CN103087110A - Saw horse carbonyl ruthenium compound and preparation method thereof - Google Patents
Saw horse carbonyl ruthenium compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a saw horse carbonyl ruthenium compound which is a carboxylic acid group and an axial 2 electronic ligand through connecting a bridging on a double-ruthenium tetracarbonyl saw horse skeleton structure, the bridged carboxylic acid group is coordinated with metal ruthenium through O, the bond strength of Ru-Co is improved by utilizing center metal Ru (I) with low price, the saw horse carbonyl ruthenium compound has good stability under physiological conditions and is beneficial to target release, CO release is controllable, and the water solubility of molecular and the CO release speed can be improved by changing bridging carboxylic acid group R1CO2 and the axial 2 electronic ligand, so that the saw horse carbonyl ruthenium compound can be functionalized efficiently and is easy to derive. The synthetic process is simpler and easy to obtain, and an efficient functionalization method for saw horse carbonyl 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 a kind of two Ruthenium carbonyl compounds of saw horse type with therapeutic treatment effect and preparation method thereof that relate to.
Background technology
Carbon monoxide (CO) is a kind of colourless, tasteless toxic gas, is considered to mammiferous " noiseless killer " always.In blood oxyphorase and CO binding ability far above with O
2Binding ability, the albumen of the saturated transportation oxygen of excessive CO, thus hinder the organism oxygen transportation, cause the body anoxic, cause death when serious.Yet the physiological Study of nearly decades finds constantly producing in human body CO gas.Marks etc. study discovery, and carbon monoxide has many physiological and pathological therapeutic actions, as anti-inflammatory immunologic rejection, Cell protection apoptosis and promotion vasodilation etc.For example, in the clinical trial of mutagenicity HO-1 mouse, confirmed that gas CO has the vital role of Cell protection.Large quantity research has confirmed that endogenous CO has beneficial physiology therapeutic action at medical field.But the applied research of exogenous CO is less, and Major Difficulties is that CO gas is insoluble in water, can't living things system quantitatively, the transmission of fixed point.
In order to realize that CO is quantitative in living things system, the transmission of fixed point, controllable release, the existing technology that adopts are with carbon monoxide-releasing molecules replacement gas CO.What disclose at present most study is that transition metal carbonyl compound is as carbon monoxide-releasing molecules.
US Patent No. 2006/0148900A1(Werner Haas etc.) disclose seven classes and can discharge the organic and inorganic and organic compound of the metal of carbon monoxide, in order to treatment or disease preventing and treating, as chronic inflammatory diseases, rheumatic arthritis; Strong inflammatory disease, arteriosclerosis, apoplexy, coronary heart disease.In body carbon monoxide molecule can with known drug group or anti-inflammatory medicaments, as the Whitfield's ointment combination.
PCT International Application No. WO 03/066067(Werner Haas etc.) the open carbonyl compound that proposes to contain transition metal is used for the treatment of or preventing disease.The general formula of transition metal-carbonyl compound that this contriver proposes is as follows: [(η
5-CpR) M (CO)
3], wherein M=Mn, Re; [(η
5-CpR) M (CO)
2X], wherein M=Fe, Ru; [(η
5-CpR) M (CO)
3X], wherein M=Cr, Mo, W; [η
5-IndM (CO)
3X], wherein M=Cr, Mo, W.Wherein Cp represents cyclopentadienyl ligands, and Ind is the cogongrass ylidene ligands, and R is H, acyl group, carboxylic acid group, peptide or halogen, and X is aryl, O
2CR, L are the 2e chelating donor of CO, alkene, N, S or P.
Report " carbon monoxide-releasing molecules CO-RM2, [Ru in the patent that the people such as SunBing Wei deliver (patent No. 201210035501) " carbon monoxide-releasing molecules suppresses the application in acute rejection after dermatoplasty "
2Cl
4(CO)
6], can be for the preparation of the medicine that suppresses acute rejection after dermatoplasty ", CO-RM2 is expected to satisfy the clinical application demand as transmission CO source.In addition, the people such as SunBing Wei discloses the application of CO-RM2 in the preparation medicament for treating early sepsis in patent 200810038045.But this carbonyl compound poorly water-soluble in DMSO solution, easily dissociates and discharges fast CO, is difficult to realize living things system CO slowly-releasing.
The people such as Motternili are in the document of 4962～4973 pages of " Dalton Trans " the 43rd phases (in May, 2007) report, half sandwich type iron carbonyl is the CO-RM lead compound of a class broad research, and cyclopentadienyl is stablized iron carbonyl unit [CpFe (CO)
3] PF
6, its poorly water-soluble is dissolved in methyl-sulphoxide (DMSO) along with the release of CO, and water-fast centralization compound precipitates, and these throw outs stop arterioles and cause medically complication.Therefore produce harmful physiology toxic side effect.
In addition, the people such as Mann have reported successfully that in " Dalton Trans " the 40th the 33rd phase of volume 1798～1800 pages (in December, 2011) the halfcystine iron carbonyl discharges molecule, it can slowly discharge CO under physiological environment, and after discharging, amino-acid residue and ferrous ion are only arranged, therefore substantially nontoxic, use safety.
Although above-mentioned disclosed transition metal carbonyl compound has been obtained effect preferably in biologic applications, but the contriver finds in R﹠D process, above-mentioned technology also exists in the process that discharges CO and is difficult to problem controlled, the target transmission, and monokaryon divalence ruthenium compounds CO-RM2 and its glycine chelate congener CO-RM3 are difficult to stable existence under the complex physiologic condition, complex structure is difficult for derivative, realizing that target discharges difficulty larger, is that the ruthenium class discharges the bottleneck that the molecular medicine treatment is used.
Summary of the invention
One of purpose of the present invention is to provide a kind of good stability, and water-soluble height can be efficiently functionalized and have a controlled carbon monoxide release performance saw horse ruthenium compound.
Two of purpose of the present invention has been to provide that a kind of technique is simple, the preparation method of the above-mentioned saw horse ruthenium compound that is easy to synthesize.
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:
In the formula I: R
1Be H-, CH
3-, CH
3(CH
2) n-, trifluoromethyl, trichloromethyl, C
6H
5-X, CH
3CH (OH)-, G-OOCH
2CH
2-, any one in HOOC-, oligomerization, poly ethylene glycol, polysaccharide, acetyl aminophenol, amantadine;
N is 1～18 positive integer;
X is halogen, nitro, hydroxyl, methyl, methoxyl group, amino, sulfonic group, to the tertiary butyl, 4-(tert-butoxycarbonyl), 3,5-dinitrobenzene, CH
3CO
2, 2-hydroxyl-5-sulfo group, 3,4, any one in 5-trihydroxy-, propenyl, 5-amino-2-hydroxyl;
R
2Be the heteroatom ligand of nitrogen, phosphine, oxygen, sulphur, or in carbon monoxide, sugar, polyoxyethylene glycol, quaternary ammonium salt, amino acid, amino acid ester, N-heterocyclic carbine, polypeptide, choline any one.
The heteroatom ligand of above-mentioned nitrogen be in pyridine, 1-Methylimidazole, imidazoles, aniline, glycine, glycine methyl ester hydrochloride, amino acid, amino acid ester, nitrile, 2 thiophene ethyl amine, thiophene-2-methylamine any one;
The heteroatom ligand of above-mentioned phosphine is triphenylphosphine, diphenylphosphine, three (2-thienyl) phosphine, three (2, the 4-3,5-dimethylphenyl) phosphuret-(t)ed hydrogen-5,5', 5 " in trisulfonic acid trisodium salt, three (2; 4,6-trimethoxyphenyl) phosphine, three sulfonate sodiums of triphenylphosphine, o-tolidine any one;
The heteroatom ligand of above-mentioned oxygen be in ether, ethanol, tetrahydrofuran (THF), furans any one;
The heteroatom ligand of above-mentioned sulphur be in hydrogen sulfide, methyl-sulphoxide, 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 be in tetramethyl ammonium chloride, tetraethylammonium bromide, benzyl tributyl brometo de amonio, benzyl triethyl ammonium bromide, benzyltrimethylammonium bromide, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, tetradecyl trimethyl ammonium chloride, octadecyl trimethyl ammonium chloride, cetyldimethylethylambromide bromide ammonium, decyl trimethyl ammonium chloride any one;
Aforementioned polypeptides is that dipeptides, cytolemma adhesin polypeptide, cell pass through in peptide, Mitochondrially targeted peptide, thymopeptide-5 any one.
The preparation method of above-mentioned saw horse ruthenium compound comprises the following steps:
(1) with Ru
3(CO)
12Be dissolved under nitrogen protection with compound 1 in organic solvent 1 to dissolving fully, Ru
3(CO)
12With the mol ratio of compound 1 be 1:3～4, reflux 8～12h, it is complete that thin-layer chromatography tracks to raw material consumption, revolves to steam to remove organic solvent 1, obtains intermediate A;
(2) under nitrogen protection, intermediate A is dissolved in organic solvent 2, reflux 1～3h is cooled to 25～50 ℃, add compound 2, the mol ratio of intermediate A and compound 2 is 1:1.5～3, stirring reaction 2～3h, revolve to steam and remove organic solvent 2, obtain sawing horse ruthenium compound;
Above-mentioned organic solvent 1 is toluene or tetrahydrofuran (THF);
Above-mentioned organic solvent 2 is tetrahydrofuran (THF) or acetonitrile;
The molecular formula of above-claimed cpd 1 is R
1CO
2, R wherein
1Be H-, CH
3-, CH
3(CH
2) n-, trifluoromethyl, trichloromethyl, C
6H
5-X, CH
3CH (OH)-, G-OOCH
2CH
2-, any one in HOOC-, oligomerization, poly ethylene glycol, polysaccharide, acetyl aminophenol, amantadine;
N is 1～18 positive integer,
X is halogen, nitro, hydroxyl, methyl, methoxyl group, amino, sulfonic group, to the tertiary butyl, 4-(tert-butoxycarbonyl), 3,5-dinitrobenzene, CH
3CO
2, 2-hydroxyl-5-sulfo group, 3,4, in 5-trihydroxy-, propenyl, 5-amino-2-hydroxyl any one;
Compound 2 is the heteroatom ligand of nitrogen, phosphine, oxygen, sulphur, be perhaps in carbon monoxide, sugar, polyoxyethylene glycol, quaternary ammonium salt, amino acid, amino acid ester, N-heterocyclic carbine, polypeptide, choline any one.
The heteroatom ligand of above-mentioned nitrogen be in pyridine, 1-Methylimidazole, imidazoles, aniline, glycine, glycine methyl ester hydrochloride, amino acid, amino acid ester, nitrile, 2 thiophene ethyl amine, thiophene-2-methylamine any one;
The heteroatom ligand of above-mentioned phosphine is triphenylphosphine, diphenylphosphine, three (2-thienyl) phosphine, three (2, the 4-3,5-dimethylphenyl) phosphuret-(t)ed hydrogen-5,5', 5 " in trisulfonic acid trisodium salt, three (2; 4,6-trimethoxyphenyl) phosphine, three sulfonate sodiums of triphenylphosphine, o-tolidine any one;
The heteroatom ligand of above-mentioned oxygen be in ether, ethanol, tetrahydrofuran (THF), furans any one;
The heteroatom ligand of above-mentioned sulphur be in hydrogen sulfide, methyl-sulphoxide, 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 be in tetramethyl ammonium chloride, tetraethylammonium bromide, benzyl tributyl brometo de amonio, benzyl triethyl ammonium bromide, benzyltrimethylammonium bromide, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, tetradecyl trimethyl ammonium chloride, octadecyl trimethyl ammonium chloride, cetyldimethylethylambromide bromide ammonium, decyl trimethyl ammonium chloride any one;
Aforementioned polypeptides is that dipeptides, cytolemma adhesin polypeptide, cell pass through in peptide, Mitochondrially targeted peptide, thymopeptide-5 any one.
Above-mentioned R
2During for carbon monoxide; step (2) is intermediate A to be dissolved in organic solvent 2 under nitrogen protection; reflux 1～2h; be cooled to 25～50 ℃, add carbon monoxide, the mol ratio of intermediate A and carbon monoxide is 1:1.5～3; stirring reaction 2～3h; revolve and steam remove portion organic solvent 2, get rid of with the CO air-flow, obtain sawing horse ruthenium compound.
Saw horse ruthenium compound of the present invention is by connect carboxylic acid group and the axial 2 electronics parts of bridging on the saw horse skeleton structure of two ruthenium four carbonyls, wherein the bridging carboxylic acid group is by O and metal Ru coordination, utilize the central metal Ru(I of lower valency) make the bond strength of Ru-CO increase, good at the physiological condition stability inferior, can realize that controlled CO discharges, be beneficial to target and discharge, and the present invention can be by changing bridging carboxylic acid group R1CO
2With axial 2 electronics parts, increase the water-soluble and CO release rate 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 of 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 the A459 lung carcinoma cell in the embodiment of the present invention 1.
Embodiment
Now in conjunction with the accompanying drawings and embodiments technical scheme of the present invention is further illustrated, but the present invention is not limited only to following embodiment.
Embodiment 1
The general structure of saw horse ruthenium compound is:
In the formula I: R
1Be C
6H
5-X, X are p-CH
3-, R
2Be methyl-sulphoxide, i.e. DMSO, chemical name are that doube bridge connects two (methyl-sulphoxide) two rutheniums of paratolunitrile four carbonyls.
The preparation method of above-mentioned saw horse ruthenium compound is comprised of following steps:
(1) with 0.20g Ru
3(CO)
12Dissolving extremely fully in being dissolved in toluene with 0.74g compound 1 under nitrogen protection, Ru
3(CO)
12With the mol ratio of compound 1 be 1:3.2, be heated to 110 ℃ of backflow 10h, it is complete that thin-layer chromatography tracks to raw material consumption, revolves to steam to remove toluene, obtains intermediate A, its structural formula is:
The molecular formula of above-claimed cpd 1 is R
1CO
2, R
1Be C
6H
5-X, X are p-CH
3-.
(2) under nitrogen protection, intermediate A is dissolved in tetrahydrofuran (THF) fully; be heated to 65 ℃ of backflow 2h; be cooled to 35 ℃; add 142 μ l methyl-sulphoxides; the mol ratio of intermediate A and methyl-sulphoxide is 1:2, and stirring reaction 2.5h revolves to steam and removes tetrahydrofuran (THF); obtain sawing horse ruthenium compound, namely doube bridge connects two (methyl-sulphoxide) two rutheniums of paratolunitrile four carbonyls.
Above-mentioned product doube bridge is connected two (methyl-sulphoxide) two rutheniums of paratolunitrile four carbonyls utilize 400MNMR nuclear magnetic resonance spectrometer and the analysis of Avatar360E.S.P.FT-IR type Fourier transformation infrared spectrometer to measure 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 the bridging carboxylic acid OCO symmetrical with asymmetric vibration absorption peak be 1577s, 1533m.
By Fig. 2 and Fig. 3 as can be known, measurement result is
1H NMR (400MHz, CDCl
3): δ (ppm) 7.71 (s, 1H), 7.25 (s, 1H), 6.91 (s, 1H), 3.74 (s, 3H), 2.03 (s, 3H).
13C NMR(400MHz, CDCl
3) δ (ppm) 204.97 (CO), 184.48 (COO), 138.62,130.45,120.32 (Imidazole C), 29.68 (N-CH
3), 23.77 (CO
2-CH
3).
This shows, embodiment 1 gained end product is that doube bridge connects two (methyl-sulphoxide) two rutheniums of paratolunitrile four carbonyls.
Embodiment 2
The general structure of the saw horse ruthenium compound of the present embodiment is the formula I, R in the formula I
1Be C
6H
5-X, X are p-CH
3-, R
2Be methyl-sulphoxide, i.e. DMSO.
The preparation method of above-mentioned saw horse ruthenium compound is comprised of following steps:
(1) with 0.20g Ru
3(CO)
12Dissolving extremely fully in being dissolved in toluene with 0.689g compound 1 under nitrogen protection, Ru
3(CO)
12With the mol ratio of compound 1 be 1:3, be heated to 110 ℃ of backflow 8h, it is complete that thin-layer chromatography tracks to raw material consumption, revolves to steam to remove toluene, obtains intermediate A, structural formula is the formula II.
(2) under nitrogen protection, intermediate A is dissolved in tetrahydrofuran (THF) fully, is heated to 65 ℃ of backflow 1h, be cooled to 25 ℃; add 106 μ l methyl-sulphoxides, the mol ratio of intermediate A and methyl-sulphoxide is 1:1.5, stirring reaction 3h; revolve to steam and remove tetrahydrofuran (THF), obtain sawing horse ruthenium compound.
Embodiment 3
The general structure of the saw horse ruthenium compound of the present embodiment is the formula I, R in the formula I
1Be C
6H
5-X, X are p-CH
3-, R
2Be methyl-sulphoxide, i.e. DMSO.
The preparation method of above-mentioned saw horse ruthenium compound is comprised of following steps:
(1) with 0.20g Ru
3(CO)
12Dissolving extremely fully in being dissolved in toluene with 0.918g compound 1 under nitrogen protection, Ru
3(CO)
12With the mol ratio of compound 1 be 1:4, be heated to 110 ℃ of backflow 12h, it is complete that thin-layer chromatography tracks to raw material consumption, revolves to steam to remove toluene, obtains intermediate A, structural formula is the formula II.
(2) under nitrogen protection, intermediate A is dissolved in tetrahydrofuran (THF), is heated to 65 ℃ of backflow 3h, be cooled to 50 ℃; add 213 μ l methyl-sulphoxides, the mol ratio of intermediate A and methyl-sulphoxide is 1:3, stirring reaction 2h; revolve to steam and remove tetrahydrofuran (THF), obtain sawing horse ruthenium compound.
Embodiment 4
In the step of above-described embodiment 1～3 (1), organic solvent 1 toluene used can be replaced with the tetrahydrofuran (THF) of equivalent, is heated to 65 ℃ of backflow 8h, and other operation is identical with corresponding embodiment, obtains intermediate A, and structural formula is the formula II; In step (2), organic solvent 2 used can be replaced with the acetonitrile of equivalent, is heated to 82 ℃ of backflow 2.5h, and other step is identical with corresponding embodiment, obtains sawing horse ruthenium compound.
Embodiment 5
Substituent R in the formula I of above-described embodiment 1～4
1Be C
6H
5-X, X can be also F, Cl, Br, I, nitro, hydroxyl, methoxyl group, amino, sulfonic group, to the tertiary butyl, 4-(tert-butoxycarbonyl), 3,5-dinitrobenzene, CH
3CO
2, 2-hydroxyl-5-sulfo group, 3,4, in 5-trihydroxy-, propenyl, 5-amino-2-hydroxyl any 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 molecular formula of step (1) is R
1CO
2, R wherein
1Correspond to C
6H
5-X, X correspond to F, Cl, Br, I, nitro, hydroxyl, methoxyl group, amino, sulfonic group, to the tertiary butyl, 4-(tert-butoxycarbonyl), 3,5-dinitrobenzene, CH
3CO
2, 2-hydroxyl-5-sulfo group, 3,4,5-trihydroxy-, propenyl or 5-amino-2-hydroxyl, other step is identical with corresponding embodiment.
Embodiment 6
Substituent R in the formula I of above-described embodiment 1～5
1Be H-, CH
3-, trifluoromethyl, trichloromethyl, CH
3CH (OH)-, G-OOCH
2CH
2-, any one in HOOC-, oligomerization, poly ethylene glycol, polysaccharide, acetyl aminophenol, 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 molecular formula of step (1) is R
1CO
2, R wherein
1Correspond to H-, CH
3-, trifluoromethyl, trichloromethyl, CH
3CH (OH)-, G-OOCH
2CH
2-, HOOC-, oligomerization, poly ethylene glycol, polysaccharide, acetyl aminophenol or amantadine, other step is identical with corresponding embodiment.
Embodiment 7
Substituent R in the formula I of above-described embodiment 1～6
1Be CH
3(CH
2) n-, n is any one positive integer of 1～18.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 molecular formula of step (1) is R
1CO
2, R wherein
1Correspond to CH
3(CH
2) n-, n corresponds to 1～18 positive integer, and other step is identical with corresponding embodiment.
Substituent R in the formula I of above-described embodiment 1～7
2DMSO can replace with the heteroatom ligand of nitrogen, can be specifically in pyridine, 1-Methylimidazole, imidazoles, aniline, glycine, glycine methyl ester hydrochloride, amino acid, amino acid ester, nitrile, 2 thiophene ethyl amine, thiophene-2-methylamine any 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 2 corresponds in carbon monoxide, pyridine, 1-Methylimidazole, imidazoles, aniline, glycine, glycine methyl ester hydrochloride, amino acid, amino acid ester, nitrile, 2 thiophene ethyl amine, thiophene-2-methylamine any one in step (2).Other step is identical with corresponding embodiment.
Embodiment 9
Substituent R in the formula I of above-described embodiment 8
2Can replace with the heteroatom ligand of phosphine or the heteroatom ligand of oxygen or other heteroatom ligands of sulphur, other substituting group is identical with corresponding embodiment.
The heteroatom ligand of above-mentioned phosphine is triphenylphosphine, diphenylphosphine, three (2-thienyl) phosphine, three (2, the 4-3,5-dimethylphenyl) phosphuret-(t)ed hydrogen-5,5', 5 " in trisulfonic acid trisodium salt, three (2; 4,6-trimethoxyphenyl) phosphine, three sulfonate sodiums of triphenylphosphine, o-tolidine any one;
The heteroatom ligand of above-mentioned oxygen be in ether, ethanol, tetrahydrofuran (THF), 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, the 4-3,5-dimethylphenyl) phosphuret-(t)ed hydrogen-5,5', 5 " in trisulfonic acid trisodium salt, three (2; 4,6-trimethoxyphenyl) phosphine, three sulfonate sodiums of triphenylphosphine, o-tolidine in any one or ether, ethanol, tetrahydrofuran (THF), furans in any one or hydrogen sulfide, thiophene, ethylphenyl sulphur any one.Other step is identical with corresponding embodiment.
Substituent R in the formula I of above-described embodiment 1～7
2Can be with in carbon monoxide, sugar, polyoxyethylene glycol, quaternary ammonium salt, amino acid, amino acid ester, N-heterocyclic carbine, choline, any one to be replaced, other substituting 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 in tetramethyl ammonium chloride, tetraethylammonium bromide, benzyl tributyl brometo de amonio, benzyl triethyl ammonium bromide, benzyltrimethylammonium bromide, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, tetradecyl trimethyl ammonium chloride, octadecyl trimethyl ammonium chloride, 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, glucose, sucrose, starch, any one or polyoxyethylene glycol or tetramethyl ammonium chloride in lactose, tetraethylammonium bromide, benzyl tributyl brometo de amonio, benzyl triethyl ammonium bromide, benzyltrimethylammonium bromide, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, tetradecyl trimethyl ammonium chloride, octadecyl trimethyl ammonium chloride, the cetyldimethylethylambromide bromide ammonium, in decyl trimethyl ammonium chloride, any one or amino acid or amino acid ester or phenodiazine imidazoles Cabbeen or three nitrogen imidazoles Cabbeens or choline are replaced, other step is identical with corresponding embodiment.
Embodiment 11
Substituent R in the formula I of above-described embodiment 1～7
2Can replace with polypeptide, can pass through with dipeptides, cytolemma adhesin polypeptide (RGD), cell namely that in peptide (CPP), Mitochondrially targeted peptide (MPP), thymopeptide-5, any one is replaced, other substituting group is identical with corresponding embodiment.
The structural formula of above-mentioned dipeptides is NH
2-GlyGlyOH.
The structural formula of above-mentioned RGD is NH
2-Thr-Arg-Gly-Asp-Leu-Lys-H.
The structural formula of above-mentioned CPP is NH
2-Thr-Phe-Ser-Asp-Leu-Lys-H.
The structural formula of above-mentioned MPP is NH
2-Phe-Arg-Phe-Lys-Lys-H.
In the preparation method of above-mentioned formula I, compound 2 correspondences of step (2) can pass through with dipeptides, cytolemma adhesin polypeptide (RGD), cell that in peptide (CPP), Mitochondrially targeted peptide (MPP), thymopeptide-5, any one is replaced, and other step is identical with corresponding embodiment.
Embodiment 12
The substituent R of above-described embodiment 10 Chinese style I
2During for carbon monoxide; step (2) can be intermediate A to be dissolved in organic solvent 2 under nitrogen protection; reflux, cooling, pass into CO (carbon monoxide converter) gas; stirring reaction; revolve and steam remove portion organic solvent 2, then pass into the CO air-flow, remove the residue acetonitrile; 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 testing horse cardiac muscle Lactoferrin (buying from Shanghai Sigma Ritchie difficult to understand trade Co., Ltd) system, take the prepared saw horse ruthenium compound (following abbreviation product 1) of embodiment 1 as example, specific as follows:
The ultraviolet spectrophotometry that is converted into 540nm and the hyp carbonyl myoglobin of 575nm (Mb-CO) by the deoxidation flesh red eggs (deoxy-Mb) of measuring the 580nm absorption is estimated.Mb-CO is used for weighing in the change in concentration at 540nm place the amount that CO discharges.
Myohaemoglobin solution is that 10mg albumen is dissolved in 10ml, and the phosphate buffer solution of 0.01M (pH=7.4) is fresh is prepared into the solution that concentration is 66 μ M.Added wherein V-Brite B (0.1%) to make albumen be converted into the deoxidation myohaemoglobin before each different concns protein determination.
Product 1 is dissolved in methyl-sulphoxide (DMSO), join the phosphate buffer solution (0.01M of the above-mentioned myohaemoglobin for preparing of 1ml (66 μ M), PH=7.4) in, discharge three kinds of different concentration of molecular testing for every kind, namely be respectively 60 μ M, 40 μ M and 20 μ M, the simulation physiological condition is within the different time (30,60,90min) with uv irradiating within the different time (5,15,25,35,45,55,65,75,85,95 and 100min) be converted into the change in concentration of Mb-CO with spectrophotometer test deoxy-Mb.Nd the results are shown in Table 1 for not detecting carbonyl myoglobin.
The change in concentration of table 1 carbonyl myoglobin
As can be seen from Table 1, all do not detect in 30～90 minutes under physiological condition and discharge CO, show that product 1 (37 ℃) under physiological condition is more stable, and under UV-irradiation saturated deoxidation myohaemoglobin within a certain period of time, and As time goes on, the concentration of carbonyl myoglobin (Mb-CO) increases gradually.
Above-mentioned experiment proves absolutely that saw horse ruthenium compound can be used as CO and discharges molecule, discharge endogenous CO under photoinduction, therefore, it can be applied to, and medical field is used for the treatment of or preventing disease, the below describes as an example of the 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 study, and is people's alveolar substrate epithelium gland cancer, easily cultivates culture condition PRMI-1640+10%CS, 5%CO
2, 37 ℃.
(2) lung cancer tumor cell activity test
Above-mentioned cell is inoculated in 96 well culture plates by 1 * 104/hole (200 μ l), treat that cell grows to 70～80%, add the product 1 of different concns (0,50,100,200,300,400,500 μ mol/L) to discharge molecule, continue to cultivate after 24 hours, it is 5mg/ml that every hole adds tetrazolium salts (MTT) solution 20 μ l(concentration); 37 ℃ are continued to hatch 4h, to guarantee tetrazolium salts fully by viable cell metabolism cracking, stop cultivating, and careful the suction abandoned supernatant liquor in the hole; Every hole adds the dimethyl sulfoxide (DMSO) (DMSO) of 150 μ l, concussion 10min; Select the 490nm wavelength, measure each hole absorbancy on enzyme-linked immunosorbent assay instrument; Result is with (x ± s) the expression of each group 6 hole OD means standard deviation.CO represents (inhibition ratio, IR) to the inhibited proliferation of cell with inhibiting rate, calculates respectively and respectively organizes inhibiting rate.Inhibiting rate (%)=(control group OD value-experimental group OD value)/control group OD value * 100%, take concentration/time as transverse axis, inhibiting rate is the longitudinal axis, curve plotting is seen Fig. 4.
As shown in Figure 4, when the release molecular conecentration that adds increased gradually, the lung carcinoma cell inhibiting rate also increased gradually, and the required release molecular conecentration of best inhibition of cancer cell rate is 100 μ g/ml.
Claims (7)
1. saw horse ruthenium compound for one kind, its general structure is:
In the formula I: R
1Be H-, CH
3-, CH
3(CH
2) n-, trifluoromethyl, trichloromethyl, C
6H
5-X, CH
3CH (OH)-, G-OOCH
2CH
2-, any one in HOOC-, oligomerization, poly ethylene glycol, polysaccharide, acetyl aminophenol, amantadine;
N is 1～18 positive integer;
X is halogen, nitro, hydroxyl, methyl, methoxyl group, amino, sulfonic group, to the tertiary butyl, 4-(tert-butoxycarbonyl), 3,5-dinitrobenzene, CH
3CO
2, 2-hydroxyl-5-sulfo group, 3,4, any one in 5-trihydroxy-, propenyl, 5-amino-2-hydroxyl;
R
2Be the heteroatom ligand of nitrogen, phosphine, oxygen, sulphur, or in carbon monoxide, sugar, polyoxyethylene glycol, quaternary ammonium salt, amino acid, amino acid ester, N-heterocyclic carbine, polypeptide, choline any one.
2. saw horse ruthenium compound according to claim 1 is characterized in that: the heteroatom ligand of described nitrogen be in pyridine, 1-Methylimidazole, imidazoles, aniline, glycine, glycine methyl ester hydrochloride, amino acid, amino acid ester, nitrile, 2 thiophene ethyl amine, thiophene-2-methylamine any one;
The heteroatom ligand of described phosphine is triphenylphosphine, diphenylphosphine, three (2-thienyl) phosphine, three (2, the 4-3,5-dimethylphenyl) phosphuret-(t)ed hydrogen-5,5', 5 " in trisulfonic acid trisodium salt, three (2; 4,6-trimethoxyphenyl) phosphine, three sulfonate sodiums of triphenylphosphine, o-tolidine any one;
The heteroatom ligand of described oxygen be in ether, ethanol, tetrahydrofuran (THF), furans any one;
The heteroatom ligand of described sulphur be in hydrogen sulfide, methyl-sulphoxide, thiophene, ethylphenyl sulphur any one.
3. saw horse ruthenium compound according to claim 1, it is characterized in that: described nitrogen heterocycle carbine ligand is phenodiazine imidazoles Cabbeen or three nitrogen imidazoles Cabbeens;
Described sugar be in glucose, sucrose, starch, lactose any one;
Described quaternary ammonium salt be in tetramethyl ammonium chloride, tetraethylammonium bromide, benzyl tributyl brometo de amonio, benzyl triethyl ammonium bromide, benzyltrimethylammonium bromide, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, tetradecyl trimethyl ammonium chloride, octadecyl trimethyl ammonium chloride, cetyldimethylethylambromide bromide ammonium, decyl trimethyl ammonium chloride any one;
Described polypeptide is that dipeptides, cytolemma adhesin polypeptide, cell pass through in peptide, Mitochondrially targeted peptide, thymopeptide-5 any one.
4. the preparation method of a saw claimed in claim 1 horse ruthenium compound is characterized in that comprising the following steps:
(1) with Ru
3(CO)
12Be dissolved under nitrogen protection with compound 1 in organic solvent 1 to dissolving fully, Ru
3(CO)
12With the mol ratio of compound 1 be 1:3～4, reflux 8～12h, it is complete that thin-layer chromatography tracks to raw material consumption, revolves to steam to remove organic solvent 1, obtains intermediate A;
(2) under nitrogen protection, intermediate A is dissolved in organic solvent 2, reflux 1～3h is cooled to 25～50 ℃, add compound 2, the mol ratio of intermediate A and compound 2 is 1:1.5～3, stirring reaction 2～3h, revolve to steam and remove organic solvent 2, obtain sawing horse ruthenium compound;
Above-mentioned organic solvent 1 is toluene or tetrahydrofuran (THF);
Above-mentioned organic solvent 2 is tetrahydrofuran (THF) or acetonitrile;
The molecular formula of above-claimed cpd 1 is R
1CO
2, R wherein
1Be H-, CH
3-, CH
3(CH
2) n-, trifluoromethyl, trichloromethyl, C
6H
5-X, CH
3CH (OH)-, G-OOCH
2CH
2-, any one in HOOC-, oligomerization, poly ethylene glycol, polysaccharide, acetyl aminophenol, amantadine;
N is 1～18 positive integer,
X is halogen, nitro, hydroxyl, methyl, methoxyl group, amino, sulfonic group, to the tertiary butyl, 4-(tert-butoxycarbonyl), 3,5-dinitrobenzene, CH
3CO
2, 2-hydroxyl-5-sulfo group, 3,4, in 5-trihydroxy-, propenyl, 5-amino-2-hydroxyl any one;
Compound 2 is the heteroatom ligand of nitrogen, phosphine, oxygen, sulphur, be perhaps in carbon monoxide, sugar, polyoxyethylene glycol, quaternary ammonium salt, amino acid, amino acid ester, N-heterocyclic carbine, polypeptide, choline any one.
5. the preparation method of saw according to claim 4 horse ruthenium compound is characterized in that: the heteroatom ligand of described nitrogen be in pyridine, 1-Methylimidazole, imidazoles, aniline, glycine, glycine methyl ester hydrochloride, amino acid, amino acid ester, nitrile, 2 thiophene ethyl amine, thiophene-2-methylamine any one;
The heteroatom ligand of described phosphine is triphenylphosphine, diphenylphosphine, three (2-thienyl) phosphine, three (2, the 4-3,5-dimethylphenyl) phosphuret-(t)ed hydrogen-5,5', 5 " in trisulfonic acid trisodium salt, three (2; 4,6-trimethoxyphenyl) phosphine, three sulfonate sodiums of triphenylphosphine, o-tolidine any one;
The heteroatom ligand of described oxygen be in ether, ethanol, tetrahydrofuran (THF), furans any one;
The heteroatom ligand of described sulphur be in hydrogen sulfide, methyl-sulphoxide, thiophene, ethylphenyl sulphur any one.
6. the preparation method of saw according to claim 4 horse ruthenium compound, it is characterized in that: described nitrogen heterocycle carbine ligand is phenodiazine imidazoles Cabbeen or three nitrogen imidazoles Cabbeens;
Described sugar be in glucose, sucrose, starch, lactose any one;
Described quaternary ammonium salt be in tetramethyl ammonium chloride, tetraethylammonium bromide, benzyl tributyl brometo de amonio, benzyl triethyl ammonium bromide, benzyltrimethylammonium bromide, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, tetradecyl trimethyl ammonium chloride, octadecyl trimethyl ammonium chloride, cetyldimethylethylambromide bromide ammonium, decyl trimethyl ammonium chloride any one;
Described polypeptide is that dipeptides, cytolemma adhesin polypeptide, cell pass through in peptide, Mitochondrially targeted peptide, thymopeptide-5 any one.
7. the preparation method of saw horse ruthenium compound according to claim 4, is characterized in that: described R
2Be carbon monoxide; step (2) is intermediate A to be dissolved in organic solvent 2 under nitrogen protection; reflux 1～2h; be cooled to 25～50 ℃, add carbon monoxide, the mol ratio of intermediate A and carbon monoxide is 1:1.5～3; stirring reaction 2～3h; revolve and steam remove portion organic solvent 2, get rid of with the CO air-flow, obtain sawing horse ruthenium compound.
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Cited By (5)
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| CN103920456A (en) * | 2014-03-25 | 2014-07-16 | 陕西师范大学 | Natural clay based carbon monoxide release material and preparation method thereof |
| CN104892724A (en) * | 2015-05-14 | 2015-09-09 | 陕西师范大学 | Dipeptide small molecule modified N-doped stable Fischer carbene compound and preparation method and application thereof |
| CN105801626A (en) * | 2016-03-22 | 2016-07-27 | 陕西师范大学 | Water-soluble pegylation Fischer carbene complex and preparation method thereof |
| CN106902355A (en) * | 2017-02-28 | 2017-06-30 | 陕西师范大学 | A kind of water-soluble polyethylene glycol carboxylate spanning saw horse ruthenium carbonyl compound and preparation method thereof |
| CN115160380A (en) * | 2022-08-17 | 2022-10-11 | 西安交通大学医学院第一附属医院 | Compound capable of controlling CO release rate and preparation method thereof |
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| CN103920456A (en) * | 2014-03-25 | 2014-07-16 | 陕西师范大学 | Natural clay based carbon monoxide release material and preparation method thereof |
| CN103920456B (en) * | 2014-03-25 | 2015-12-30 | 陕西师范大学 | Based on the carbon monoxide releasable material and preparation method thereof of natural clay |
| CN104892724A (en) * | 2015-05-14 | 2015-09-09 | 陕西师范大学 | Dipeptide small molecule modified N-doped stable Fischer carbene compound and preparation method and application thereof |
| CN105801626A (en) * | 2016-03-22 | 2016-07-27 | 陕西师范大学 | Water-soluble pegylation Fischer carbene complex and preparation method thereof |
| CN105801626B (en) * | 2016-03-22 | 2018-03-06 | 陕西师范大学 | A kind of water soluble pegylation Fischer carbene compounds and preparation method thereof |
| CN106902355A (en) * | 2017-02-28 | 2017-06-30 | 陕西师范大学 | A kind of water-soluble polyethylene glycol carboxylate spanning saw horse ruthenium carbonyl compound and preparation method thereof |
| CN106902355B (en) * | 2017-02-28 | 2020-05-29 | 陕西师范大学 | Water-soluble polyethylene glycol carboxylate bridged saw horse ruthenium carbonyl compound and preparation method thereof |
| CN115160380A (en) * | 2022-08-17 | 2022-10-11 | 西安交通大学医学院第一附属医院 | Compound capable of controlling CO release rate and preparation method thereof |
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