CN105801626B - A kind of water soluble pegylation Fischer carbene compounds and preparation method thereof - Google Patents
A kind of water soluble pegylation Fischer carbene compounds and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
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- -1 glycol monomethyl ether amino acid ester hydrochlorides Chemical class 0.000 claims abstract description 8
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- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
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- HAUXSVQKDKQHTF-UHFFFAOYSA-N carbon monoxide;chromium Chemical compound [Cr].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] HAUXSVQKDKQHTF-UHFFFAOYSA-N 0.000 description 3
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- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
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- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
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- FQNHWXHRAUXLFU-UHFFFAOYSA-N carbon monoxide;tungsten Chemical class [W].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] FQNHWXHRAUXLFU-UHFFFAOYSA-N 0.000 description 2
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
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- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
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- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VOLMSPGWNYJHQQ-UHFFFAOYSA-N Pyranone Natural products CC1=C(O)C(=O)C(O)CO1 VOLMSPGWNYJHQQ-UHFFFAOYSA-N 0.000 description 1
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- 239000011651 chromium Substances 0.000 description 1
- 238000011278 co-treatment Methods 0.000 description 1
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 1
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
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- SVMGVNXXUVNGRK-UHFFFAOYSA-N oxomethylideneiron Chemical group O=C=[Fe] SVMGVNXXUVNGRK-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of water soluble pegylation Fischer carbene compounds, the structural formula of the compound isIn formula M represent Cr or Mo, R represent H,
Description
Technical field
The invention belongs to synthesize pharmaceutical technology field, and in particular to a kind of water soluble pegylation Fischer Cabbeens
Compound and preparation method thereof.
Background technology
CO is referred to as " noiseless killer " by people always, but with small-sized messenger molecule NO and H2S development, people gradually recognize
It is also a kind of important messenger molecule in human body to know CO, has cardiovascular diastole, suppression malignant cell proliferation, protection ischemic
Many therapeutic efficiencies such as reperfusion injury, anti-inflammatory, antibacterial；But CO have dissolved in water it is small, in vivo easily with hemoglobin knot
Conjunction, difficult quantitative transmission etc. limit to.Transition metal carbonyl compound class carbon monoxide-releasing molecules (CO Releasing
Molecules, CO-RMs) although solving the limitation in transmission, due to the strong-hydrophobicity of coordinated carbonyl, most of transition gold
The water solubility for belonging to carbonyls is all bad, it is difficult to for the biosystem using water as medium.
Three carbonyl glycine ruthenic chlorides (II) (CORM-3) are the water-soluble carbon monoxide-releasing molecules synthesized earliest, stable
Property it is good, CO can be sustained, can relax ischemia reperfusion injury, inhibition nf allograft rejection, suppress macrophage
Cell NO is generated, and weakens neuritis that cardiovascular inflammation and haemoglutinin induce etc..CORM-3 discharges half-life period for 98 in pure water
Hour, the half-life period that CO is discharged in physiological environment drops to 20.4 minutes, and half-life period drops to 3.6 points in human plasma
Clock, therefore can not roundabout hemoglobin progress sustained release CO treatments in vivo using CORM-3.
Lynam and Fairlamb groups find that series natural amino acid pyranone can be used as electron part and cyclopentadiene
Base carbonyl iron unit is coordinated, and forms water-soluble carbonyls, but by doing lactic dehydrogenase cell toxicant to such compound
Property test find (IC50=71 μM) its have stronger cytotoxicity (Dalton Trans, in September, 2007, the 33rd phase 3603~
Page 3605).
Man groups have successfully synthesized serial carbonyl by introducing water miscible carboxylic acid functional and have discharged molecule [Mn suddenly
(CO)4(η2-S2CNMeCH2CO2H)], the carbon monoxide of per molecule release molecule releasable three molecule altogether, passes through RAW264.7
Macrophage toxicity test shows that the toxicity of compound is small, can suppress the generation of lipopolysaccharide-induced nitrite, but such
The half-life period of release molecule only has 0.8 minute (Dalton Trans, 2011, volume 40 page 4230~4235).
Ford groups increase substantially this tungsten carbonyl using tungsten carbonyl as release molecular precursor using classic water-soluble phosphorus part
Water solubility, CO release experiments show, if placed it in dark surrounds, can a period of time stable in the air, use
The light of 300~370nm scopes excites, and such compound meeting photodissociation discharges CO, but this part is not easy to derive, and can only synthesize one
Discharge molecule (Inorg.Chem, 2010, volume 49 page 1180~1185).
The content of the invention
The shortcomings that technical problems to be solved by the invention are to overcome existing metal carbonyl to exist, there is provided a kind of
Thermostabilization is preferable, toxicity is relatively low and has preferably water-soluble and biocompatibility, can realize the water-soluble of sustained release carbon monoxide
Property Pegylation Fischer carbene compounds, and the preparation method of the compound.
Technical scheme is the Fischer Cabbeens of water-soluble polyethylene glycol modification used by solution above-mentioned technical problem
The structural formula of compound is as follows：
In formula M represent Cr or Mo, R represent H-,In
Any one, n be 1~3 integer.
Preferably R of the invention represents H-.
The present invention further preferably R is representedN is 2.
The preparation method of above-mentioned water soluble pegylation Fischer carbene compounds is as follows：
In anhydrous and oxygen-free, N2Under protective condition, using methanol as solvent, by shown in the Fischer Cabbeens shown in formula 1 and formula 2
Poly glycol monomethyl ether amino acid ester hydrochlorides, triethylamine in molar ratio be 1:1:1, reaction is stirred at room temperature 4~6 hours, post
Chromatographic isolation, obtains water soluble pegylation Fischer carbene compounds, and specific reaction equation is as follows：
Beneficial effects of the present invention are as follows：
1st, the present invention is modified Fischer Cabbeens by polyethylene glycol, and the heat for not only increasing Fischer Cabbeens is steady
Qualitative, biocompatibility, reduces the toxicity of molecule, and substantially increases the water solubility of molecule.
2nd, synthetic method of the present invention is simple and easy to get, and gained Pegylation Fischer carbene compounds can delay in aqueous phase
CO is released, carbon monoxide molecule can be discharged rapidly under ultraviolet light, there is preferable response to light, for a water-soluble oxygen
Change carbon emissions molecule and open a new road.
3rd, the half-life period of Pegylation Fischer carbene compounds of the present invention is in more than 404s.
Brief description of the drawings
Fig. 1 is the mono-crystalline structures figure of Pegylation Fischer carbene compounds prepared by embodiment 2.
Fig. 2 is the carbon after Pegylation Fischer carbene compounds degraded prepared by embodiment 1~11 discharges 2 hours
Oxygen myoglobin concentration block diagram.
Fig. 3 is the Pegylation Fischer carbene compounds of the preparation of embodiment 1~11 under 365nm ultraviolet lights
Half-life period block diagram.
Fig. 4 be embodiment 1 prepare Pegylation Fischer carbene compounds under various concentrations to RAW264.7
The block diagram of inhibiting rate.
Embodiment
The present invention is described in more detail with reference to the accompanying drawings and examples, but protection scope of the present invention is not limited only to
These embodiments.
Embodiment 1
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
Weigh the Fischer Cabbeens and 265.6mg (1mmol) one of the pentacarbonyl chromium shown in 500.2mg (1mmol) formulas 1-1
Glycol monoethyl ether amino acid ester hydrochlorides are placed in Schlenk bottles, using vacuum line operating technology, in anhydrous and oxygen-free, N2
(99.999%) protection is lower adds methanol and 140 μ L (1mmol) triethylamines that 15mL is dried, and reaction 5 hours, post color is stirred at room temperature
Spectrum separation is (using the volume ratio of dichloromethane and petroleum ether as 3:1 mixed liquor is eluent), obtain the poly- second two of oily yellow
Refine Fischer carbene compounds (112.9mg, yield 64%), its reaction equation is as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：Vco=2056cm-1, 1928cm-1, 1748cm-1；1H NMR (400MHz, CDCl3)δ(ppm)：9.34 (s, 1H), 9.16-9.04 (m, 0.2H), 4.72 (s, 0.4H), 4.43
(s, 2H), 4.22 (s, 2H), 3.64 (s, 2H), 3.39 (s, 3H), 2.84 (s, 0.6H), 2.67 (s, 3H)；13C NMR
(400MHz, CDCl3)δ(ppm)：287.23,222.73,217.45,167.32,69.86,65.36,58.98,47.89,
36.91。
Embodiment 2
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
In embodiment 1, the equimolar monoethylene glycol list first of monoethylene glycol monomethyl ether glycine ester hydrochloride used
Ether phenyl alanine ester hydrochloride is replaced, and other steps are same as Example 1, obtain the Pegylation Fischer of yellow oily
Carbene compound (276mg, yield 62%), its reaction equation is as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：Vco=2056cm-1, 1927cm-1, 1744cm-1；1H NMR (400MHz, CDCl3)δ(ppm)：9.16 (s, 1H), 8.75 (s, 0.35H), 7.33 (s, 3H), 7.19 (s, 2H),
4.77 (s, 1H), 4.46-4.28 (m, 2H), 3.58 (d, 2H), 3.40 (s, 3H), 3.17 (d, 2H), 2.29 (s, 3H)；13C NMR
(101MHz, CDCl3)δ(ppm)：282.38,224.13,218.82,170.46,135.12,130.83,129.44,71.27,
66.72,61.62,60.32,40.60,36.95.
Products therefrom is dissolved in dichloromethane, and adds the n-hexane of 2.5 times of methylene chloride volume, at -21 DEG C
Place 3 days, obtain yellow needles Pegylation Fischer carbene compound crystal, its mono-crystalline structures is as shown in figure 1, belong to
Tetragonal system, P4 (1) space group, cell parameter
α=90 °, β=90 °, γ=90 °, unit cell volume areZ=4, crystal size be 0.14mm × 0.12mm ×
0.10mm。
Embodiment 3
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
In embodiment 1, the equimolar monoethylene glycol list first of monoethylene glycol monomethyl ether glycine ester hydrochloride used
Ether tyrosine ester hydrochloride is replaced, and other steps are same as Example 1, obtain the Pegylation Fischer cards of yellow oily
Guest's compound (103mg, yield 23%), its reaction equation is as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：Vco=2056cm-1, 1928cm-1, 1735cm-1；1H NMR (400MHz, CDCl3)δ(ppm)：9.14 (s, 1H), 7.02 (s, 2H), 6.82 (s, 2H), 6.51-5.74 (m,
2H), 4.70 (s, 1H), 4.09 (s, 2H), 3.86 (s, 3H), 3.08 (d, 2H), 2.32 (s, 3H)；13C NMR (101MHz,
CDCl3)δ(ppm)：285.04,222.78,217.44,171.61,155.82,130.66,125.76,116.00,69.87,
65.15,60.49,58.90,38.23,35.57.
Embodiment 4
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
In embodiment 1, the equimolar diethylene glycol list first of monoethylene glycol monomethyl ether glycine ester hydrochloride used
Ether glycine ester hydrochloride is replaced, and other steps are same as Example 1, obtain the Pegylation Fischer cards of yellow oily
Guest's compound (198mg, yield 48%), its reaction equation is as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：Vco=2056cm-1, 1927cm-1, 1747cm-1；1H NMR (400MHz, CDCl3)δ(ppm)：9.33 (s, 1H), 4.44 (s, 2H), 4.21 (s, 2H), 3.75 (s, 2H), 3.64
(d, 2H), 3.55 (s, 2H), 3.38 (s, 3H), 2.68 (s, 3H)；13C NMR (101MHz, CDCl3)δ(ppm)：218.88
73.27,71.94,70.03,60.49,49.35.
Embodiment 5
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
In embodiment 1, the equimolar diethylene glycol list first of monoethylene glycol monomethyl ether glycine ester hydrochloride used
Ether phenyl alanine ester hydrochloride is replaced, and other steps are same as Example 1, obtain the Pegylation Fischer of yellow oily
Carbene compound compound, its reaction equation are as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：Vco=2056cm-1, 1927cm-1, 1748cm-1；1H NMR (400MHz, CDCl3)δ(ppm)：9.23 (s, 1H), 7.33 (s, 3H), 7.19 (s, 2H), 4.76 (s, 1H), 4.41
(s, 2H), 3.74 (s, 2H), 3.65 (s, 2H), 3.56 (s, 2H), 3.38 (s, 3H), 3.30-3.08 (m, 2H), 3.17-2.99
(m, 1H), 2.27 (s, 3H)；13C NMR (101MHz, CDCl3)δ(ppm)：286.99,224.14,218.84,170.41,
135.57,130.85,130.64,128.57,71.92,70.00,66.78,61.67,60.49,40.60,36.94.
Embodiment 6
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
In embodiment 1, the equimolar diethylene glycol list first of monoethylene glycol monomethyl ether glycine ester hydrochloride used
Ether tyrosine ester hydrochloride is replaced, and other steps are same as Example 1, obtain the Pegylation Fischer cards of yellow oily
Guest's compound (76mg, yield 30%), its reaction equation is as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：Vco=2056cm-1, 1927cm-1, 1745cm-1；1H NMR (400MHz, CDCl3)δ(ppm)：9.13 (s, 1H), 7.02 (d, 2H), 6.81 (d, 2H), 4.70 (d, 1H), 4.12
(d, 2H), 3.85 (s, 3H), 3.22-3.00 (m, 2H), 3.00 (dd, 2H), 2.32 (s, 3H), 2.04 (s, 2H)；13C NMR
(101MHz, CDCl3)δ(ppm)：286.87,224.14,218.85,170.99,157.09,132.01,127.26,117.56,
61.99,61.78,54.64,39.86,36.99,22.47,15.57.
Embodiment 7
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
In embodiment 1, the equimolar monoethylene glycol list first of monoethylene glycol monomethyl ether glycine ester hydrochloride used
Ether leucine ester hydrochloride is replaced, and other steps are same as Example 1, obtain the Pegylation Fischer cards of yellow oily
Guest's compound (139mg, yield 31%), its reaction equation is as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：Vco=2056cm-1, 1927cm-1, 1742cm-1；1H NMR (400MHz, CDCl3)δ(ppm)：9.07 (s, 1H), 4.57 (d, 1H), 4.36 (ddd, 2H), 3.61 (s, 2H),
3.37 (s, 3H), 2.69 (s, 3H), 1.92-1.77 (m, 2H), 1.76-1.64 (m, 1H), 0.99 (dd, 6H)；13C NMR
(101MHz, CDCl3)δ(ppm)：224.14,218.96,171.07,71.32,66.40,60.30,59.62,43.05,
37.31,26.29,23.87,23.59,2.43.
Embodiment 8
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
In embodiment 1, the equimolar triethylene glycol list first of monoethylene glycol monomethyl ether glycine ester hydrochloride used
Ether phenyl alanine ester hydrochloride is replaced, and other steps are same as Example 1, obtain yellow oily Pegylation Fischer cards
Guest's compound (278mg, yield 53%), its reaction equation is as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：Vco=2056cm-1, 1927cm-1, 1747cm-1；1H NMR (400MHz, CDCl3)δ(ppm)：9.52 (s, 1H), 7.33 (d, 3H), 7.19 (d, 2H), 4.77 (s, 1H), 4.39
(s, 2H), 3.75 (s, 2H), 3.66 (s, 3H), 3.64 (s, 2H), 3.55 (s, 2H), 3.37 (s, 3H), 3.29 (d, 2H),
3.23-3.00 (m, 2H)；13CNMR (101MHz, CDCl3)δ(ppm)：282.21,224.25,218.90,170.40,135.76,
130.85,130.59,129.35,71.98,69.98,66.77,61.77,60.41,48.85,40.51,36.85.
Embodiment 9
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
In embodiment 1, the equimolar triethylene glycol list first of monoethylene glycol monomethyl ether glycine ester hydrochloride used
Ether glycine ester hydrochloride is replaced, and other steps are same as Example 1, obtain Pegylation Fischer carbene compounds
(247mg, yield 56%), its reaction equation is as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：2056cm-1, 1928cm-1, 1748cm-1；1H
NMR (400MHz, CDCl3)δ(ppm)：9.53 (s, 1H), 4.47-4.35 (m, 2H), 4.22 (d, 2H), 3.73 (dd, 2H),
3.67-3.59 (m, 6H), 3.54 (dd, 2H), 3.36 (s, 3H), 2.65 (s, 3H)；13C NMR (101MHz, CDCl3)δ(ppm)：
284.82,221.92,216.55,166.37,76.45,76.13,75.81,70.87,69.72-69.24,67.51,64.33,
57.90,46.97,35.70.
Embodiment 10
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
In embodiment 1, the Fischer cards of the equimolar pentacarbonyl molybdenum of the Fischer Cabbeens of pentacarbonyl chromium used
Guest replaces, and other steps are same as Example 1, obtain the Pegylation Fischer carbene compounds of claret oily
(243mg, yield 61%), its reaction equation is as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：Vco=2056cm-1, 1927cm-1, 1747cm-1；1H NMR (400MHz, CDCl3)δ(ppm)：9.15 (d, 1H), 4.66 (d, 2H), 4.43 (d, 2H), 3.73-3.56 (m,
2H), 3.40 (d, 3H), 2.82 (s, 3H)；13C NMR (101MHz, CDCl3)δ(ppm)：168.67,156.95,130.32,
124.21,115.49,69.63,64.81,57.70,54.02,35.15.
Embodiment 11
By taking the following Pegylation Fischer carbene compounds of preparation structure formula as an example：
In embodiment 1, the Fischer cards of the equimolar pentacarbonyl molybdenum of the Fischer Cabbeens of pentacarbonyl chromium used
Guest replaces, the equimolar diethylene glycol monomethyl ether glycinate hydrochloric acid of monoethylene glycol monomethyl ether glycine ester hydrochloride used
Salt is replaced, and other steps are same as Example 1, obtain the Pegylation Fischer carbene compounds of claret oily
(299mg, yield 68%), its reaction equation is as follows：
The structural characterization data of products therefrom are：IR(CH2Cl2, cm-1)：Vco=2056cm-1, 1931cm-1, 1748cm-1；1H NMR (400MHz, CDCl3)δ(ppm)：9.30 (s, 1H), 9.0 (s, 0.3H), 4.65 (d, 0.6H), 4.44 (dd, 2H),
4.18 (d, 2H), 3.80-3.72 (m, 2H), 3.65 (dd, 2H), 3.59-3.53 (m, 2H), 3.48 (s, 0.5H), 3.40-3.36
(m, 3H), 2.82 (s, 1H), 2.65 (s, 3H)；13C NMR (101MHz, CDCl3)δ(ppm)：279.67,214.46,207.89,
168.72,73.27,71.93,70.02,66.82,60.48,48.86,38.51.
In order to prove beneficial effects of the present invention, the Pegylation Fischer cards that inventor prepares to embodiment 1~11
Guest's compound (hereinafter referred to as determinand) has carried out various performance tests, and specific test case is as follows：
1st, water-soluble test
Using the water solubility of Determination of oil-water partition coefficient determination method test determinand, 1 the results are shown in Table.
1 water-soluble test result of table
| Determinand | Determinand is in n-octyl alcohol phase concentration | Determinand is in aqueous-phase concentration | LogD |
| Embodiment 1 | 2.4386 | 0.1026 | 1.38 |
| Embodiment 2 | 2.1109 | 0.0391 | 1.73 |
| Embodiment 3 | 1.9222 | 0.06648 | 1.46 |
| Embodiment 4 | 2.1461 | 0.09593 | 1.35 |
| Embodiment 5 | 1.8522 | 0.05198 | 1.55 |
| Embodiment 6 | 1.7352 | 0.06478 | 1.43 |
| Embodiment 7 | 2.229 | 0.05645 | 1.60 |
| Embodiment 8 | 1.554 | 0.08368 | 1.27 |
| Embodiment 9 | 1.8889 | 0.0968 | 1.29 |
| Embodiment 10 | 2.2308 | 0.0749 | 1.47 |
| Embodiment 11 | 1.9903 | 0.07158 | 1.44 |
From table 1, Pegylation of the present invention significantly improves the water solubility of Fischer carbene compounds.
2nd, CO release performances are tested
Weigh 5mg myoglobins to be added in 5mL volumetric flasks, then the phosphate buffer solution with 5mL pH=7.4 is abundant
Dissolving, is configured to myoglobin solution.1mL myoglobin solutions are drawn with liquid-transfering gun to add in cuvette, then add 25mg
Na2S2O4, at ambient temperature, use the ultraviolet-visible spectrophotometer myoglobins that is reduced of test wavelength for 500~
Ultra-violet absorption spectrum in the range of 600nm, CO gases are then passed through into the myoglobin solution being reduced until solution colour
Redden, it is the ultra-violet absorption spectrum in the range of 500~600nm to test it in wavelength.
1.3mg determinands are dissolved in 130 μ LDMSO, obtain mother liquor, then mother liquor is diluted with DMSO, is configured to 60
μm ol/L and 20 μm of ol/L determinand standard liquid.
(1) aqueous phase degraded CO releases
5 μ L60 μm ol/L determinand standard liquids and 1mL myoglobin solutions are added in cuvette, and add 25mg
Na2S2O4, it is well mixed, the sealing of 1 dropstone wax oil is added above cuvette, is then tested using ultraviolet-visible spectrophotometer
Wavelength is the ultra-violet absorption spectrum in the range of 500~600nm, and determinand stops test after not discharging CO, wherein degraded release 2 is small
When after carbonyl myoglobin concentration it is as shown in Figure 2.As seen from the figure, what prepared by the embodiment of the present invention 1,3,4,6,9,10,11 is poly-
PEGylation Fischer carbene compounds can discharge more CO in aqueous phase.
(2) 365nm photoinductions CO discharges
5 μ L20 μm ol/L determinand standard liquids and 1mL myoglobin solutions are added in cuvette, and add 25mg
Na2S2O4, it is well mixed, the sealing of 1 dropstone wax oil is added above cuvette, is then tested using ultraviolet-visible spectrophotometer
Wavelength is the ultra-violet absorption spectrum in the range of 500~600nm.Sweep test 5 times is (every time under conditions of initially not light stimulus
Sweep spacing 30s, 5 groups of data are surveyed every time), determinand has weak CO releases, then uses wavelength to exist for 365nm ultraviolet light
1s, determinand energy quick release CO are irradiated under 10% transmitance, after scanning 7 times, all compounds hardly discharge CO；Then
Wavelength is used to irradiate 5s under 100% transmitance for 365nm ultraviolet light, after scanning 2 times, there is no CO releases for determinand.
As seen from Figure 3, the half-life period maximum of Pegylation Fischer carbene compounds of the present invention can reach 1940s, and minimum can also reach
To 404s.
From the above experiments, it was found that Pegylation Fischer carbene compounds prepared by embodiment 1~11 are in aqueous phase
In slower release carbon monoxide, there are some even aqueous phases not discharge carbon monoxide.And the release under conditions of illumination quickly
Carbon monoxide, illustrate that Pegylation Fischer carbene compounds have extraordinary optical Response, and released with preferable CO
Put performance, the compound of each molecule discharges more CO.
3rd, cell toxicity test
Above-mentioned experiment absolutely proves that Pegylation Fischer carbene compounds can be used as CO release molecules, in aqueous phase
Or CO is discharged under photoinduction, therefore, it can apply to medical domain and is used to treat or prevent disease, huge with mouse monokaryon below
Exemplified by phagocyte leukaemia (RAW264.7), the Pegylation Fischer carbene compounds prepared using embodiment 1 are entered
Row experiment, specific experiment are as follows：
(1) cell is handled
RAW264.7 (DMEM) cell line frozen is taken, after 37 DEG C of quick-thawings, 1000 revs/min centrifuge 5 minutes, use
Culture medium cleans 1~2 time (because the material harmful to cell proliferation growth is added during freezing), with culture medium weight
Centrifuged again after outstanding, gained RAW264.7 cells add complete medium and cultivated, and change a subculture, observation cell life daily
Long situation, cover with rear standby.
(2) cell viability is tested
It is 5 × 10 that cell concentration is adjusted after RAW264.7 cells cover with4Cells/mL, 96 well culture plates are inoculated in, often
The μ L of hole 100, in 37 DEG C, 5%CO2Culture 24 hours in incubator.Then empirically packet adds various concentrations in 96 orifice plates
(0,50,100,200,300,400,500 μm of ol/L) Pegylation Fischer carbene compounds of gradient, per the μ L of hole 150,
Every group of three multiple holes, cultivate 2 hours.Then, the cell of the various concentrations of culture is used to 365nm UV illuminations respectively 20 minutes
Not illumination, and carry out MTT detections after opening in dark place 8 hours：15 μ L tetrazolium saltses (MTT) are added in every hole, in 37 DEG C, 5%CO2
Culture lucifuge is incubated 4 hours in incubator, the liquid to exhaust in hole, adds 200 μ L DMSO, and room temperature is shaken 10 minutes in shaking table,
Same time point OD values are measured in 492nm wavelength with ELIASA, the analysis of cell proliferative effect is carried out with the OD values measured.
From MTT results：IC under RAW264.7 cell illumination conditions50It is worth for 238.5 μm of ol/L, RAW264.7 cells
IC under the conditions of not illumination50It is worth for 152.3 μm of ol/L.CO is represented with inhibiting rate the inhibited proliferation of cell, is calculated respectively
Each group inhibiting rate：Inhibiting rate (%)=(control group OD values-experimental group OD values)/control group OD value × 100%, using concentration as horizontal stroke
Axle, inhibiting rate are the longitudinal axis, draw curve, as a result see Fig. 4.
Above-mentioned Fig. 4 experimental result is visible, and when the release molecular concentration of addition gradually increases, cell inhibitory rate is also gradual
Increase, and its inhibiting rate can reach 90.6% in the case of not illumination when concentration is 500 μm of ol/L.Illustrate the poly- second two of the present invention
Refine the water-soluble increase of Fischer carbene compounds, reduce its cytotoxicity.
Claims (4)
- A kind of 1. water soluble pegylation Fischer carbene compounds, it is characterised in that the following institute of structural formula of the compound Show：In formula M represent Cr or Mo, R represent H-,In it is any One kind, n are 1~3 integer.
- 2. water soluble pegylation Fischer carbene compounds according to claim 1, it is characterised in that：Described R Represent H-.
- 3. water soluble pegylation Fischer carbene compounds according to claim 1, it is characterised in that：Described R RepresentN is 2.
- 4. the preparation method of the water soluble pegylation Fischer carbene compounds described in claim 1, it is characterised in that： In anhydrous and oxygen-free, N2Under protective condition, using methanol as solvent, by the poly- second two shown in the Fischer Cabbeens shown in formula 1 and formula 2 Alcohol monomethyl ether amino acid ester hydrochlorides, triethylamine are 1 in molar ratio:1:1, react at room temperature 4~6 hours, pillar layer separation, obtain Water soluble pegylation Fischer carbene compounds；Above-mentioned M represents Cr or Mo, R represent H-,In it is any One kind, n are 1~3 integer.
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