CN103087110B - Saw horse ruthenium compound and preparation method thereof - Google Patents
Saw horse ruthenium compound and preparation method thereof Download PDFInfo
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Abstract
Saw horse ruthenium compound of the present invention is carboxylic acid group and the axial 2 electronics parts by connecting bridging in the saw horse skeleton structure at two ruthenium four carbonyls, wherein bridging carboxylic acid group is by O and metal Ru coordination, utilize the central metal Ru(I of lower valency) bond strength of Ru-CO is increased, good at physiological condition stability inferior, can realize controlled CO discharges, be beneficial to target and discharge, and the present invention can be by changing bridging carboxylic acid group R1CO2With axial 2 electronics parts, increase the water-soluble and CO rate of release of molecule, can be efficiently functionalized, be easy to derive, synthesis technique of the present invention is fairly simple to be easy to get, and the efficient functionalized method of saw horse ruthenium is provided.
Description
Technical field
The invention belongs to the studying technological domain of the two ruthenium transition metal carbonyl compounds of saw horse type, special standby relating toA kind of two Ruthenium carbonyl compounds of saw horse type with therapeutic treatment effect and preparation method thereof.
Background technology
Carbon monoxide (CO) is a kind of colourless, tasteless toxic gas, is considered to mammiferous always" noiseless killer ". In blood hemoglobin and CO binding ability far above with O2Binding ability, mistakeThe albumen of the saturated transport oxygen of CO of amount, thus organism oxygen transportation hindered, cause body anoxic, tightWhen heavy, cause death. But the physiological Study of nearly decades finds in human body that the moment is producing CO gas.Marks etc. study discovery, and carbon monoxide has many physiological and pathological therapeutic actions, rejection as anti-in anti-inflammatory,Cell protection apoptosis and promotion blood vessel dilatation etc. For example, in the clinical testing of mutability HO-1 mouse,Confirm that gas CO has the important function of Cell protection. Large quantity research has confirmed that endogenous CO existsMedical domain has prebiotic reason therapeutic action. But the application study of exogenous CO is less, and Major Difficulties existsBe insoluble in water in CO gas, cannot living things system quantitatively, the transmission of fixed point.
In order to realize, CO is quantitative in living things system, the transmission of fixed point, and controllable release is existing adoptedTechnology is to replace gas CO with carbon monoxide-releasing molecules. What disclose at present most study is transition metalCarbonyls is as carbon monoxide-releasing molecules.
US Patent No. 2006/0148900A1(WernerHaas etc.) disclose seven classes and can discharge oneOrganic and inorganic and the organic compound of the metal of carbonoxide, in order to treatment or disease preventing and treating, as chronic inflammation,Rheumatic arthritis; Strong inflammation disease, arteriosclerosis, apoplexy, coronary heart disease. In body, carbon monoxide dividesSon can with known drug group or anti-inflammatory medicaments, as salicylic acid combination.
PCT International Application No. WO 03/066067(WernerHaas etc.) open propose containing transition metalCarbonyls is used for the treatment of or prevent disease. Leading to of transition metal-carbonyls that this inventor proposesFormula is as follows: [(η5-CpR)M(CO)3], wherein M=Mn, Re; [(η5-CpR)M(CO)2X], whereinM=Fe、Ru；[(η5-CpR)M(CO)3X], wherein M=Cr, Mo, W; [η5-IndM(CO)3X]，Wherein M=Cr, Mo, W. Wherein Cp represents cyclopentadienyl ligands, and Ind is cogongrass ylidene ligands, and R isH, acyl group, carboxylic acid group, peptide or halogen, X is aryl, O2CR, L be CO, alkene, N, S orThe 2e chelating donor of P.
" carbon monoxide-releasing molecules exists the patent (patent No. 201210035501) that the people such as Sun Ping Wei deliverAfter dermatoplasty, suppress the application in acute rejection " middle report " carbon monoxide-releasing moleculesCO-RM2，[Ru2Cl4(CO)6], can be for the preparation of the medicine of acute rejection after inhibition dermatoplastyThing ", CO-RM2 is expected to meet clinical practice demand as transmission CO source. In addition, Sun Ping Wei etc.People discloses CO-RM2 and has prepared in medicament for treating early sepsis in patent 200810038045Application. But this carbonyl compound poorly water-soluble, in DMSO solution, easily dissociates and discharges fast CO,Be difficult to realize living things system CO slowly-releasing.
The people such as Motternili are in 4962～4973 pages of " DaltonTrans " the 43rd phases (in May, 2007)In the document of report, half sandwich type carbonyl iron is the CO-RM lead compound of a class broad research,Cyclopentadienyl group is stablized carbonyl iron unit [CpFe (CO)3]PF6, its poorly water-soluble, is dissolved in methyl-sulfoxide(DMSO), along with the release of CO, water-fast centralization compound precipitates, these sedimentsStop arteriole and cause complication medically. Therefore produce harmful physiology toxic and side effect.
In addition, the people such as Mann is 1798～1800 page (2011 of " DaltonTrans " the 40th the 33rd phase of volumeDecember in year) successfully report that cysteine carbonyl iron discharges molecule, it can be slow under physiological environmentDischarge CO, and only have amino acid residue and ferrous ion after discharging, therefore substantially nontoxic, use peaceEntirely.
Although above-mentioned disclosed transition metal carbonyl compound has been obtained good effect in biologic applicationsReally, but inventor in R&D process, find, above-mentioned technology discharge in the process of CO, also exist difficultWith problem controlled, target transmission, and monokaryon divalence ruthenium compounds CO-RM2 and its glycineChelating congener CO-RM3 is difficult to stable existence under complex physiologic condition, and complex structure is difficult for spreading outRaw, realize target release difficulty larger, be the bottleneck that ruthenium class discharges molecular medicine treatment application.
Summary of the invention
One of object of the present invention is to provide a kind of good stability, water-soluble height, efficiently senseChange and there is controlled carbon monoxide release performance and saw horse ruthenium compound.
Two of object of the present invention has been to provide the above-mentioned saw horse carbonyl that a kind of technique is simple, be easy to synthesizeThe preparation method of ruthenium compound.
Solving the problems of the technologies described above the technical solution adopted in the present invention is that this compound structure general formula is as follows:
Formula I
In formula I: R1For H-, CH3-、CH3(CH2) n-, trifluoromethyl, trichloromethyl, C6H5-X、CH3CH(OH)-、G-OOCH2CH2-, HOOC-, oligomerization, poly ethylene glycol, polysaccharide, acetyl ammoniaAny one in base phenol, amantadine;
N is 1～18 positive integer;
X is halogen, nitro, hydroxyl, methyl, methoxyl group, amino, sulfonic group, to the tert-butyl group, 4-(uncleButoxy carbonyl), 3,5-dinitro, CH3CO2, 2-hydroxyl-5-sulfo group, 3,4,5-trihydroxy, acrylic,Any one in 5-amino-2-hydroxyl;
R2For the heteroatom ligand of nitrogen, phosphine, oxygen, sulphur, or carbon monoxide, sugar, polyethylene glycol,In quaternary ammonium salt, amino acid, amino-acid ester, N-heterocyclic carbine, polypeptide, choline any one.
The heteroatom ligand of above-mentioned nitrogen is pyridine, 1-methylimidazole, imidazoles, aniline, glycine, sweet ammoniaIn acid methyl ester hydrochloride salt, amino acid, amino-acid ester, nitrile, 2 thiophene ethyl amine, thiophene-2-methylamine any oneKind;
The heteroatom ligand of above-mentioned phosphine is triphenylphosphine, diphenylphosphine, three (2-thienyl) phosphine, three (2,4-3,5-dimethylphenyl) hydrogen phosphide-5,5', 5 " trisulfonic acid trisodium salt, three (2,4,6-trimethoxyphenyl) phosphine, threeIn three sulfonate sodiums of Phenylphosphine, o-tolidine any one;
The heteroatom ligand of above-mentioned oxygen be in ether, ethanol, oxolane, furans any one;
The heteroatom ligand of above-mentioned sulphur be in hydrogen sulfide, methyl-sulfoxide, thiophene, ethylphenyl sulphur any one.
Above-mentioned nitrogen heterocycle carbine ligand is phenodiazine imidazoles Cabbeen or three nitrogen imidazoles Cabbeens;
Above-mentioned sugar be in glucose, sucrose, starch, lactose any one;
Above-mentioned quaternary ammonium salt is tetramethyl ammonium chloride, tetraethylammonium bromide, benzyl tributyl ammonium bromide, benzylTriethyl group ammonium bromide, benzyltrimethylammonium bromide, dioctadecyl dimethyl ammonium chloride, octadecyl twoMethyl-benzyl ammonium chloride, tetradecyl trimethyl ammonium chloride, OTAC, hexadecaneIn base dimethyl ethyl ammonium bromide, decyl trimethyl ammonium chloride any one;
Aforementioned polypeptides is that dipeptides, cell membrane adhesin polypeptide, cell pass through peptide, Mitochondrially targeted peptide, thymus gland fiveIn peptide any one.
The preparation method of above-mentioned saw horse ruthenium compound comprises the following steps:
(1) by Ru3(CO)12Be dissolved under nitrogen protection with compound 1 in organic solvent 1 to completeDissolve Ru3(CO)12With the mol ratio of compound 1 be 1:3～4, add hot reflux 8～12h, thin layer lookIt is complete that spectrum tracks to consumption of raw materials, revolves to steam to remove organic solvent 1, obtains intermediate A;
(2) under nitrogen protection, intermediate A is dissolved in organic solvent 2, adds hot reflux 1～3h,Be cooled to 25～50 DEG C, add compound 2, the mol ratio of intermediate A and compound 2 is 1:1.5～3,Stirring reaction 2～3h, revolves to steam and removes organic solvent 2, obtains sawing horse ruthenium compound;
Above-mentioned organic solvent 1 is toluene or oxolane;
Above-mentioned organic solvent 2 is oxolane or acetonitrile;
The molecular formula of above-claimed cpd 1 is R1CO2, wherein R1For H-, CH3-、CH3(CH2)n-、Trifluoromethyl, trichloromethyl, C6H5-X、CH3CH(OH)-、G-OOCH2CH2-, HOOC-, widowAny one in poly-, poly ethylene glycol, polysaccharide, Paracetamol, amantadine;
N is 1～18 positive integer,
X is halogen, nitro, hydroxyl, methyl, methoxyl group, amino, sulfonic group, to the tert-butyl group, 4-(uncleButoxy carbonyl), 3,5-dinitro, CH3CO2, 2-hydroxyl-5-sulfo group, 3,4,5-trihydroxy, acrylic,In 5-amino-2-hydroxyl any one;
Compound 2 is the heteroatom ligand of nitrogen, phosphine, oxygen, sulphur, or is carbon monoxide, sugar, poly-secondIn glycol, quaternary ammonium salt, amino acid, amino-acid ester, N-heterocyclic carbine, polypeptide, choline any one.
The heteroatom ligand of above-mentioned nitrogen is pyridine, 1-methylimidazole, imidazoles, aniline, glycine, sweet ammoniaIn acid methyl ester hydrochloride salt, amino acid, amino-acid ester, nitrile, 2 thiophene ethyl amine, thiophene-2-methylamine any oneKind;
The heteroatom ligand of above-mentioned phosphine is triphenylphosphine, diphenylphosphine, three (2-thienyl) phosphine, three (2,4-3,5-dimethylphenyl) hydrogen phosphide-5,5', 5 " trisulfonic acid trisodium salt, three (2,4,6-trimethoxyphenyl) phosphine, threeIn three sulfonate sodiums of Phenylphosphine, o-tolidine any one;
The heteroatom ligand of above-mentioned oxygen be in ether, ethanol, oxolane, furans any one;
The heteroatom ligand of above-mentioned sulphur be in hydrogen sulfide, methyl-sulfoxide, thiophene, ethylphenyl sulphur any one.
Above-mentioned nitrogen heterocycle carbine ligand is phenodiazine imidazoles Cabbeen or three nitrogen imidazoles Cabbeens;
Above-mentioned sugar be in glucose, sucrose, starch, lactose any one;
Above-mentioned quaternary ammonium salt is tetramethyl ammonium chloride, tetraethylammonium bromide, benzyl tributyl ammonium bromide, benzylTriethyl group ammonium bromide, benzyltrimethylammonium bromide, dioctadecyl dimethyl ammonium chloride, octadecyl twoMethyl-benzyl ammonium chloride, tetradecyl trimethyl ammonium chloride, OTAC, hexadecaneIn base dimethyl ethyl ammonium bromide, decyl trimethyl ammonium chloride any one;
Aforementioned polypeptides is that dipeptides, cell membrane adhesin polypeptide, cell pass through peptide, Mitochondrially targeted peptide, thymus gland fiveIn peptide any one.
Above-mentioned R2During for carbon monoxide, step (2) is under nitrogen protection, intermediate A to be dissolved inIn machine solvent 2, add hot reflux 1～2h, be cooled to 25～50 DEG C, add carbon monoxide, intermediate AWith the mol ratio of carbon monoxide be 1:1.5～3, stirring reaction 2～3h, revolves and steams remove portion organic solvent 2,Get rid of with CO air-flow, obtain sawing horse ruthenium compound.
Saw horse ruthenium compound of the present invention is by connecting in the saw horse skeleton structure at two ruthenium four carbonylsThe carboxylic acid group of bridging and axial 2 electronics parts, wherein bridging carboxylic acid group is by O and metal Ru coordination,Utilize the central metal Ru(I of lower valency) bond strength of Ru-CO is increased, under physiological conditionGood stability, can realize controlled CO and discharge, and be beneficial to target and discharge, and the present invention can be by changingBridging carboxylic acid group R1CO2With axial 2 electronics parts, increase the water-soluble and CO rate of release of molecule,Can be efficiently functionalized, be easy to derive, synthesis technique of the present invention is fairly simple to be easy to get, and saw horse is providedThe efficient functionalized method of ruthenium.
Brief description of the drawings
Fig. 1 is the infrared spectrogram of N1 in the embodiment of the present invention 1.
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of N1 in the embodiment of the present invention 1.
Fig. 3 is the carbon-13 nmr spectra figure of N1 in the embodiment of the present invention 1.
Fig. 4 is the inhibition experimental data chart of N1 to A459 lung carcinoma cell in the embodiment of the present invention 1.
Detailed description of the invention
Now in conjunction with the accompanying drawings and embodiments technical scheme of the present invention is further described, but the present inventionBe not limited only to following embodiment.
Embodiment 1
The general structure of saw horse ruthenium compound is:
Formula I
In formula I: R1For C6H5-X, X is p-CH3-，R2For methyl-sulfoxide, i.e. DMSO, chemical nameFor doube bridge connects two (methyl-sulfoxide) two rutheniums of paratolunitrile four carbonyls.
The preparation method of above-mentioned saw horse ruthenium compound is made up of following steps:
(1) by 0.20gRu3(CO)12In being dissolved in toluene with 0.74g compound 1 under nitrogen protection extremelyDissolve Ru completely3(CO)12With the mol ratio of compound 1 be 1:3.2, be heated to 110 DEG C of backflow 10h,It is complete that thin-layer chromatography tracks to consumption of raw materials, revolves to steam to remove toluene, obtains intermediate A, and its structural formula is:
Formula II
The molecular formula of above-claimed cpd 1 is R1CO2，R1For C6H5-X, X is p-CH3-。
(2) under nitrogen protection, intermediate A is dissolved in oxolane completely, is heated to 65 DEG C and returnsStream 2h, is cooled to 35 DEG C, adds 142 μ l methyl-sulfoxides, the mol ratio of intermediate A and methyl-sulfoxideFor 1:2, stirring reaction 2.5h, revolves to steam and removes oxolane, obtains sawing horse ruthenium compound, twoTwo (methyl-sulfoxide) two rutheniums of bridging paratolunitrile four carbonyls.
Above-mentioned product doube bridge is connected to two (methyl-sulfoxide) two rutheniums of paratolunitrile four carbonyls and utilize 400MNuclear magnetic resonance spectrometer and Avatar360E.S.P.FT-IR type Fourier transformation infrared spectrometer are analyzedMeasure its molecular composition, referring to Fig. 1 and Fig. 2, Fig. 3.
As shown in Figure 1, IR (KBr, cm-1): with the carbonyl vibration absorption peak of metal-complexing be 2017vs,1955m, 1926vs, on bridging carboxylic acid, OCO symmetry is 1577s with asymmetric vibration absorption peak, 1533m.
From Fig. 2 and Fig. 3, measurement result is1HNMR(400MHz,CDCl3)：δ(ppm)7.71(s,1H),7.25(s,1H),6.91(s,1H),3.74(s,3H),2.03(s,3H).13CNMR（400MHz,CDCl3）δ(ppm)204.97(CO),184.48(COO),138.62,130.45,120.32(ImidazoleC),29.68(N-CH3),23.77(CO2-CH3)。
This shows, embodiment 1 gained end-product is that doube bridge connects paratolunitrile four carbonyls two (twoFirst sulfoxide) two rutheniums.
Embodiment 2
The general structure of the saw horse ruthenium compound of the present embodiment is formula I, R in formula I1For C6H5-X，X is p-CH3-，R2For methyl-sulfoxide, i.e. DMSO.
The preparation method of above-mentioned saw horse ruthenium compound is made up of following steps:
(1) by 0.20gRu3(CO)12Extremely complete in being dissolved in toluene with 0.689g compound 1 under nitrogen protectionCL, Ru3(CO)12With the mol ratio of compound 1 be 1:3, be heated to 110 DEG C of backflow 8h, thin layer lookIt is complete that spectrum tracks to consumption of raw materials, revolves to steam to remove toluene, obtains intermediate A, and structural formula is formula II.
(2) under nitrogen protection, intermediate A is dissolved in oxolane completely, is heated to 65 DEG C and returnsStream 1h, is cooled to 25 DEG C, adds 106 μ l methyl-sulfoxides, the mol ratio of intermediate A and methyl-sulfoxideFor 1:1.5, stirring reaction 3h, revolves to steam and removes oxolane, obtains sawing horse ruthenium compound.
Embodiment 3
The general structure of the saw horse ruthenium compound of the present embodiment is formula I, R in formula I1For C6H5-X，X is p-CH3-，R2For methyl-sulfoxide, i.e. DMSO.
The preparation method of above-mentioned saw horse ruthenium compound is made up of following steps:
(1) by 0.20gRu3(CO)12In being dissolved in toluene with 0.918g compound 1 under nitrogen protection extremelyDissolve Ru completely3(CO)12With the mol ratio of compound 1 be 1:4, be heated to 110 DEG C of backflow 12h, thinIt is complete that layer chromatography tracks to consumption of raw materials, revolves to steam to remove toluene, obtains intermediate A, and structural formula is formula II.
(2) under nitrogen protection, intermediate A is dissolved in oxolane, is heated to 65 DEG C of backflow 3h,Be cooled to 50 DEG C, add 213 μ l methyl-sulfoxides, the mol ratio of intermediate A and methyl-sulfoxide is 1:3,Stirring reaction 2h, revolves to steam and removes oxolane, obtains sawing horse ruthenium compound.
Embodiment 4
In the step (1) of above-described embodiment 1～3, organic solvent 1 toluene used can be used the tetrahydrochysene of equivalentFurans is replaced, and is heated to 65 DEG C of backflow 8h, and other operation is identical with corresponding embodiment, obtains intermediate A,Structural formula is formula II; In step (2), organic solvent 2 used can be replaced with the acetonitrile of equivalent, heatingTo 82 DEG C of backflow 2.5h, other step is identical with corresponding embodiment, obtains sawing horse ruthenium compound.
Embodiment 5
Substituent R in the formula I of above-described embodiment 1～41For C6H5-X, X can be also F, Cl, Br,I, nitro, hydroxyl, methoxyl group, amino, sulfonic group, to the tert-butyl group, 4-(tert-butoxycarbonyl), 3,5-Dinitro, CH3CO2, 2-hydroxyl-5-sulfo group, 3,4, in 5-trihydroxy, acrylic, 5-amino-2-hydroxylAny one, other substituting group is identical with corresponding embodiment.
In the preparation method of the saw horse ruthenium compound of above-mentioned formula I, compound 1 molecule of step (1)Formula is R1CO2, wherein R1Correspond to C6H5-X, X correspond to F, Cl, Br, I, nitro, hydroxyl,Methoxyl group, amino, sulfonic group, to the tert-butyl group, 4-(tert-butoxycarbonyl), 3,5-dinitro, CH3CO2、2-hydroxyl-5-sulfo group, 3,4,5-trihydroxy, acrylic or 5-amino-2-hydroxyl, other step and correspondingEmbodiment is identical.
Embodiment 6
Substituent R in the formula I of above-described embodiment 1～51For H-, CH3-, trifluoromethyl, trichloromethyl,CH3CH(OH)-、G-OOCH2CH2-, HOOC-, oligomerization, poly ethylene glycol, polysaccharide, acetyl ammoniaAny one in base phenol, amantadine, other substituting group is identical with corresponding embodiment.
In the preparation method of the saw horse ruthenium compound of above-mentioned formula I, compound 1 molecule of step (1)Formula is R1CO2, wherein R1Correspond to H-, CH3-, trifluoromethyl, trichloromethyl, CH3CH(OH)-、G-OOCH2CH2-, HOOC-, oligomerization, poly ethylene glycol, polysaccharide, Paracetamol or amantadine,Other step is identical with corresponding embodiment.
Embodiment 7
Substituent R in the formula I of above-described embodiment 1～61For CH3(CH2) n-, what n was 1～18 is anyA positive integer. Other substituting group is identical with corresponding embodiment.
In the preparation method of the saw horse ruthenium compound of above-mentioned formula I, compound 1 molecule of step (1)Formula is R1CO2, wherein R1Correspond to CH3(CH2) n-, n corresponds to 1～18 positive integer, other stepIdentical with corresponding embodiment.
Embodiment 8
Substituent R in the formula I of above-described embodiment 1～72DMSO can come with the heteroatom ligand of nitrogenReplacing, can be specifically pyridine, 1-methylimidazole, imidazoles, aniline, glycine, glycine methyl ester saltIn hydrochlorate, amino acid, amino-acid ester, nitrile, 2 thiophene ethyl amine, thiophene-2-methylamine any one, otherSubstituting group identical with corresponding embodiment.
In the preparation method of the saw horse ruthenium compound of above-mentioned formula I, compound 2 correspondences in step (2)For carbon monoxide, pyridine, 1-methylimidazole, imidazoles, aniline, glycine, glycine methyl ester hydrochloride,In amino acid, amino-acid ester, nitrile, 2 thiophene ethyl amine, thiophene-2-methylamine any one. Other stepIdentical with corresponding embodiment.
Embodiment 9
Substituent R in the formula I of above-described embodiment 82Can use the heteroatom ligand of phosphine or the hetero atom of oxygenOther heteroatom ligands of part or sulphur replace, and other substituting group is identical with corresponding embodiment.
The heteroatom ligand of above-mentioned phosphine is triphenylphosphine, diphenylphosphine, three (2-thienyl) phosphine, three (2,4-3,5-dimethylphenyl) hydrogen phosphide-5,5', 5 " trisulfonic acid trisodium salt, three (2,4,6-trimethoxyphenyl) phosphine, threeIn three sulfonate sodiums of Phenylphosphine, o-tolidine any one;
The heteroatom ligand of above-mentioned oxygen be in ether, ethanol, oxolane, furans any one;
Other heteroatom ligands of above-mentioned sulphur be in hydrogen sulfide, thiophene, ethylphenyl sulphur any one;
In the preparation method of above-mentioned formula I, in step (2), compound 2 corresponds to triphenylphosphine, diphenylPhosphine, three (2-thienyl) phosphine, three (2,4-3,5-dimethylphenyl) hydrogen phosphide-5,5', 5 " trisulfonic acid trisodium salt, three (2,4,6-trimethoxyphenyl) any one or second in phosphine, three sulfonate sodiums of triphenylphosphine, o-tolidineIn ether, ethanol, oxolane, furans, in any one or hydrogen sulfide, thiophene, ethylphenyl sulphur, appointMeaning is a kind of. Other step is identical with corresponding embodiment.
Embodiment 10
Substituent R in the formula I of above-described embodiment 1～72Can use carbon monoxide, sugar, polyethylene glycol,In quaternary ammonium salt, amino acid, amino-acid ester, N-heterocyclic carbine, choline, any one is replaced, otherSubstituting group is identical with corresponding embodiment.
Above-mentioned sugar can be specifically in glucose, sucrose, starch, lactose any one.
Above-mentioned quaternary ammonium salt can be specifically tetramethyl ammonium chloride, tetraethylammonium bromide, benzyl tributyl bromineChange ammonium, benzyl triethyl ammonium bromide, benzyltrimethylammonium bromide, dioctadecyl dimethyl ammonium chloride,Stearyl dimethyl benzyl ammonium chloride, tetradecyl trimethyl ammonium chloride, the chlorination of octadecyl trimethylIn ammonium, cetyldimethylethylambromide bromide ammonium, decyl trimethyl ammonium chloride any one.
Above-mentioned N-heterocyclic carbine can be phenodiazine imidazoles Cabbeen or three nitrogen imidazoles Cabbeens.
In the preparation method of above-mentioned formula I, compound 2 correspondences of step (2) can be used carbon monoxide, PortugalAny one or polyethylene glycol or tetramethyl ammonium chloride, tetrem in grape sugar, sucrose, starch, lactoseBase ammonium bromide, benzyl tributyl ammonium bromide, benzyl triethyl ammonium bromide, benzyltrimethylammonium bromide, twoOctadecyl alkyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, the chlorination of myristyl trimethylAmmonium, OTAC, cetyldimethylethylambromide bromide ammonium, ten alkyl trimethyl chlorineChange in ammonium any one or amino acid or amino-acid ester or phenodiazine imidazoles Cabbeen or three nitrogen imidazoles CabbeensOr choline is replaced, other step is identical with corresponding embodiment.
Embodiment 11
Substituent R in the formula I of above-described embodiment 1～72Can replace with polypeptide, can use dipeptides,Cell membrane adhesin polypeptide (RGD), cell pass through peptide (CPP), Mitochondrially targeted peptide (MPP), thymus gland fiveIn peptide, any one is replaced, and other substituting group is identical with corresponding embodiment.
The structural formula of above-mentioned dipeptides is NH2-GlyGlyOH。
The structural formula of above-mentioned RGD is NH2-Thr-Arg-Gly-Asp-Leu-Lys-H。
The structural formula of above-mentioned CPP is NH2-Thr-Phe-Ser-Asp-Leu-Lys-H。
The structural formula of above-mentioned MPP is NH2-Phe-Arg-Phe-Lys-Lys-H。
In the preparation method of above-mentioned formula I, compound 2 correspondences of step (2) can be used dipeptides, cell membraneAdhesin polypeptide (RGD), cell pass through in peptide (CPP), Mitochondrially targeted peptide (MPP), thymopeptide-5 appointsMeaning one is replaced, and other step is identical with corresponding embodiment.
Embodiment 12
The substituent R of above-described embodiment 10 Chinese style I2During for carbon monoxide, step (2) can be at nitrogenUnder gas protection, intermediate A is dissolved in organic solvent 2, adds hot reflux, cooling, pass into carbon monoxideGas, stirring reaction, revolves and steams remove portion organic solvent 2, then pass into CO air-flow, removes residue secondNitrile, other step is identical with corresponding embodiment, obtains the saw horse ruthenium compound of formula I.
Above-mentioned saw horse ruthenium compound can be used as CO and discharges molecule, by horse cardiac muscle Lactoferrin(buying from Ritchie difficult to understand trade Co., Ltd of Shanghai Sigma) system, test, prepared with embodiment 1Saw horse ruthenium compound (following abbreviation product 1) be example, specific as follows:
Be converted into 540nm and 575nm by the deoxidation flesh red eggs (deoxy-Mb) of measuring 580nm absorptionThe ultraviolet spectrophotometry of hyp carbonyl myoglobin (Mb-CO) is evaluated. Mb-CO existsThe change in concentration at 540nm place is used for weighing the amount that CO discharges.
Myoglobins solution is that 10mg albumen is dissolved in to 10ml, the phosphate buffer solution (pH=7.4) of 0.01MFreshly be prepared into the solution that concentration is 66 μ M. Before each variable concentrations protein determination, add whereinSodium dithionite (0.1%) makes albumen be converted into deoxidation myoglobins.
Product 1 is dissolved in to methyl-sulfoxide (DMSO), joins the above-mentioned myoglobins preparing of 1mlIn the phosphate buffer solution (0.01M, PH=7.4) of (66 μ M), discharge three kinds of molecular testings for every kindDifferent concentration, is respectively 60 μ M, 40 μ M and 20 μ M, and simulation physiological condition is in the different timeIn (30,60,90min) and with ultraviolet irradiation within the different time (5,15,25,35,45,55,65,75,85,95 and 100min) be converted into Mb-CO's with spectrophotometer test deoxy-MbChange in concentration. Nd, for not detecting carbonyl myoglobin, the results are shown in Table 1.
The change in concentration of table 1 carbonyl myoglobin
As can be seen from Table 1, within physiological condition 30～90 minutes, all do not detect and discharge CO, showProduct 1 (37 DEG C) under physiological condition is more stable, and can be within a certain period of time under UV-irradiationSaturated deoxidation myoglobins, and As time goes on, the concentration of carbonyl myoglobin (Mb-CO) byCumulative large.
Above-mentioned experiment absolutely proves that saw horse ruthenium compound can be used as CO and discharges molecule, in photoinductionLower release endogenous CO, therefore, it can be applied to, and medical domain is used for the treatment of or prevent disease, underFace describes as an example of Human Lung Cancer cell experiment example, specifically:
(1) cell line selection and cultivation
A549 is the human lung cancer cell line who is most commonly used to research, is people's alveolar substrate epithelium gland cancer, Yi PeiSupport condition of culture PRMI-1640+10%CS, 5%CO2，37℃。
(2) lung cancer tumor cell activity test
By above-mentioned cell, by 1 × 104/hole, (200 μ l) are inoculated in 96 well culture plates, treat that cell grows to70～80%, add the product of variable concentrations (0,50,100,200,300,400,500 μ mol/L)1 discharges molecule, continues to cultivate after 24 hours, and every hole adds tetrazolium salts (MTT) solution 20 μ l(concentration to be5mg/ml); 37 DEG C are continued to hatch 4h, to ensure that tetrazolium salts is completely by living cells metabolism cracking, stop trainingSupport, careful suction abandoned supernatant in hole; Every hole adds the dimethyl sulfoxide (DMSO) (DMSO) of 150 μ l, concussion10min; Select 490nm wavelength, on enzyme-linked immunosorbent assay instrument, measure each hole absorbance; Result is with respectivelyOrganize 6 hole OD means standard deviation (x ± s) represent. CO is to inhibition for the inhibited proliferation of cellRate represents (inhibitionratio, IR), calculates respectively each group of inhibiting rate. Inhibiting rate (%)=(contrastGroup OD value-experimental group OD value)/control group OD value × 100%, taking concentration/time as transverse axis,Inhibiting rate is the longitudinal axis, and curve plotting, is shown in Fig. 4.
As shown in Figure 4, in the time that the release molecular concentration adding increases gradually, lung carcinoma cell inhibiting rate also byCumulative large, and the required release molecular concentration of best inhibition of cancer cell rate is 100 μ g/ml.
Claims (2)
1. a saw horse ruthenium compound, its general structure is:
In formula I: R1For H-, CH3-、CH3(CH2) phenyl that replaces of n-, trifluoromethyl, trichloromethyl, X,CH3CH (OH)-, HOOC-, oligomeric ethylene glycol, poly ethylene glycol, polysaccharide, Paracetamol, goldJust any one in alkanamine;
N is 1～18 positive integer;
X is halogen, nitro, hydroxyl, methyl, methoxyl group, amino, sulfonic group, to the tert-butyl group, 4-(uncleButoxy carbonyl), 3,5-dinitro, CH3CO2, 2-hydroxyl-5-sulfo group, 3,4,5-trihydroxy, acrylic,Any one in 5-amino-2-hydroxyl;
R2For methyl-sulfoxide.
2. a preparation method for saw horse ruthenium compound claimed in claim 1, is characterized in that bagDraw together following steps:
(1) by Ru3(CO)12Be dissolved under nitrogen protection with compound 1 in organic solvent 1 to completeDissolve Ru3(CO)12With the mol ratio of compound 1 be 1:3～4, add hot reflux 8～12h, thin layer lookIt is complete that spectrum tracks to consumption of raw materials, revolves to steam to remove organic solvent 1, obtains intermediate A;
(2) under nitrogen protection, intermediate A is dissolved in organic solvent 2, adds hot reflux 1～3h,Be cooled to 25～50 DEG C, add compound 2, the mol ratio of intermediate A and compound 2 is 1:1.5～3,Stirring reaction 2～3h, revolves to steam and removes organic solvent 2, obtains sawing horse ruthenium compound;
Above-mentioned organic solvent 1 is toluene or oxolane;
Above-mentioned organic solvent 2 is oxolane or acetonitrile;
Above-claimed cpd 1 is R1CO2H, wherein R1For H-, CH3-、CH3(CH2) n-, trifluoromethyl,Phenyl, CH that trichloromethyl, X replace3CH (OH)-, HOOC-, oligomeric ethylene glycol, poly second twoAny one in alcohol, polysaccharide, Paracetamol, amantadine;
N is 1～18 positive integer,
X is halogen, nitro, hydroxyl, methyl, methoxyl group, amino, sulfonic group, to the tert-butyl group, 4-(uncleButoxy carbonyl), 3,5-dinitro, CH3CO2, 2-hydroxyl-5-sulfo group, 3,4,5-trihydroxy, acrylic,In 5-amino-2-hydroxyl any one;
Compound 2 is methyl-sulfoxide.
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Non-Patent Citations (2)
| Title |
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| Mesomorphic Metallo-Dendrimers Based on the Metal−Metal Bonded Ru2(CO)4 Sawhorse Unit;Stéphane Frein;《Chem. Mater.》;20080108;第20卷(第4期);第1342页合成部分，Supporting Information第2页 * |
| Sawhorse-type diruthenium tetracarbonyl complexes;Bruno Therrien et al.;《Coordination Chemistry Reviews》;20091130;第253卷(第21-22期);第2645页左栏第1段、右栏第1段，第2662页图40，第2644页表1，第2641页图3，左栏第3段，第2663左栏第2-5段，第2657页图29，第2643页第3段下方方程式，第4段， * |
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