ' is selected from H, carbon atom number as 1~6 alkyl or phenyl.
The synthetic method of above-mentioned formula (I) compound includes the following steps:
(1)cis-Ru(L)2Cl2It heats and reacts under protection of argon gas with X-BrPIP, reaction is finished, and is cooled to room temperature, is added water dilute
It releases, is filtered to remove insoluble matter, excessive acid or salt containing Y-ion is added in filtrate, stands overnight, obtains [Ru (L)2(X-
BrPIP)]Yn；Wherein, L is optionally from the various heterocyclic compounds and more heterocyclic compounds for nitrogen-atoms that can be coordinated with metal Ru
Object, racemic modification and optical isomer including the compound, preferably bipyridyl and Phen and their optical siomerism
Body；Y is acid ion, preferably perchlorate, chlorate anions, hexafluoro-phosphate radical；N is to make ruthenium (II) complex and its optical isomer
The number of the whole acid ion in electroneutral, is positive integer, such as 1,2,3,4,5,6,7 etc.；X-BrPIP is
(2) [the Ru (L) that will be prepared in step (1)2(X-BrPIP)]Yn, it is added in microwave reactor, it is certain molten
Agent dissolution is added under argon gas protectionIt is auxiliary to be put into microwave in microwave reactor for palladium catalyst and copper catalyst
Heating is helped to react.After reaction, it is filtered to remove insoluble matter, obtains reaction solution；
Wherein, R is optionally from following group, and hydrogen, trimethyl silicon substrate, the alkyl or carbon atom that carbon atom number is 1~6 are 1
~6 substitution alkyl, phenyl or substituted-phenyl, pyridyl group or substituted pyridinyl, furosemide feeding base or substituted furan base, pyrrole radicals or take
For pyrrole radicals, thiazole or substituted thiazolyl；The alkyl, phenyl, pyridyl group, furyl, thiazole, the substituent group of pyrroles are optional certainly
Hydroxyl, nitro, halogen, amino, carboxyl, cyano, sulfydryl, the naphthenic base that carbon atom number is 3~8, SO3H, carbon atom number is 1~6
Alkyl, carbon atom number be 2~6 alkenyl, carbon atom be 2~6 alkynyl group, hydroxyl (C1-C6) alkyl, amino (C1-C6)
Alkyl, CO2R’、CONR’R’、COR’、SO2R’R’、(C1-C6) alkoxy, (C1-C6) alkylthio group ,-N=NR ', NR ' R ' or trifluoro
(C1-C6) alkyl；Wherein, the alkyl or phenyl that the R ' is selected from H, carbon atom number is 1~6；
(3) reaction solution obtained above, column chromatographic purifying, acetonitrile elution are collected the second colour band of brownish red, are spin-dried for, vacuum
Drying is to get target compound.
In the step of above method (2), the temperature of the Microwave-assisted firing is 110 DEG C~150 DEG C, and the reaction time is
10min~40min, the solvent are acetonitrile；In step (3), the column chromatography is that neutral alumina column chromatographs.
The technology path for preparing alkynyl-modified racemic ruthenium (II) compound is as follows:
In above-mentioned route, R is optionally from following group, hydrogen, trimethyl silicon substrate, alkyl or the carbon original that carbon atom number is 1~6
The substitution alkyl that son is 1~6, phenyl or substituted-phenyl, pyridyl group or substituted pyridinyl, furyl or substituted furan base, pyrroles
Base or substituted azole base, thiazole or substituted thiazolyl；The alkyl, phenyl, pyridyl group, furyl, thiazole, pyrroles substituent group
Optionally from hydroxyl, nitro, halogen, amino, carboxyl, cyano, sulfydryl, the naphthenic base that carbon atom number is 3~8, SO3H, carbon atom number
For 1~6 alkyl, carbon atom number be 2~6 alkenyl, carbon atom be 2~6 alkynyl group, hydroxyl (C1-C6) alkyl, amino
(C1-C6) alkyl, CO2R’、CONR’R’、COR’、SO2R’R’、(C1-C6) alkoxy, (C1-C6) alkylthio group ,-N=NR ', NR ' R '
Or trifluoro (C1-C6) alkyl；Wherein, the alkyl or phenyl that the R ' is selected from H, carbon atom number is 1~6；The acetenyl position that R replaces
Set ortho position, the meta position, contraposition, the preferably contraposition of phenyl ring that can be located at phenyl ring；L is optionally from the various generations that can be coordinated with metal Ru
The heterocyclic compound and poly-heterocyclic compounds of nitrogen-atoms, racemic modification and optical isomer including the compound, preferably join
Pyridine and Phen and their optical isomer；Y is acid ion, preferably perchlorate, chlorate anions, hexafluoro-phosphate radical；n
For make ruthenium (II) complex and its optical isomer be integrally in electroneutral acid ion number, be positive integer, such as 1,2,
3,4,5,6,7 etc..
The technology path for preparing alkynyl-modified chiral ruthenium (II) compound is as follows:
In above-mentioned route, R is optionally from following group, hydrogen, trimethyl silicon substrate, alkyl or the carbon original that carbon atom number is 1~6
The substitution alkyl that son is 1~6, phenyl or substituted-phenyl, pyridyl group or substituted pyridinyl, furyl or substituted furan base, pyrroles
Base or substituted azole base, thiazole or substituted thiazolyl；The alkyl, phenyl, pyridyl group, furyl, thiazole, pyrroles substituent group
Optionally from hydroxyl, nitro, halogen, amino, carboxyl, cyano, sulfydryl, the naphthenic base that carbon atom number is 3~8, SO3H, carbon atom number
For 1~6 alkyl, carbon atom number be 2~6 alkenyl, carbon atom be 2~6 alkynyl group, hydroxyl (C1-C6) alkyl, amino
(C1-C6) alkyl, CO2R’、CONR’R’、COR’、SO2R’R’、(C1-C6) alkoxy, (C1-C6) alkylthio group ,-N=NR ', NR ' R '
Or trifluoro (C1-C6) alkyl；Wherein, the alkyl or phenyl that the R ' is selected from H, carbon atom number is 1~6；The acetenyl position that R replaces
Set ortho position, the meta position, contraposition, the preferably contraposition of phenyl ring that can be located at phenyl ring；L is optionally from the various generations that can be coordinated with metal Ru
The heterocyclic compound and poly-heterocyclic compounds of nitrogen-atoms, racemic modification and optical isomer including the compound, preferably join
Pyridine and Phen and their optical isomer；Y is acid ion, preferably perchlorate, chlorate anions, hexafluoro-phosphate radical；n
For make ruthenium (II) complex and its optical isomer be integrally in electroneutral acid ion number, be positive integer, such as 1,2,
3,4,5,6,7 etc..
Detailed description of the invention
Fig. 1 is complex A- [Ru (bpy)2(p-BEPIP)](ClO4)2Fluorescent emission figure.
Fig. 2 is complex [Ru (phen)2(p-BEPIP)](ClO4)2Fluorescence emission spectrogram of compound, wherein abscissa be hair
Ejected wave is long, and ordinate is relative intensity of fluorescence.
Fig. 3 is complex [Ru (phen)2(p-BEPIP)](ClO4)2With the interaction of various concentration calf thymus DNA
Change in fluorescence spectrogram, wherein abscissa is launch wavelength, and ordinate is relative intensity of fluorescence.
Fig. 4 is complex [Ru (bpy)2(p-BEPIP)](ClO4)2ESI-MS.
Fig. 5 is complex [Ru (bpy)2(p-BEPIP)](ClO4)2's1H NMR。
Fig. 6 is complex [Ru (phen)2(p-BEPIP)](ClO4)2ESI-MS.
Fig. 7 is complex [Ru (phen)2(p-BEPIP)](ClO4)2's1H NMR。
Specific embodiment
With reference to following non-limiting embodiments, present invention is described.
[Ru(bpy)2(p-BrPIP)]2+Refer to:
[Ru(bpy)2(p-BEPIP)]2+Refer to:
[Ru(bpy)2(p-TEPIP)]2+Refer to:
[Ru(bpy)2(p-EPIP)]2+Refer to:
Λ-[Ru(bpy)2(p-BrPIP)]2+Refer to:
Δ-[Ru(bpy)2(p-BrPIP)]2+Refer to:
P-BEPIP refers to:
P-TEPIP refers to:
P-EPIP refers to:
Bpy refers to that bipyridyl, phen refer to that Phen, Py refer to that pyridine, p- represent contraposition.
Embodiment 1
Starting ruthenium complexes cis- [Ru (bpy)2Cl2]·2H2O can refer to document the method and be prepared: J.Liu,
W.J.Mei, L.J.Lin, K.C.Zheng, H.Chao, F.C.Yun, L.N.Ji, Inorg.Chim.Acta (2004,357,
285)。
The synthesis of ligand p-BrPIP can refer to preparation method described in following files and obtain: J.Liu, W.J.Mei,
L.J.Lin, K.C.Zheng, H.Chao, F.C.Yun, L.N.Ji, Inorg.Chim.Acta (2004,357,285)；
B.P.Sullivan, D.J.Salmon, T.J.Meyer, Inorg.Chem., (1978,17,3334)；W.J.Mei, Y.Z.Ma,
J.Liu, J.C.Chen, K.C.Zheng, L.N.Ji, J.H.Yao, Trans.Met.Chem. (2006,31,277).
[Ru(bpy)2(p-BrPIP)](ClO4)2Synthesis
Cis- [Ru (bpy) is put into 50ml three-necked bottle2Cl2]·2H2O (105mg, 0.2mmol), p-BrPIP
(113mg, 0.3mmol), 30ml ethylene glycol and water mixed solvent (volume ratio 9:1) lead to argon gas 10min, under protection of argon gas
120 DEG C are heated to reflux 6 hours, and reaction is finished, and is cooled to room temperature, and add water 45ml to dilute, are filtered to remove insoluble matter, obtain peony filter
Liquid is added excessive sodium perchlorate in filtrate, stands overnight, generate a large amount of salmon precipitations, filters to obtain precipitating, uses water respectively,
It is dry in vacuum desiccator after ether washing for several times, obtain orange/yellow solid.The dissolution of crude product acetonitrile, it is neutral to cross 200-300 mesh
Alumina column, main red component under acetonitrile elution, decompression are spin-dried for solvent, obtain brown-red solid, yield 65%.ESI-MS
(inCH3CN, m/z): 789.2 ([M-H]+, calculated value: 788.1)；1H NMR(in DMSO-d6, δ/ppm) and 9.06 (d, J=
8.3Hz, 2H), 8.86 (d, J=8.1Hz, 2H), 8.82 (d, J=8.1Hz, 2H), 8.26 (d, J=8.0Hz, 2H), 8.19-
8.22 (t, J=8.0Hz, 2H), 8.10 (t, J=8.0Hz, 2H), 8.04 (d, J=5.3,2H), 7.91 (dd, J=8.3Hz,
2H), 7.88-7.81 (m, 2H), 7.60 (dd, J=3.8,4H), 7.60-7.56 (m, 2H), 7.38-7.30 (m, 2H)
[Ru(phen)2(p-BrPIP)](ClO4)2Synthetic method be similar to [Ru (bpy)2(p-BrPIP)](ClO4)2's
Synthesis.
2 microwave of embodiment synthesizes alkynyl-modified racemic target compound
[Ru(bpy)2(p-BEPIP)](ClO4)2Microwave-assisted synthesis
Take [Ru (bpy)2(p-BrPIP)](ClO4)2120mg is added in the microwave reaction pipe of 30ml, be added 20ml without
Water-acetonitrile and stirrer are added phenylacetylene (0.14ml, 1.25mmol) under argon gas protection, and palladium catalyst and copper catalyst are close
It is put into 110 DEG C of microwave radiation reaction 15min, reaction in microwave reactor after closing to finish, is filtered to remove impurity, decompression is spin-dried for.It is thick to produce
Product are dissolved with acetonitrile, cross 200-300 mesh neutral alumina column, and the second colour band of brownish red is collected in acetonitrile elution, and decompression is spin-dried for obtaining
Brown-red solid, yield 89.2%.ESI-MS(in CH3CN, m/z) as shown in Figure 4: 809.3 ([M+H]+, calculated value:
808.2)；1H NMR(in DMSO-d6, δ/ppm) and 9.04 (d, J=8.2Hz, 2H), 8.89 (d, J=8.2Hz, 2H), 8.85
(d, J=8.2Hz, 2H), 8.41 (d, J=8.0Hz, 2H), 8.22 (t, J=8.0Hz, 2H), 8.11 (t, J=8.0Hz, 2H),
7.93 (d, J=4.3Hz, 2H), 7.88 (d, J=5.6,2H), 7.84 (dd, J=8.2Hz, 2H), 7.74 (d, J=8.4Hz,
2H), 7.64-7.62 (m, 4H), 7.62-7.61 (t, 2H), 7.61-7.58 (t, 2H), 7.49-7.43 (m, 1H), 7.41-7.34
(t, 2H), as shown in Figure 5.
[Ru(phen)2(p-BEPIP)](ClO4)2Microwave-assisted synthesis
Experimental method is similar to [Ru (bpy)2(p-BEPIP)](ClO4)2Microwave-assisted synthesis, will
[Ru(bpy)2(p-BrPIP)](ClO4)2Replace with [Ru (phen)2(p-BrPIP)](ClO4)2, yield is
51.4%.ESI-MS(inCH3CN, m/z) as shown in Figure 6: 857.3 ([M+H]+, calculated value: 856.2)；1H NMR(in DMSO-
d6, δ/ppm) 9.04 (d, J=8.1Hz, 2H), 8.83-8.71 (d, J=8.3,4H), 8.44 (d, J=8.4,2H), 8.39 (s,
4H), 8.12 (ddd, J=10.2,5.3,1.2Hz, 4H), 7.88 (d, J=4.5Hz, 2H), 7.78 (ddd, J=8.5,5.3,
3.5Hz, 4H), 7.72 (d, J=4.9Hz, 2H), 7.70 (t, J=4.9Hz, 2H), 7.63-7.56 (d, J=5.2Hz, 2H),
7.46 (t, J=5.0Hz, 2H), as shown in Figure 7.
Other alkynyl-modified racemic ruthenium complexes are prepared using microwave-assisted in same method.By mass spectrum with
The sample that nuclear magnetic resonance spectroscopy analysis means confirm is target compound, and purity is good.
3 microwave of embodiment synthesizes the target compound of alkynyl-modified chirality
Chiral ruthenium complex Λ-[Ru (bpy)2(p-BrPIP)]2+、Δ-[Ru(bpy)2(p-BrPIP)]2+It can refer to document
The method: Chen T., Mei W.-J.*, Wong Y.-S., Liu J., Liu Y., Xie H.-S.and Zheng W.-
J.*, Med.Chem.Commun. (2010,1,73) are prepared.
A-[Ru(bpy)2(p-BEPIP)](ClO4)2Microwave-assisted synthesis
Take A- [Ru (bpy)2(p-BrPIP)](ClO4)2120mg is added in the microwave reaction pipe of 30ml, and 20ml is added
Anhydrous acetonitrile and stirrer are added phenylacetylene (0.14ml, 1.25mmol) under argon gas protection, palladium catalyst and copper catalyst,
110 DEG C of microwave radiation reaction 15min in microwave reactor are put into after closed.Reaction is finished, and insoluble matter, filtrate acetonitrile are filtered to remove
The alumina column for crossing 200-300 mesh purifies to obtain target product.Yield is 89.2%.ESI-MS(in CH3CN, m/z): 809.3
([M+H]+, calculated value: 808.2)；1H NMR(in DMSO-d6, δ/ppm) and 9.07 (d, J=8.1Hz, 2H), 8.90 (d, J=
8.2Hz, 2H), 8.86 (d, J=8.2Hz, 2H), 8.41 (d, J=8.3Hz, 2H), 8.29-8.18 (m, 2H), 8.12 (t, J=
7.4Hz, 2H), 7.98 (d, J=4.4Hz, 2H), 7.88 (t, J=6.9Hz, 4H), 7.78 (d, J=7.9Hz, 2H), 7.61
(dd, J=12.5,5.7Hz, 6H), 7.47 (dd, J=4.8,1.7Hz, 3H), 7.37 (t, J=6.5Hz, 2H).
Δ-[Ru(bpy)2(p-BEPIP)](ClO4)2Microwave-assisted synthesis
Experimental method is similar to Λ-[Ru (bpy)2(p-BEPIP)](ClO4)2Microwave-assisted synthesis, by Λ-[Ru
(bpy)2(p-BrPIP)](ClO4)2Replace with Δ-[Ru (bpy)2(p-BrPIP)](ClO4)2, yield 51.4%.ESI-MS
(inCH3CN, m/z): 809.1 ([M+H]+, calculated value: 808.2)
Same method is synthetically prepared to obtain other alkynyl-modified chiral ruthenium complexes using microwave.Pass through mass spectrum and core
The sample that magnetic resonance hydrogen spectrum analysis means confirm is target compound, and purity is good.
The application of alkynyl-modified ruthenium complex
4 ruthenium containing acetenyl of embodiment (II) Compound ira vitro anti-tumor activity
Compound ira vitro anti-tumor activity is evaluated with IC50 value (concentration required for 50% cell growth inhibition): will be thin
Born of the same parents are inoculated in the RPMI1640 culture medium (including appropriate penicillin and streptomycin and glutamine) containing 10% calf serum by certain density
96 orifice plates in, 5%CO2, after cultivating 24 hours under the conditions of 37 DEG C, use various concentration test medicine instead and (be configured to 1 μ g/ with PBS
ML working solution, when use, are diluted with culture medium as needed) fresh culture, continue culture 48 hours；Then 50 μ are added in every hole
50% trichloroacetic acid (TCA, final concentration of 10%) to stand after five minutes, distill water washing 5 times, be air-dried, addition is pre-chilled in L
100 μ LMTT dye liquors, dyeing processing 10min, 1% acetum wash cell 4 times, remove unbonded dyestuff, be air-dried, most
After 150 μ L10mmol/L Tris solution are added, after mixing well, microplate reader measures OD value under 490nm wavelength.Each sample
Each concentration parallel laboratory test 6 times, is averaged.
Using above-mentioned experimental program, MCF-7 adenocarcinoma of breast epithelial cell line is selected to test a variety of the compound of the present invention,
IC of the invention as the result is shown50(μM) value is below 50, has potential industrial application valence in the clinical treatment of tumor disease
Value.
Influence of 1 complex of table to MCF-7 cell inhibitory effect
The fluorescence emission spectrum of embodiment 5 acetenyl ruthenium (II) compound
5.1 weigh 10mg Λ-[Ru (bpy)2(p-BEPIP)](ClO4) with 10mLDMSO dissolution be configured to the molten of 1mg/mL
Liquid takes to be added in flat bottom surface ware to be placed in drying box on a small quantity and slowly dries solvent, tests chemical combination using fluorescence inverted microscope
The fluorescent emission figure of object, as a result as shown in Figure 1, the compound being prepared has stronger fluorescent emission.
5.2 prepare 4 μM of preparation-obtained [Ru (phen)2(p-BEPIP)](ClO4)2Solution, sepectrophotofluorometer
3.0mL complex solution is added in sample cell, 460nm or so light source activation complex solution records and matches within the scope of 500-750nm
The fluorescence emission spectrum for closing object, as a result as shown in Fig. 2, complex has stronger fluorescent emission；
5.3 according to 5.2 methods, are often separated by 5min microsyringe [Ru (phen) into sample cell2(p-BEPIP)]
(ClO4)22 μ L calf thymus DNA solution are added in solution, pass the concentration of calf thymus DNA and complex than according to a certain percentage
Increase, detects the variation of its fluorescence emission spectrum, until saturation, as a result as shown in figure 3, being continuously added with calf thymus DNA,
The fluorescence intensity of complex increases in dosage, according to formula: [DNA]/(εa-εb)=[DNA]/(εb-εf)+1/Kb -1(εb-
εf), the concentration of [DNA] representation DNA, ε in formulaa, εfAnd εbIt respectively represents in each DNA concentration, it is free and be bonded with DNA full
The molar absorption coefficient of the complex of sum.The intercept calculations incorporated constant K intersected by fitting a straight line with y-axisbObtain 1.54X108M-1。
Acetenyl ruthenium (II) compound has stronger fluorescent emission, phase strong with calf thymus DNA binding force as the result is shown
Change in fluorescence is obvious after interaction, and having in terms of DNA fluorescence diagnostic probe with solar cell material is potentially answered
With value.
Claims (6)
1. a kind of preparation method of ruthenium (II) complex of formula (I), described method includes following steps:
(1)cis-Ru(L)2Cl2It heats and reacts under protection of argon gas with X-BrPIP, reaction is finished, and it is cooled to room temperature, is diluted with water,
It is filtered to remove insoluble matter, excessive acid or salt containing Y-ion is added in filtrate, stands overnight, obtains [Ru (L)2(X-BrPIP)]
Yn；Wherein, L is outer including the compound optionally from the various heterocyclic compounds with nitrogen-atoms that can be coordinated with metal Ru
Raceme or optical isomer；Y is acid ion；N is to make ruthenium (II) complex and its optical isomer is integrally in electroneutral
The number of acid ion is positive integer；
X-BrPIP is
(2) [the Ru (L) that will be prepared in step (1)2(X-BrPIP)]Yn, it is added in microwave reactor, certain solvent is molten
Solution is added under argon gas protectionPalladium catalyst and copper catalyst are put into microwave-assisted in microwave reactor add
Thermal response is filtered to remove insoluble matter after reaction, obtains reaction solution；
Wherein, R is optionally from following group, and hydrogen, trimethyl silicon substrate, the alkyl or carbon atom that carbon atom number is 1~6 are 1~6
Replace alkyl, phenyl or substituted-phenyl, pyridyl group or substituted pyridinyl, furyl or substituted furan base, pyrrole radicals or substitution pyrrole
Cough up base, thiazole or substituted thiazolyl；The alkyl, phenyl, pyridyl group, furyl, thiazole, pyrroles substituent group optionally from hydroxyl
Base, nitro, halogen, amino, carboxyl, cyano, sulfydryl, the naphthenic base that carbon atom number is 3~8, SO3H, carbon atom number is 1~6
Alkynyl group that alkenyl that alkyl, carbon atom number are 2~6, carbon atom are 2~6, hydroxyl (C1-C6) alkyl, amino (C1-C6) alkane
Base, CO2R'、CONR'R'、COR’、SO2R’、(C1-C6) alkoxy, (C1-C6) alkylthio group ,-N=NR', NR'R ' or trifluoro (C1-
C6) alkyl；Wherein, the alkyl or phenyl that the R ' is selected from H, carbon atom number is 1~6；
(3) reaction solution obtained above, column chromatographic purifying, acetonitrile elution are collected the second colour band of brownish red, are spin-dried for, be dried in vacuo,
Up to target compound.
2. preparation method as described in claim 1, it is characterised in that the L is bipyridyl, Phen or their light
Learn isomers.
3. preparation method as described in claim 1, it is characterised in that the Y is perchlorate, chlorate anions or hexafluorophosphoric acid
Root.
4. preparation method described in claim 1, it is characterised in that in step (2), the temperature of the Microwave-assisted firing is 110
DEG C~150 DEG C, the reaction time is 10min~40min.
5. preparation method described in claim 1, it is characterised in that in step (2), the solvent used is acetonitrile.
6. preparation method described in claim 1, it is characterised in that in step (3), the column chromatography is neutral alumina column layer
Analysis.
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| Chiral Ruthenium Complexes Induce Apoptosis of Tumor Cell and Interact with Bovine Serum Albumin;Interact with Bovine Serum Albumin et al.;《Chirality》;20111219;第24卷(第2期);第174—180页 * |
| Chiral ruthenium polypyridyl complexes as mitochondria-targeted apoptosis inducers;Tianfeng Chen et al.;《MedChemComm》;20100616;第1卷;第73—75页 * |
| Imidazo [4,5f][1,10] phenanthroline derivatives as inhibitor of c-myc gene expression in A549 cells via NF-κB pathway;Dong-dong Sun et al.;《Bioorganic & Medicinal Chemistry Letters》;20111123;第22卷;第102—105页 * |
| Luminescent Ruthenium Tripod Complexes: Properties in Solution Luminescent Ruthenium Tripod Complexes: Properties in Solution;Srinidhi Ramachandra et al.;《Inorganic Chemistry》;20101231;第50卷;第1581—1591页 * |
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