CN105801626A - Water-soluble pegylation Fischer carbene complex and preparation method thereof - Google Patents
Water-soluble pegylation Fischer carbene complex and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims description 12
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 title abstract 2
- 238000010668 complexation reaction Methods 0.000 title 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052750 molybdenum Inorganic materials 0.000 claims abstract description 6
- 229910052804 chromium Inorganic materials 0.000 claims abstract description 4
- -1 carbene compound Chemical class 0.000 claims description 49
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 15
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- 230000001681 protective effect Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims 1
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- 150000002148 esters Chemical class 0.000 abstract description 16
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- 238000006555 catalytic reaction Methods 0.000 abstract 1
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- 238000001308 synthesis method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
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- 238000012360 testing method Methods 0.000 description 14
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
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- 0 CC(NC(Cc1ccccc1)C(OCCOC)=O)=*(C)*CCOCCOC(C(*)Cc1ccccc1)=O Chemical compound CC(NC(Cc1ccccc1)C(OCCOC)=O)=*(C)*CCOCCOC(C(*)Cc1ccccc1)=O 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- 229910004878 Na2S2O4 Inorganic materials 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 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
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
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- 238000010586 diagram Methods 0.000 description 3
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- 229960005190 phenylalanine Drugs 0.000 description 3
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- 235000008729 phenylalanine Nutrition 0.000 description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 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
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- 229910052799 carbon Inorganic materials 0.000 description 2
- FQNHWXHRAUXLFU-UHFFFAOYSA-N carbon monoxide;tungsten Chemical group [W].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] FQNHWXHRAUXLFU-UHFFFAOYSA-N 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
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- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- YSTZOIZIUXECPH-UHFFFAOYSA-N 2-isocyanatoacetic acid Chemical compound OC(=O)CN=C=O YSTZOIZIUXECPH-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 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
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 108010018251 carboxymyoglobin Proteins 0.000 description 1
- 238000013043 cell viability test Methods 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 238000011278 co-treatment Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
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- 239000003480 eluent Substances 0.000 description 1
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- 238000007710 freezing Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
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- 239000004310 lactic acid Substances 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 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 water-soluble pegylation Fischer carbene complex. The structural formula of the complex can be seen in the description, wherein M represents Cr or Mo, R represents any one of H- and other three groups (please see the groups in the description), and n is an integer from 1 to 3. The complex is prepared from Fischer carbine and methoxypolyethylene glycol amino-acid ester hydrochloride under the catalysis of triethylamine at the room temperature, and the synthesis method is simple. Fischer carbine is modified by polyethylene glycol, and therefore the thermal stability and biological compatibility of Fischer carbine are improved, the toxicity of molecules is reduced, the water solubility of molecules is greatly improved, the combined complex can slowly release CO in a water phase, can rapidly release CO molecules under the irradiation of ultraviolet light and has good responsiveness to light, and a new road is developed for water-soluble CO molecule release.
Description
Technical field
The invention belongs to synthesize pharmaceutical technology field, be specifically related to a kind of water soluble pegylation Fischer Cabbeen
Compound and preparation method thereof.
Background technology
CO is referred to as " noiseless killer " by people always, but along with small-sized messenger molecule NO and H2The development of S, people gradually recognize
Know a kind of important messenger molecule in being also human body to CO, there is diastole cardiovascular, suppression malignant cell proliferation, protection ischemia
Reperfusion injury, anti-inflammatory, many therapeutic efficiencies such as antibacterial；But CO has to dissolve in water and little, internal easily ties with hemoglobin
Close, difficult quantitative transmission etc. is limited to.Transition metal carbonyl compound class carbon monoxide-releasing molecules (CO Releasing
Molecules, CO-RMs) although the limitation that solves in transmission, but due to the strong-hydrophobicity of coordinated carbonyl, most of transition gold
The water solublity belonging to carbonyl compound is the most bad, it is difficult to for the living things system with water as medium.
Three carbonyl glycine ruthenic chlorides (II) (CORM-3) are the water solublity carbon monoxide-releasing molecules synthesized the earliest, stable
Property is good, can relax ischemia reperfusion injury, inhibition nf allograft rejection with slow release CO, suppress huge and bite
Cell NO generates, and weakens cardiovascular inflammation and the neuritis etc. of haemoglutinin induction.It is 98 that CORM-3 discharges the half-life in pure water
Hour, the half-life discharging CO in physiological environment drops to 20.4 minutes, and in human plasma the half-life drop to 3.6 points
Clock, therefore uses CORM-3 roundabout hemoglobin cannot carry out sustained release profile in vivo test CO treatment.
Lynam and Fairlamb group finds that series natural aminoacid pyranone can be as to electron donor ligand and cyclopentadiene
Base carbonyl iron unit is coordinated, and forms water solublity carbonyl compound, but by this compounds is done lactic acid dehydrogenase cell toxicant
Property test find (IC50=71 μMs) its have stronger cytotoxicity (Dalton Trans, in JIUYUE, 2007, the 33rd phase 3603～
Page 3605).
Man group has successfully synthesized serial carbonyl by the water miscible carboxylic acid functional of introducing and has suddenly discharged molecule [Mn
(CO)4(η2-S2CNMeCH2CO2H)], the carbon monoxide of per molecule release the most releasable three molecules of molecule, passes through RAW264.7
Macrophage toxicity test shows that this toxicity of compound is little, can suppress the generation of lipopolysaccharide-induced nitrite, but such
The half-life of release molecule only has 0.8 minute (Dalton Trans, 2011, volume 40 page 4230～4235).
Ford group, with tungsten carbonyl for release molecular precursor, uses classic water-soluble phosphorus part to increase substantially this tungsten carbonyl
Water solublity, CO release experiment shows, if placing it in dark surrounds, can a period of time stable in the air, use
The light of 300～370nm scopes excites, and this compounds photodissociation can discharge CO, but this part is difficult to derive, and can only synthesize one
Release molecule (Inorg.Chem, 2010, volume 49 page 1180～1185).
Summary of the invention
The technical problem to be solved is the shortcoming overcoming existing metal carbonyl to exist, it is provided that a kind of
Thermally-stabilised preferably, toxicity is relatively low and has preferable water solublity and biocompatibility, be capable of the water-soluble of slow release carbon monoxide
Property Pegylation Fischer carbene compound, and the preparation method of this compound.
Solve the Fischer Cabbeen that above-mentioned technical problem be employed technical scheme comprise that this water-soluble polyethylene glycol is modified
The structural formula of compound is as follows:
In formula M represent Cr or Mo, R represent H-,In
Any one, n is the integer of 1～3.
The preferred R of the present invention represents H-.
The present invention further preferably R representsN is 2.
The preparation method of above-mentioned water soluble pegylation Fischer carbene compound is as follows:
At anhydrous and oxygen-free, N2Under protective condition, with methanol as solvent, shown in the Fischer Cabbeen shown in formula 1 and formula 2
Poly glycol monomethyl ether amino acid ester hydrochlorides, triethylamine be 1:1:1 in molar ratio, be stirred at room temperature reaction 4～6 hours, post
Chromatographic isolation, obtains water soluble pegylation Fischer carbene compound, and concrete reaction equation is as follows:
Beneficial effects of the present invention is as follows:
1, Fischer Cabbeen is modified by the present invention by Polyethylene Glycol, and the heat not only increasing Fischer Cabbeen is steady
Qualitative, biocompatibility, reduces the toxicity of molecule, and substantially increases the water solublity of molecule.
2, synthetic method of the present invention is simple and easy to get, and gained Pegylation Fischer carbene compound can delay in aqueous phase
Release CO, carbon monoxide molecule can be discharged rapidly under ultraviolet light irradiates, light be had preferable response, for water solublity one oxygen
Change carbon emissions molecule and open a new road.
3, the half-life of Pegylation Fischer carbene compound of the present invention is all at more than 404s.
Accompanying drawing explanation
Fig. 1 is the mono-crystalline structures figure of the Pegylation Fischer carbene compound of embodiment 2 preparation.
Fig. 2 is the carbon after Pegylation Fischer carbene compound degraded prepared by embodiment 1～11 discharges 2 hours
Oxygen myoglobin concentration block diagram.
Fig. 3 is that the Pegylation Fischer carbene compound of embodiment 1～11 preparation is under 365nm ultraviolet light irradiates
Half-life block diagram.
Fig. 4 be embodiment 1 preparation Pegylation Fischer carbene compound under variable concentrations to RAW264.7
The block diagram of suppression ratio.
Detailed description of the invention
The present invention is described in more detail with embodiment below in conjunction with the accompanying drawings, but protection scope of the present invention is not limited only to
These embodiments.
Embodiment 1
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
Weigh Fischer Cabbeen and the 265.6mg (1mmol) of the pentacarbonyl chromium shown in 500.2mg (1mmol) formula 1-1
Glycol monoethyl ether amino acid ester hydrochlorides is placed in Schlenk bottle, uses vacuum line operating technology, at 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 hour, post color are stirred at room temperature
Spectrum separates (mixed liquor with the volume ratio of dichloromethane and petroleum ether as 3:1 is as eluent), obtains the poly-second two of oily yellow
Alcoholization Fischer carbene compound (112.9mg, productivity 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
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
In embodiment 1, monoethylene glycol monomethyl ether glycine ester hydrochloride used is by equimolar monoethylene glycol list first
Ether phenyl alanine ester hydrochloride is replaced, and other step is same as in Example 1, obtains the Pegylation Fischer of yellow oily
Carbene compound (276mg, productivity 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 normal hexane of methylene chloride volume 2.5 times, transfer at-21 DEG C
Putting 3 days, obtain yellow needles Pegylation Fischer carbene compound crystal, its mono-crystalline structures is as it is shown in figure 1, just belong to
Prismatic crystal system, P4 (1) space group, cell parameter α
=90 °, β=90 °, γ=90 °, unit cell volume isZ=4, crystal size be 0.14mm × 0.12mm ×
0.10mm。
Embodiment 3
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
In embodiment 1, monoethylene glycol monomethyl ether glycine ester hydrochloride used is by equimolar monoethylene glycol list first
Ether tyrosine ester hydrochlorate is replaced, and other step is same as in Example 1, obtains the Pegylation Fischer card of yellow oily
Guest's compound (103mg, productivity 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
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
In embodiment 1, monoethylene glycol monomethyl ether glycine ester hydrochloride used is by equimolar diethylene glycol list first
Ether glycine ester hydrochloride is replaced, and other step is same as in Example 1, obtains the Pegylation Fischer card of yellow oily
Guest's compound (198mg, productivity 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
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
In embodiment 1, monoethylene glycol monomethyl ether glycine ester hydrochloride used is by equimolar diethylene glycol list first
Ether phenyl alanine ester hydrochloride is replaced, and other step is same as in Example 1, obtains the Pegylation Fischer of yellow oily
Carbene compound compound, its reaction equation is 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
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
In embodiment 1, monoethylene glycol monomethyl ether glycine ester hydrochloride used is by equimolar diethylene glycol list first
Ether tyrosine ester hydrochlorate is replaced, and other step is same as in Example 1, obtains the Pegylation Fischer card of yellow oily
Guest's compound (76mg, productivity 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
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
In embodiment 1, monoethylene glycol monomethyl ether glycine ester hydrochloride used is by equimolar monoethylene glycol list first
Ether leucine ester hydrochloride is replaced, and other step is same as in Example 1, obtains the Pegylation Fischer card of yellow oily
Guest's compound (139mg, productivity 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
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
In embodiment 1, monoethylene glycol monomethyl ether glycine ester hydrochloride used is by equimolar triethylene glycol list first
Ether phenyl alanine ester hydrochloride is replaced, and other step is same as in Example 1, obtains yellow oily Pegylation Fischer card
Guest's compound (278mg, productivity 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
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
In embodiment 1, monoethylene glycol monomethyl ether glycine ester hydrochloride used is by equimolar triethylene glycol list first
Ether glycine ester hydrochloride is replaced, and other step is same as in Example 1, obtains Pegylation Fischer carbene compound
(247mg, productivity 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
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
In embodiment 1, the Fischer Cabbeen of the pentacarbonyl chromium used Fischer card of equimolar pentacarbonyl molybdenum
Guest replaces, and other step is same as in Example 1, obtains the Pegylation Fischer carbene compound of claret oily
(243mg, productivity 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
As a example by preparing the Pegylation Fischer carbene compound that structural formula is following:
In embodiment 1, the Fischer Cabbeen of the pentacarbonyl chromium used Fischer card of equimolar pentacarbonyl molybdenum
Guest replaces, and monoethylene glycol monomethyl ether glycine ester hydrochloride used is with equimolar diethylene glycol monomethyl ether glycinate hydrochloric acid
Salt is replaced, and other step is same as in Example 1, obtains the Pegylation Fischer carbene compound of claret oily
(299mg, productivity 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 card that embodiment 1～11 is prepared by inventor
Guest's compound (hereinafter referred to as determinand) has carried out various performance test, and concrete test case is as follows:
1, water solublity test
Use the water solublity of Determination of oil-water partition coefficient algoscopy test determinand, the results are shown in Table 1.
Table 1 water solublity test result
| Determinand | Determinand is at n-octyl alcohol phase concentration | Determinand is at 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 solublity of Fischer carbene compound.
2, CO release performance test
Weigh 5mg Myoglobin and join in 5mL volumetric flask, then abundant with the phosphate buffer solution of 5mL pH=7.4
Dissolve, be configured to myoglobin solution.Draw 1mL myoglobin solution with liquid-transfering gun to add in cuvette, be subsequently adding 25mg
Na2S2O4, at ambient temperature, use the ultraviolet-visible spectrophotometer Myoglobin that is reduced of test wavelength be 500～
Ultra-violet absorption spectrum in the range of 600nm, is then passed through CO gas until solution colour in the myoglobin solution being reduced
Redden, test its ultra-violet absorption spectrum in the range of wavelength is 500～600nm.
1.3mg determinand is dissolved in 130 μ LDMSO, obtains mother solution, then mother solution DMSO is diluted, be configured to 60
The determinand standard solution of μm ol/L and 20 μm ol/L.
(1) aqueous phase degraded CO release
5 μ L60 μm ol/L determinand standard solution and 1mL myoglobin solution are joined in cuvette, and adds 25mg
Na2S2O4, mix homogeneously, add 1 dropstone wax oil above cuvette and seal, then use ultraviolet-visible spectrophotometer test to exist
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 little
Carbonyl myoglobin concentration time after is as shown in Figure 2.As seen from the figure, the embodiment of the present invention 1,3,4,6,9,10,11 preparation is poly-
PEGylation Fischer carbene compound all can discharge more CO in aqueous phase.
(2) 365nm photoinduction CO release
5 μ L20 μm ol/L determinand standard solution and 1mL myoglobin solution are joined in cuvette, and adds 25mg
Na2S2O4, mix homogeneously, add 1 dropstone wax oil above cuvette and seal, then use ultraviolet-visible spectrophotometer test to exist
Wavelength is the ultra-violet absorption spectrum in the range of 500～600nm.Sweep test 5 times under conditions of initially not photostimulation is (every time
Sweep spacing 30s, surveys 5 groups of data every time), determinand has weak CO to discharge, and the ultraviolet light then using wavelength to be 365nm exists
Irradiating 1s under the transmitance of 10%, determinand can quickly discharge CO, and after scanning 7 times, all compounds discharge CO hardly；Then
Using wavelength is that the ultraviolet light of 365nm irradiates 5s under the transmitance of 100%, and after scanning 2 times, determinand no longer has CO to discharge.
As seen from Figure 3, the half-life maximum of Pegylation Fischer carbene compound of the present invention can reach 1940s, and minimum also can reach
To 404s.
From the above experiments, it was found that the Pegylation Fischer carbene compound of embodiment 1～11 preparation is at aqueous phase
In slower release carbon monoxide, have some even aqueous phases not discharge carbon monoxide.And release quickly under conditions of illumination
Carbon monoxide, illustrates that Pegylation Fischer carbene compound has an extraordinary optical Response, and has preferable CO and release
Put performance, the compound of every a part discharges more CO.
3, cell toxicity test
Above-mentioned experiment absolutely proves that Pegylation Fischer carbene compound can discharge molecule as CO, at aqueous phase
Or under photoinduction, discharge CO, therefore, it can apply to medical domain for treating or preventing disease, huge with mouse monokaryon below
As a example by phagocyte leukaemia (RAW264.7), the Pegylation Fischer carbene compound of embodiment 1 preparation is used to enter
Row test, concrete test is as follows:
(1) cell processes
Taking frozen RAW264.7 (DMEM) cell line, after 37 DEG C of quick-thawings, 1000 revs/min are centrifuged 5 minutes, use
Culture medium cleans 1～2 time (because adding the material harmful to cell proliferation growth during freezing), with cultivating basic weight
Being centrifuged after Xuan, gained RAW264.7 cell adds complete medium and cultivates, and changes a subculture every day, and observation of cell is raw again
Long situation, standby after covering with.
(2) cell viability test
Adjusting cell concentration after RAW264.7 cell covers with is 5 × 104Cells/mL, is inoculated in 96 well culture plates, often
Hole 100 μ L, at 37 DEG C, 5%CO2Cultivate 24 hours in incubator.Then in 96 orifice plates, empirically packet adds variable concentrations
(0,50,100,200,300,400,500 μm ol/L) Pegylation Fischer carbene compound of gradient, every hole 150 μ L,
Often the multiple hole of group three, cultivates 2 hours.Subsequently, the cell of the variable concentrations cultivated is used 365nm UV illumination 20 minutes respectively
Not illumination, and carry out MTT detection after opening in dark place 8 hours: add 15 μ L tetrazolium salts (MTT) in every hole, at 37 DEG C, 5%CO2
Cultivating lucifuge in incubator to hatch 4 hours, the liquid in exhaustion hole, add 200 μ L DMSO, room temperature is shaken 10 minutes in shaking table,
Measure same time point OD value by microplate reader at 492nm wavelength, carry out the analysis of cell proliferation impact by the OD value recorded.
From MTT result: the IC under RAW264.7 cell illumination condition50Value is 238.5 μm ol/L, RAW264.7 cell
IC under the conditions of not illumination50Value is 152.3 μm ol/L.The inhibited proliferation suppression ratio of cell is represented by CO, calculates respectively
Respectively organize suppression ratio: suppression ratio (%)=(matched group OD value-experimental group OD value)/matched group OD value × 100%, with concentration as horizontal stroke
Axle, suppression ratio is the longitudinal axis, draws curve, and result is shown in Fig. 4.
The experimental result of above-mentioned Fig. 4 is visible, and when the release molecular concentration added is gradually increased, cell inhibitory rate is the most gradually
Increase, and in the case of not illumination, its suppression ratio can reach 90.6% when concentration is 500 μm ol/L.The poly-second of the present invention two is described
The water solublity of alcoholization Fischer carbene compound increases, and reduces its cytotoxicity.
Claims (4)
1. a water soluble pegylation Fischer carbene compound, it is characterised in that the following institute of structural formula of this compound
Show:
In formula M represent Cr or Mo, R represent H-,In any
One, n is the integer of 1～3.
Water soluble pegylation Fischer carbene compound the most according to claim 1, it is characterised in that: described R
Represent H-.
Water soluble pegylation Fischer carbene compound the most 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 compound described in claim 1, it is characterised in that:
At anhydrous and oxygen-free, N2Under protective condition, with methanol as solvent, by the Fischer Cabbeen shown in formula 1 and the poly-second two shown in formula 2
Alcohol monomethyl ether amino acid ester hydrochlorides, triethylamine are 1:1:1 in molar ratio, room temperature reaction 4～6 hours, and pillar layer separation obtains
Water soluble pegylation Fischer carbene compound；
Above-mentioned M represent Cr or Mo, R represent H-,In any
One, n is the integer of 1～3.
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