CN103788134A - Microwave assisted preparation method of alkynyl modified ruthenium (II) complex and application thereof - Google Patents
Microwave assisted preparation method of alkynyl modified ruthenium (II) complex and application thereof Download PDFInfo
- Publication number
- CN103788134A CN103788134A CN201210433440.7A CN201210433440A CN103788134A CN 103788134 A CN103788134 A CN 103788134A CN 201210433440 A CN201210433440 A CN 201210433440A CN 103788134 A CN103788134 A CN 103788134A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- carbonatoms
- substituted
- phenyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
The invention discloses an alkynyl-containing ruthenium (II) complex, its synthesis method and application. In the invention, the alkynyl-containing ruthenium (II) complex prepared by a microwave assisted method has a structural general formula shown as (I). The alkynyl-containing ruthenium (II) complex provided by the invention has very good results in inhibiting tumor cells. The alkynyl-containing ruthenium (II) complex has strong fluorescence emission, can interact with DNA to generate obvious fluorescence changes, and has strong adhesion with DNA, thus having potential application value in DNA fluorescence diagnostic probes and solar cell materials. Therefore, the alkynyl-containing ruthenium (II) complex provided by the invention can be used for preparing drugs for prevention or treatment of cancers. In addition, the alkynyl-containing ruthenium (II) complex can also be used for DNA fluorescence diagnostic probes and solar cells as well as photosensitizers.
Description
Technical field
The present invention relates to pharmaceutical chemistry, molecular biology and molecular material and learn field, be specifically related to the preparation method of a kind of alkynyl-modified ruthenium (II) title complex and the application at the advantage aspect inhibition tumor cell effect, DNA fluorescence diagnosis probe, solar cell material aspect as a kind of novel title complex.
Background technology
Ruthenium complexe becomes one of the study hotspot in the fields such as pharmaceutical chemistry research in recent years, chemicobiology, bio-inorganic chemistry as the research of antitumor drug.For example, the people such as Clarke have summarized the antitumour activity of ruthenium complexe, particularly antimetastatic activity (Chem.Rev., 1999,99,2511); Sava is at " Metal Compounds in Cancer Therapy (metallic compound in cancer therapy) " (Chapman and Hall work, S P Fricker edits, London, 1994,65-91) in summarized the antimetastatic activity of ruthenium complexe.Along with the not isoplastic part of various bands that gos deep into of ruthenium complexe research is also synthesized to sign out, we synthesize with reference to other antitumor drug design the factor of considering with regard to the angle of pharmaceutical analysis screening, and a series of alkynyl-modified ruthenium complexees that contain have been synthesized in design.
Have lot of documents be reported in SARS drug design and synthetic in introduce alkynyl to strengthen its activity, research finds to introduce this class group active and in conjunction with there being oneself advantage aspect strong and weak.Common medicine has in estradiol, deoxyuridine, tretinoin, antimycotic furanone derivatives and various Pyrmidine nucleoside derivatives class medicine can see alkynyl-modified design.
The people such as Zhang Yingchun once reported contains the antibiotic research of rare diine class high efficiency anti-tumor, exactly because have this class medicine of this unique texture of enediyne ring and just have very strong antitumor action, the result that this may be special with this must advantage causes entering on cell.(World?Notes?on?Antibiotics，2008，Vol.29，No.l)
The people such as S.Ramachandra are in the time studying ruthenium complexe as semiconductor material, design is synthesized and has characterized 7 kinds with alkynyl-modified Ru-polypyridine compound, this also further should be used as basic theoretical investigation and exploration in field of medicaments research for alkynyl-modified ruthenium complexe, prove the possibility, particularly Ru (bpy) of this compounds on synthesizing
2-EPIP, Ru (bpy)
2synthetic and the sign of-TMS-EPIP will have good directive significance by synthetic compound to us.(Inorg.Chem.2011,50,1581-1591) and Xiong Xingquan etc. to the research take Pd catalyzed coupling reaction also as the introducing of alkynyl has proposed good direction.The people such as (Huaqiao University's journal, 2011, Vol.32, No.2) Jin Xuanye have proposed a kind of complete method that is suitable for general alkynyl group introducing in the time that research palladium catalyzes and synthesizes Pyrmidine nucleoside derivatives, for alkynyl is laid a good foundation in the introduction of ruthenium complexe.(Chin.J.Org.Chem.，VOl，29，2009，NO.1，44～54)
In the metal complexes with anti-tumor activity, ruthenium complexe has been subject to widely paying close attention to, and generally believes in the world, and ruthenium and ruthenium complexe belong to hypotoxicity, easily absorbs and excretion very soon in vivo, will become one of the most promising cancer therapy drug.Ruthenium complexe and cis-platinum ruthenium complexe as prepare antitumor drug developmental research of application for a long time, aspect some fields, also reach its maturity perfect, even existing some drugs molecule enters clinical stage, also has own advantage and application in antitumor application as a kind of many pyridines and phenanthroline ruthenium complexe wherein.
We design and have synthesized alkynyl-modified [Ru(bpy)2(dppzi), mainly contain following innovation: the one, the introducing of alkynyl, this be ruthenium complexe that a class is new, employing be new synthetic method the advances ruthenium complexe very large directive significance that further develops to research, and the introducing of alkynyl may promote effect that drug molecule cross-film absorbs, strengthen medicine and enter the probability of cell, reduce poisonous side effect of medicine aspect and have larger researching value and Research Significance increasing drug effect; The 2nd, the comprehensive and systematic design of molecule, this time study us and also studied the impact of different isomerization body except applying three class alkynyl groups for alkynyl-modified [Ru(bpy)2(dppzi), the prerequisite of title complex is used respectively to racemic compound, levorotatory compound and dextrorotatory compound, to study not selectivity and the medicine different properties of isomorphism type.In addition we have also studied phenanthroline class except many pyridines also to have carried out expansion for the kind of ruthenium complexe, have enriched the Research foundation of alkynyl-modified ruthenium complexe.Also having the important point is exactly that we go up Songashira reaction in the experiment carbon carbon linked reaction of alkynyl specifically and complete by microwave synthesizer, and this preparation method and technology are current or brand-new at home.
Aspect clinical diagnosis and treatment, highly sensitive, highly selective, quick and low cost detection of biological vivo acid is very important.In recent years, metal nano material is with its unique physical and chemical performance, be widely used in biomolecule detection field, ruthenium complex is with its satisfactory stability and photovoltaic effect, become a kind of desirable sensing luminescent material, we believe that the title complex of ruthenium is by being prepared into Optochemical sensor in conjunction with gold nano, conveniently may have huge advantage and potentiality leaved for development at the clinical fluorescence diagnosis probe of preparation.
Ruthenium complex luminous efficiency is high, and the life-span is long, and its emission wavelength is in visible region, is conducive to biological detection, and method is simple, can develop into a kind of new bio probe sensor.
Domestic having been reported utilized bipyridyl ruthenium title complex ([Ru (II) (bpy)
3]
2+6H
2o, carries out the preparation of fluorescent probe, DNA molecular light switch ruthenium title complex [Ru (phen)
2(dppz)]
2+report be again just the greatness application of a ruthenium complexe probe.Ruthenium (II) multi-pyridine ligand has good chemical stability, oxidation-reduction quality, excited state reaction activity, on-radiation and suitable lifetime of excited state, but it is quite limited can to carry out the ruthenium compound of DNA detection probe as nucleic acid molecule photoswitch.Ruthenium (II) title complex has very important application prospect at the aspect such as bonding mark and Novel Optoelectronic Device of the detection of DNA identification, DNA mismatch, DNA quantitative analysis, DNA protein.
Traditional energy, as limited in the reserves of oil, Sweet natural gas and coal, therefore Renewable Energy Development becomes one of the focus of world attention.Solar-energy photo-voltaic cell can be directly electric energy by solar energy converting. for the regeneration of the energy provides direct and clean approach, and the different novel molecular designing that can be used as solar cell has also become urgent problem instantly.
Alkynyl-modified [Ru(bpy)2(dppzi) is a kind of heterogeneous ring compound that contains 2 nitrogen-atoms, and the electronic structure that it is unique and photoelectric properties make this compounds have good photoluminescent property and conductivity.In recent years, both at home and abroad utilizing this quasi-molecule to design and also obtained major progress when the research of synthetic photoelectric functional material and photoelectric device.Up to the present. Polypyridine ruthenium complexe owing to thering is wide visible absorption, good stability and suitable oxidizing potential is acknowledged as best photosensitizers, the total efficiency that can make sunlight transfer electric energy to exceedes 10%.In addition, alkynyl-modified [Ru(bpy)2(dppzi) becomes one of development emphasis of high temperature resistant luminous organic material with its good thermostability, is exactly a good example in the research in the fields such as organic solar batteries.
Except serving as solar cell design, alkynyl-modified [Ru(bpy)2(dppzi) can also use as photosensitizers.Emerge in recent years large quantities of novel dyestuffs, comprising ruthenium complexe dyestuff, pure organic dye and metalloporphyrin dyestuff etc.Among these dyestuffs, [Ru(bpy)2(dppzi) because its thermodynamic stability is good, the active high and characteristic such as the life-span is long and luminescent properties is good of abundant, the excited state reaction of photochemical light physical message, become at present the most promising sensitizing agent.
Summary of the invention
The object of the invention is the development according to existing ruthenium complexe, and a kind of alkynyl-modified ruthenium (II) compound and synthetic method and application are provided.The high affinity interaction to tumour cell according to existing bibliographical information and alkynyl group, we foretell that alkynyl-modified [Ru(bpy)2(dppzi) may have its special advantage at anti-tumor aspect, therefore the synthetic a series of compounds of design.Preparation-obtained target compound is in the application for the preparation for the treatment of and/or preventing in the medicine of cancer; As DNA fluorescence diagnosis probe and as the application in solar cell and photosensitizers; The pharmaceutical composition that comprises target compound and one or more pharmaceutically acceptable vehicle is in the application for the preparation for the treatment of and/or preventing in the medicine of cancer.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
A kind of as shown in the formula alkynyl-modified ruthenium (II) title complex and the optical isomer thereof shown in (I):
Wherein, in formula, R is optional from following group, and hydrogen is trimethyl silicon based, carbonatoms is the substituted alkyl that 1～6 alkyl or carbon atom are 1～6, phenyl or substituted-phenyl, pyridyl or substituted pyridinyl, furyl or substituted furan base, pyrryl or substituted azole base, thiazole or substituted thiazolyl; L in formula optionally from various can with the heterogeneous ring compound for nitrogen-atoms of metal Ru coordination and poly-heterocyclic compounds, comprise racemic modification and the optical isomer of described compound, preferably dipyridyl and phenanthroline and their optical isomer; The ethynyl position that in formula, R replaces can be positioned at ortho position, a position or the contraposition of phenyl ring, preferably the contraposition of phenyl ring; In formula, Y is acid ion, preferably perchlorate, chlorate anions, hexafluoro-phosphate radical; In formula, n, for to make ruthenium (II) title complex and optical isomer entirety thereof be the number of electroneutral acid ion, is positive integer, for example 1,2,3,4,5,6,7 etc.
Cycloalkyl, SO that abovementioned alkyl, phenyl, pyridyl, furyl, thiazole, pyrroles's substituting group is optionally 3～8 from hydroxyl, nitro, halogen, amino, carboxyl, cyano group, sulfydryl, carbonatoms
3the alkyl that H, carbonatoms are 1～6, the alkenyl that carbonatoms is 2～6, alkynyl group, hydroxyl (C that carbon atom is 2～6
1-C
6) alkyl, amino (C
1-C
6) alkyl, CO
2r ', CONR ' R ', COR ', SO
2r ' R ', (C
1-C
6) alkoxyl group, (C
1-C
6) alkylthio ,-N=NR ', NR ' R ' or trifluoro (C
1-C
6) alkyl; Wherein, described R ' is selected from the alkyl or phenyl that H, carbonatoms are 1～6.
The synthetic method of above-mentioned formula (I) compound comprises the steps:
(1) cis-Ru (L)
2cl
2with X-BrPIP reacting by heating under argon shield, reaction is finished, and is cooled to room temperature, and thin up, removes by filter insolubles, adds excessive acid or salt containing Y ion in filtrate, and hold over night, obtains [Ru (L)
2(X-BrPIP)] Y
n; Wherein, L optionally from various can with the heterogeneous ring compound for nitrogen-atoms of metal Ru coordination and poly-heterocyclic compounds, comprise racemic modification and the optical isomer of described compound, preferably dipyridyl and phenanthroline and their optical isomer; Y is acid ion, preferably perchlorate, chlorate anions, hexafluoro-phosphate radical; N, for to make ruthenium (II) title complex and optical isomer entirety thereof be the number of electroneutral acid ion, is positive integer, for example 1,2,3,4,5,6,7 etc.; X-BrPIP is
(2) by [Ru (L) preparing in step (1)
2(X-BrPIP)] Y
n, joining in microwave reactor, certain dissolution with solvents, under argon shield, adds
palladium catalyst and copper catalyst, put into the reaction of microwave reactor Microwave-assisted firing.After reaction finishes, remove by filter insolubles, obtain reaction solution;
Wherein, R is optional from following group, and hydrogen is trimethyl silicon based, carbonatoms is the substituted alkyl that 1～6 alkyl or carbon atom are 1～6, phenyl or substituted-phenyl, pyridyl or substituted pyridinyl, furan is fed base or substituted furan base, pyrryl or substituted azole base, thiazole or substituted thiazolyl; Cycloalkyl, SO that described alkyl, phenyl, pyridyl, furyl, thiazole, pyrroles's substituting group is optionally 3～8 from hydroxyl, nitro, halogen, amino, carboxyl, cyano group, sulfydryl, carbonatoms
3the alkyl that H, carbonatoms are 1～6, the alkenyl that carbonatoms is 2～6, alkynyl group, hydroxyl (C that carbon atom is 2～6
1-C
6) alkyl, amino (C
1-C
6) alkyl, CO
2r ', CONR ' R ', COR ', SO
2r ' R ', (C
1-C
6) alkoxyl group, (C
1-C
6) alkylthio ,-N=NR ', NR ' R ' or trifluoro (C
1-C
6) alkyl; Wherein, described R ' is selected from the alkyl or phenyl that H, carbonatoms are 1～6;
(3) reaction solution obtained above, column chromatography purification, acetonitrile wash-out, collects red-brown the second colour band, is spin-dried for, and vacuum-drying, obtains target compound.
In the step (2) of aforesaid method, the temperature of described Microwave-assisted firing is 110 ℃～150 ℃, and the reaction times is 10min～40min, and described solvent is acetonitrile; In step (3), described column chromatography is neutral alumina column chromatography.
The technological line of preparing alkynyl-modified racemize ruthenium (II) compound is as follows:
In above-mentioned route, R is optional from following group, and hydrogen is trimethyl silicon based, carbonatoms is the substituted alkyl that 1～6 alkyl or carbon atom are 1～6, phenyl or substituted-phenyl, pyridyl or substituted pyridinyl, furyl or substituted furan base, pyrryl or substituted azole base, thiazole or substituted thiazolyl; Cycloalkyl, SO that described alkyl, phenyl, pyridyl, furyl, thiazole, pyrroles's substituting group is optionally 3～8 from hydroxyl, nitro, halogen, amino, carboxyl, cyano group, sulfydryl, carbonatoms
3the alkyl that H, carbonatoms are 1～6, the alkenyl that carbonatoms is 2～6, alkynyl group, hydroxyl (C that carbon atom is 2～6
1-C
6) alkyl, amino (C
1-C
6) alkyl, CO
2r ', CONR ' R ', COR ', SO
2r ' R ', (C
1-C
6) alkoxyl group, (C
1-C
6) alkylthio ,-N=NR ', NR ' R ' or trifluoro (C
1-C
6) alkyl; Wherein, described R ' is selected from the alkyl or phenyl that H, carbonatoms are 1～6; The ethynyl position that R replaces can be positioned at ortho position, a position, the contraposition of phenyl ring, preferably the contraposition of phenyl ring; L optionally from various can with the heterogeneous ring compound for nitrogen-atoms of metal Ru coordination and poly-heterocyclic compounds, comprise racemic modification and the optical isomer of described compound, preferably dipyridyl and phenanthroline and their optical isomer; Y is acid ion, preferably perchlorate, chlorate anions, hexafluoro-phosphate radical; N, for to make ruthenium (II) title complex and optical isomer entirety thereof be the number of electroneutral acid ion, is positive integer, for example 1,2,3,4,5,6,7 etc.
The technological line of preparing alkynyl-modified chirality ruthenium (II) compound is as follows:
In above-mentioned route, R is optional from following group, and hydrogen is trimethyl silicon based, carbonatoms is the substituted alkyl that 1～6 alkyl or carbon atom are 1～6, phenyl or substituted-phenyl, pyridyl or substituted pyridinyl, furyl or substituted furan base, pyrryl or substituted azole base, thiazole or substituted thiazolyl; Cycloalkyl, SO that described alkyl, phenyl, pyridyl, furyl, thiazole, pyrroles's substituting group is optionally 3～8 from hydroxyl, nitro, halogen, amino, carboxyl, cyano group, sulfydryl, carbonatoms
3the alkyl that H, carbonatoms are 1～6, the alkenyl that carbonatoms is 2～6, alkynyl group, hydroxyl (C that carbon atom is 2～6
1-C
6) alkyl, amino (C
1-C
6) alkyl, CO
2r ', CONR ' R ', COR ', SO
2r ' R ', (C
1-C
6) alkoxyl group, (C
1-C
6) alkylthio ,-N=NR ', NR ' R ' or trifluoro (C
1-C
6) alkyl; Wherein, described R ' is selected from the alkyl or phenyl that H, carbonatoms are 1～6; The ethynyl position that R replaces can be positioned at ortho position, a position, the contraposition of phenyl ring, preferably the contraposition of phenyl ring; L optionally from various can with the heterogeneous ring compound for nitrogen-atoms of metal Ru coordination and poly-heterocyclic compounds, comprise racemic modification and the optical isomer of described compound, preferably dipyridyl and phenanthroline and their optical isomer; Y is acid ion, preferably perchlorate, chlorate anions, hexafluoro-phosphate radical; N, for to make ruthenium (II) title complex and optical isomer entirety thereof be the number of electroneutral acid ion, is positive integer, for example 1,2,3,4,5,6,7 etc.
Accompanying drawing explanation
Fig. 1 is title complex A-[Ru (bpy)
2(p-BEPIP)] (ClO
4)
2fluorescent emission figure.
Fig. 2 is title complex [Ru (phen)
2(p-BEPIP)] (ClO
4)
2fluorescence emission spectrogram, wherein X-coordinate is emission wavelength, ordinate zou is relative intensity of fluorescence.
Fig. 3 is title complex [Ru (phen)
2(p-BEPIP)] (ClO
4)
2with the interactional change in fluorescence spectrogram of different concns calf thymus DNA, wherein X-coordinate is emission wavelength, and ordinate zou is relative intensity of fluorescence.
Fig. 4 is title complex [Ru (bpy)
2(p-BEPIP)] (ClO
4)
2eSI-MS.
Fig. 5 is title complex [Ru (bpy)
2(p-BEPIP)] (ClO
4)
2's
1h NMR.
Fig. 6 is title complex [Ru (phen)
2(p-BEPIP)] (ClO
4)
2eSI-MS.
Fig. 7 is title complex [Ru (phen)
2(p-BEPIP)] (ClO
4)
2's
1h NMR.
Embodiment
With reference to following non-limiting example, 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 dipyridyl, and phen refers to phenanthroline, and Py refers to pyridine, and p-represents contraposition.
Initial ruthenium complex cis-[Ru (bpy)
2cl
2] 2H
2o can reference literature described in method prepare: 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 synthetic of part p-BrPIP can obtain with reference to the preparation method described in following file: 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)] (ClO
4)
2synthetic
In 50ml three-necked bottle, drop into cis-[Ru (bpy)
2cl
2] 2H
2o (105mg; 0.2mmol), p-BrPIP (113mg, 0.3mmol); 30ml ethylene glycol and water mixed solvent (volume ratio is 9:1); logical argon gas 10min, 120 ℃ of reflux 6 hours under argon shield, reaction is finished; be cooled to room temperature; the 45ml that adds water dilution, removes by filter insolubles, obtains dark red filtrate; in filtrate, add excessive sodium perchlorate; hold over night, produces a large amount of salmon precipitations, filters to obtain precipitation; water respectively; after ether washing for several times, dry in vacuum drier, obtain orange/yellow solid.Thick product acetonitrile dissolves, and crosses 200-300 order neutral alumina column, main red component under acetonitrile drip washing, and decompression is spin-dried for solvent, obtains red-brown solid, productive rate 65%.ESI-MS (inCH
3cN, m/z): 789.2 ([M-H]
+, calculated value: 788.1);
1h NMR (in DMSO-d
6, 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)] (ClO
4)
2synthetic method be similar to [Ru (bpy)
2(p-BrPIP)] (ClO
4)
2synthetic.
Embodiment 2 microwaves synthesize alkynyl-modified racemic target compound
[Ru (bpy)
2(p-BEPIP)] (ClO
4)
2microwave-assisted synthetic
Get [Ru (bpy)
2(p-BrPIP)] (ClO
4)
2120mg; join in the microwave reaction pipe of 30ml; add 20ml anhydrous acetonitrile and stirrer, under argon shield, add phenylacetylene (0.14ml; 1.25mmol); palladium catalyst and copper catalyst, put into 110 ℃ of microwave radiations reaction 15min of microwave reactor after airtight, and reaction is finished; remove by filter impurity, decompression is spin-dried for.Thick product dissolves with acetonitrile, crosses 200-300 order neutral alumina column, and acetonitrile drip washing, collects red-brown the second colour band, and decompression is spin-dried for and obtains red-brown solid, productive rate 89.2%.ESI-MS (in CH
3cN, m/z) as shown in Figure 4: 809.3 ([M+H]
+, calculated value: 808.2),
1h NMR (in DMSO-d
6, δ/ppm) 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)] (ClO
4)
2microwave-assisted synthetic
Experimental technique is similar to [Ru (bpy)
2(p-BEPIP)] (ClO
4)
2microwave-assisted synthetic, will
[Ru (bpy)
2(p-BrPIP)] (ClO
4)
2replace with [Ru (phen)
2(p-BrPIP)] (ClO
4)
2, productive rate is 51.4%.ESI-MS (inCH
3cN, m/z) as shown in Figure 6: 857.3 ([M+H]
+, calculated value: 856.2);
1h NMR (in DMSO-d
6, δ/ppm) and 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.
Same method utilizes microwave-assisted to prepare other alkynyl-modified racemize ruthenium complexe.Confirm that by mass spectrum and proton nmr spectra analysis means the sample obtaining is target compound, and purity is good.
The target compound of the synthetic alkynyl-modified chirality of embodiment 3 microwaves
Chiral ruthenium complex Λ-[Ru (bpy)
2(p-BrPIP)]
2+, Δ-[Ru (bpy)
2(p-BrPIP)]
2+method described in can reference literature: 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) prepares.
A-[Ru (bpy)
2(p-BEPIP)] (ClO
4)
2microwave-assisted synthetic
Get A-[Ru (bpy)
2(p-BrPIP)] (ClO
4)
2120mg, joins in the microwave reaction pipe of 30ml, adds 20ml anhydrous acetonitrile and stirrer; under argon shield, add phenylacetylene (0.14ml, 1.25mmol); palladium catalyst and copper catalyst, put into 110 ℃ of microwave radiations reaction 15min of microwave reactor after airtight.Reaction is finished, and removes by filter insolubles, and filtrate is crossed 200-300 object alumina column with acetonitrile and purified and obtain target product.Productive rate is 89.2%.ESI-MS (in CH
3cN, m/z): 809.3 ([M+H]
+, calculated value: 808.2);
1h NMR (in DMSO-d
6, 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)] (ClO
4)
2microwave-assisted synthetic
Experimental technique is similar to Λ-[Ru (bpy)
2(p-BEPIP)] (ClO
4)
2microwave-assisted synthetic, by Λ-[Ru (bpy)
2(p-BrPIP)] (ClO
4)
2replace with Δ-[Ru (bpy)
2(p-BrPIP)] (ClO
4)
2, productive rate is 51.4%.ESI-MS (inCH
3cN, m/z): 809.1 ([M+H]
+, calculated value: 808.2)
Same method is utilized synthetic other the alkynyl-modified chiral ruthenium complex for preparing of microwave.Confirm that by mass spectrum and proton nmr spectra analysis means the sample obtaining is target compound, and purity is good.
The application of alkynyl-modified ruthenium complexe
IC50 value for compound anti tumor activity in vitro (the needed concentration of 50% cell growth inhibition) is evaluated: cell is inoculated in 96 orifice plates of the RPMI1640 substratum (including appropriate penicillin and streptomycin and glutamine) that contains 10% calf serum to 5%CO by certain density
2, under 37 ℃ of conditions, cultivate after 24 hours, use the fresh culture of the tested medicine of different concns (be mixed with 1 μ g/mL working fluid with PBS, dilute with substratum on demand when use) instead, continue to cultivate 48 hours; Then every hole adds 50 μ L precooling 50% trichoroacetic acid(TCA)s (TCA, final concentration is 10%), leaves standstill after 5 minutes, distilled water wash 5 times, dry air, adds 100 μ LMTT dye liquors, and 10min is processed in dyeing, 1% acetum washed cell 4 times, remove not combination dye, dry air, finally adds 150 μ L10mmol/L Tris solution, after fully mixing, microplate reader is measured OD value under 490nm wavelength.The each concentration parallel laboratory test of each sample 6 times, averages.
Adopt above-mentioned experimental program, select MCF-7 adenocarcinoma of breast epithelial cell line to test multiple compound of the present invention, result shows IC of the present invention
50(μ M) is worth all lower than 50, has potential industrial application value in the clinical treatment of tumor disease.
The impact of table 1 title complex on MCF-7 cell inhibitory effect
The fluorescence emission spectrum of embodiment 5 ethynyl ruthenium (II) compounds
5.1 take 10mg Λ-[Ru (bpy)
2(p-BEPIP)] (ClO
4) dissolve and be mixed with the solution of 1mg/mL with 10mLDMSO, take a morsel to be added to and in flat bottom surface ware, be placed in loft drier slowly dry solvent, the fluorescent emission figure that adopts fluorescence inverted microscope test compounds, as shown in Figure 1, the compound preparing has stronger fluorescent emission to result.
Preparation-obtained [the Ru (phen) of 5.2 preparation 4 μ M
2(p-BEPIP)] (ClO
4)
2solution, adds 3.0mL complex solution in spectrophotofluorometer sample pool, 460nm left and right light source activation complex solution records the fluorescence emission spectrum of 500-750nm scope inner complex, and as shown in Figure 2, title complex has stronger fluorescent emission to result;
5.3 according to 5.2 methods, microsyringe [Ru (phen) in sample pool for the 5min of being often separated by
2(p-BEPIP)] (ClO
4)
2solution adds 2 μ L calf thymus DNA solution, the concentration ratio of calf thymus DNA and title complex is increased progressively according to a certain percentage, detect the variation of its fluorescence emission spectrum, until saturated, result as shown in Figure 3, along with constantly adding of calf thymus DNA, the fluorescence intensity of title complex is dosage and increases, according to formula: [DNA]/(ε
a-ε
b)=[DNA]/(ε
b-ε
f)+1/K
b -1(ε
b-ε
f), the concentration of [DNA] representation DNA in formula, ε
a, ε
fand ε
brepresent respectively in each DNA concentration, free and with the molar absorptivity of the saturated title complex of DNA bonding.By the fitting a straight line intercept calculations incorporated constant K crossing with y axle
bobtain 1.54X10
8m
-1.
Result shows that ethynyl ruthenium (II) compound has stronger fluorescent emission, strong with calf thymus DNA bonding force, after interacting, change in fluorescence is obvious, in the potential using value that has aspect DNA fluorescence diagnosis probe and solar cell material.
Claims (9)
1. ruthenium (II) title complex of formula (I)
Wherein, in formula, R is optional from following group, and hydrogen is trimethyl silicon based, carbonatoms is the substituted alkyl that 1～6 alkyl or carbon atom are 1～6, phenyl or substituted-phenyl, pyridyl or substituted pyridinyl, furyl or replacement furan are fed base, pyrryl or substituted azole base, thiazole or substituted thiazolyl; Cycloalkyl, SO that described alkyl, phenyl, pyridyl, furan food in one's mouth base, thiazole, pyrroles's substituting group is optionally 3～8 from hydroxyl, nitro, halogen, amino, carboxyl, cyano group, sulfydryl, carbonatoms
3the alkyl that H, carbonatoms are 1～6, the alkenyl that carbonatoms is 2～6, alkynyl group, hydroxyl (C that carbon atom is 2～6
1-C
6) alkyl, amino (C
1-C
6) alkyl, CO
2r ', CONR ' R ', COR ', SO
2r ' R ', (C
1-C
6) alkoxyl group, (C
1-C
6) alkylthio ,-N=NR ', NR ' R ' or trifluoro (C
1-C
6) alkyl; Wherein, described R ' is selected from the alkyl or phenyl that H, carbonatoms are 1～6; The ethynyl position that in formula, R replaces can be positioned at ortho position, a position, the contraposition of phenyl ring, preferably the contraposition of phenyl ring; L in formula optionally from various can with the heterogeneous ring compound of the nitrogen atom of metal Ru coordination and poly-heterocyclic compounds, comprise racemic modification and the optical isomer of described compound, preferably dipyridyl and phenanthroline and optical isomer thereof; In formula, Y is acid ion, preferably perchlorate, hexafluoro-phosphate radical, chlorate anions; In formula, n, for to make ruthenium (II) title complex and optical isomer entirety thereof be the number of electroneutral acid ion, is positive integer.
2. the synthetic method of compound described in claim 1, described method comprises the steps:
(1) cis-Ru (L)
2cl
2with X-BrPIP reacting by heating under argon shield, reaction is finished, and is cooled to room temperature, and thin up, removes by filter insolubles, adds excessive acid or salt containing Y ion in filtrate, and hold over night, obtains [Ru (L)
2(X-BrPIP)] Y
n; Wherein, L optionally from various can with the heterogeneous ring compound for nitrogen-atoms of metal Ru coordination and poly-heterocyclic compounds, comprise racemic modification and the optical isomer of described compound, preferably dipyridyl and phenanthroline and their optical isomer; Y is acid ion, preferably perchlorate, chlorate anions, hexafluoro-phosphate radical; N, for to make ruthenium (II) title complex and optical isomer entirety thereof be the number of electroneutral acid ion, is positive integer; X-BrPIP is
(2) by [Ru (L) preparing in step (1)
2(X-BrPIP)] Y
n, joining in microwave reactor, certain dissolution with solvents, under argon shield, adds
palladium catalyst and copper catalyst, put into the reaction of microwave reactor Microwave-assisted firing, after reaction finishes, removes by filter insolubles, obtains reaction solution;
Wherein, R is optional from following group, and hydrogen is trimethyl silicon based, carbonatoms is the substituted alkyl that 1～6 alkyl or carbon atom are 1～6, phenyl or substituted-phenyl, pyridyl or substituted pyridinyl, furyl or substituted furan base, pyrryl or substituted azole base, thiazole or substituted thiazolyl; Cycloalkyl, SO that described alkyl, phenyl, pyridyl, furan food in one's mouth base, thiazole, pyrroles's substituting group is optionally 3～8 from hydroxyl, nitro, halogen, amino, carboxyl, cyano group, sulfydryl, carbonatoms
3the alkyl that H, carbonatoms are 1～6, the alkenyl that carbonatoms is 2～6, alkynyl group, hydroxyl (C that carbon atom is 2～6
1-C
6) alkyl, amino (C
1-C
6) alkyl, CO
2r ', CONR ' R ', COR ', SO
2r ' R ', (C
1-C
6) alkoxyl group, (C
1-C
6) alkylthio ,-N=NR ', NR ' R ' or trifluoro (C
1-C
6) alkyl; Wherein, described R ' is selected from the alkyl or phenyl that H, carbonatoms are 1～6;
(3) reaction solution obtained above, column chromatography purification, acetonitrile wash-out, collects red-brown the second colour band, is spin-dried for, and vacuum-drying, obtains target compound.
3. preparation method claimed in claim 2, is characterized in that in step (2), the temperature of described Microwave-assisted firing is 110 ℃～150 ℃, and the reaction times is 10min～40min.
4. preparation method claimed in claim 2, is characterized in that, in step (2), the solvent of described use is acetonitrile.
5. preparation method claimed in claim 2, is characterized in that, in step (3), described column chromatography is neutral alumina column chromatography.
6. the formula of claim 1 (I) compound is in the application for the preparation for the treatment of and/or preventing in the medicine of cancer.
7. the formula of claim 1 (I) compound is as DNA fluorescence diagnosis probe and as the application of solar cell and photosensitizers.
8. pharmaceutical composition, the formula that comprises claim 1 (I) compound and one or more pharmaceutically acceptable vehicle.
9. the composition of claim 8 is in the application for the preparation for the treatment of and/or preventing in the medicine of cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210433440.7A CN103788134B (en) | 2012-11-02 | 2012-11-02 | A kind of preparation method and applications of microwave-assisted alkynyl-modified ruthenium (II) complex |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210433440.7A CN103788134B (en) | 2012-11-02 | 2012-11-02 | A kind of preparation method and applications of microwave-assisted alkynyl-modified ruthenium (II) complex |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103788134A true CN103788134A (en) | 2014-05-14 |
| CN103788134B CN103788134B (en) | 2019-01-01 |
Family
ID=50664228
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210433440.7A Active CN103788134B (en) | 2012-11-02 | 2012-11-02 | A kind of preparation method and applications of microwave-assisted alkynyl-modified ruthenium (II) complex |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103788134B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709202A (en) * | 2013-12-26 | 2014-04-09 | 广东药学院 | Ruthenium (II) complex, preparation method thereof, and application of complex as cell fluorescent dye |
| CN105238814A (en) * | 2015-09-02 | 2016-01-13 | 广东药学院 | Application of ruthenium complex serving as nucleic acid vector of target cell nucleus |
| CN108570076A (en) * | 2018-05-04 | 2018-09-25 | 广东药科大学 | A kind of ruthenium complex and its synthetic method and application containing alkynyl |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101701024A (en) * | 2009-10-30 | 2010-05-05 | 暨南大学 | Ruthenium complex, preparation method thereof and application thereof |
-
2012
- 2012-11-02 CN CN201210433440.7A patent/CN103788134B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101701024A (en) * | 2009-10-30 | 2010-05-05 | 暨南大学 | Ruthenium complex, preparation method thereof and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| DONG-DONG SUN ET AL.: "Imidazo [4,5f][1,10] phenanthroline derivatives as inhibitor of c-myc gene expression in A549 cells via NF-κB pathway", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 22, 23 November 2011 (2011-11-23), pages 102 - 105 * |
| INTERACT WITH BOVINE SERUM ALBUMIN ET AL.: "Chiral Ruthenium Complexes Induce Apoptosis of Tumor Cell and Interact with Bovine Serum Albumin", 《CHIRALITY》, vol. 24, no. 2, 19 December 2011 (2011-12-19), pages 174 - 180 * |
| SRINIDHI RAMACHANDRA ET AL.: "Luminescent Ruthenium Tripod Complexes: Properties in Solution Luminescent Ruthenium Tripod Complexes: Properties in Solution", 《INORGANIC CHEMISTRY》, vol. 50, 31 December 2010 (2010-12-31), pages 1581 - 1591 * |
| TIANFENG CHEN ET AL.: "Chiral ruthenium polypyridyl complexes as mitochondria-targeted apoptosis inducers", 《MEDCHEMCOMM》, vol. 1, 16 June 2010 (2010-06-16), pages 73 - 75 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709202A (en) * | 2013-12-26 | 2014-04-09 | 广东药学院 | Ruthenium (II) complex, preparation method thereof, and application of complex as cell fluorescent dye |
| CN105238814A (en) * | 2015-09-02 | 2016-01-13 | 广东药学院 | Application of ruthenium complex serving as nucleic acid vector of target cell nucleus |
| EP3138924A1 (en) | 2015-09-02 | 2017-03-08 | Guangdong Pharmaceutical University | Application of ruthenium complexes as nucleic acid vectors of target cell nucleuses |
| CN105238814B (en) * | 2015-09-02 | 2018-11-09 | 广东药科大学 | Application of the ruthenium complex as targeting cell nucleus acid vectors |
| CN108570076A (en) * | 2018-05-04 | 2018-09-25 | 广东药科大学 | A kind of ruthenium complex and its synthetic method and application containing alkynyl |
| WO2019210715A1 (en) * | 2018-05-04 | 2019-11-07 | 广东药科大学 | Alkynyl-containing ruthenium complex, and synthesis method therefor and use thereof |
| US11420990B2 (en) | 2018-05-04 | 2022-08-23 | Guangdong Pharmaceutical University | Ruthenium complex containing alkynyl group, method of synthesizing the same and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103788134B (en) | 2019-01-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wenzel et al. | Multinuclear cytotoxic metallodrugs: physicochemical characterization and biological properties of novel heteronuclear gold–titanium complexes | |
| Kumar et al. | Ruthenium (II) complexes of saccharin with dipyridoquinoxaline and dipyridophenazine: Structures, biological interactions and photoinduced DNA damage activity | |
| Wang et al. | Heteroleptic Ir (III) N6 complexes with long-lived triplet excited states and in vitro photobiological activities | |
| Santra et al. | Chemistry of azopyrimidines. Part II. Synthesis, spectra, electrochemistry and X-ray crystal structures of isomeric dichloro bis [2-(arylazo) pyrimidine] complexes of ruthenium (II) | |
| Fernández-Moreira et al. | Bioconjugated rhenium (I) complexes with amino acid derivatives: synthesis, photophysical properties, and cell imaging studies | |
| Guan et al. | Bismuth-carboxylate ligand 1, 3, 6, 8-Tetrakis (p-benzoic acid) pyrene frameworks, photophysical properties, biological imaging, and fluorescent sensor for biothiols | |
| Valladolid et al. | Phenanthroline ligands are biologically more active than their corresponding ruthenium (II) arene complexes | |
| Nguyen et al. | Gold (I) and platinum (II) tetracenes and tetracenyldiacetylides: structural and fluorescence color changes induced by σ-metalation | |
| Saha et al. | Structural characterization and spectroelectrochemical, anion sensing and solvent dependence photophysical studies of a bimetallic Ru (ii) complex derived from 1, 3-di (1 H-imidazo [4, 5-f][1, 10] phenanthroline-2-yl) benzene | |
| Welsh et al. | Synthesis and antiproliferative activity of benzimidazole-based, trinuclear neutral cyclometallated and cationic, N^ N-chelated ruthenium (ii) complexes | |
| Lagref et al. | Artificial photosynthesis based on dye-sensitized nanocrystalline TiO2 solar cells | |
| Xu et al. | Molecular tectonics: design of enantiopure luminescent heterometallic Ir (III)–Cd (II) coordination network | |
| Rohacova et al. | Trinuclear and tetranuclear Re (I) rings connected with phenylene, vinylene, and ethynylene chains: synthesis, photophysics, and redox properties | |
| Lin et al. | An efficient probe of cyclometallated phosphorescent iridium complex for selective detection of cyanide | |
| CN112125887B (en) | Bipyridine-based ligand compound and preparation method and application thereof | |
| CN103709202B (en) | Ruthenium (II) complex and preparation method thereof and its it is used as the application of cell fluorescence dyestuff | |
| Zhang et al. | Binuclear Ru–Ru and Ir–Ru complexes for deep red emission and photocatalytic water reduction | |
| CN108570076A (en) | A kind of ruthenium complex and its synthetic method and application containing alkynyl | |
| Solís-Ruiz et al. | Light activation of cyclometalated ruthenium complexes drives towards caspase 3 dependent apoptosis in gastric cancer cells | |
| Tyulyaeva | Modern Approaches in the Synthesis of Noble Metal Porphyrins for Their Practical Application | |
| CN103788134A (en) | Microwave assisted preparation method of alkynyl modified ruthenium (II) complex and application thereof | |
| CN103509059B (en) | A kind of Cyclometalated ruthenium complex and its preparation method and application | |
| Rezvani et al. | Synthesis, crystal structure, electrochemical and fluorescence studies of a novel Zn (II)-fluorophore, 1, 10-phenanthroline-5, 6-dione (phen-dione) | |
| Chuprin et al. | Synthesis and reactivity of the apically functionalized (pseudo) macrobicyclic iron (ii) tris-dioximates and their hybrid phthalocyaninatoclathrochelate derivatives comprising reactive and vector terminal groups | |
| CN103012401A (en) | Preparation method and application of anthraquinone polypyridine ligand and ruthenium-anthraquinone complex |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 510000 No. 40 Guanghanyu Street, Baogang, Haizhu District, Guangzhou City, Guangdong Province Patentee after: Guangdong Pharmaceutical University Address before: 510006 280 East Ring Road outside Guangzhou University, Guangzhou, Guangdong Patentee before: Guangdong Pharmaceutical University |