CN101857597A - Diethylene triamine pentaacetic acid or ethylene diamine tetraacetic acid or amine triacetic acid modified porphyrin, preparation method and application thereof - Google Patents
Diethylene triamine pentaacetic acid or ethylene diamine tetraacetic acid or amine triacetic acid modified porphyrin, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a diethylene triamine pentaacetic acid or ethylene diamine tetraacetic acid or amine triacetic acid modified porphyrin, a preparation method and an application thereof. The modified porphyrin has a structure shown in the specification of the invention. The diethylene triamine pentaacetic acid or ethylene diamine tetraacetic acid or amine triacetic acid modified porphyrin (I) has good water solubility and biocompatibility, and the system has higher singlet oxygen generation behavior and stronger optical absorptivity and has obvious effects in the fields of photodynamic therapeutic medicament and the like which are proven by tests based on cells and mice.
Description
Technical field
The present invention relates to a kind of porphyrin, relate to a kind of diethylene-triamine pentaacetic acid or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin and Preparation method and use particularly.
Background technology
Optical dynamic therapy (PDT) is based on the novel method of treatment that light, photosensitizers and oxygen constitute.For traditional chemotherapy radiotherapy and surgical operation, PDT has characteristics such as operation wound indication little, that have orientation selectivity, treatment disease is wide.The core of optical dynamic therapy is a photosensitizers.The performance quality of photosensitizers has directly determined its curative effect and purposes.The development of photosensitizers at present roughly comprises porphyrin class, phthalocyanines and other small molecules photosensitizers, however obtain clinically approved applications still based on porphyrins, comprise photofrin, compounds such as porphyrin monomethyl ether, Foscasn.Every kind of photosensitive drug all has the indication of its response, and this is that this comprises the ability of physiological metabolism, cellular localization, light absorption wavelength and the generation singlet of medicine owing to the self-characteristic of response light sensitizing drug and the characteristic matching situation of corresponding disease.At present still there is not a kind of photosensitive drug to have general adaptability.Thereby development of new, photosensitive drug has world's ubiquity efficiently.
Porphyrins is a system with big aromatic structure, and solubility property is very poor in its water, and the water miscible method of traditional improvement comprises that glycosyl and PEG fragment realize by introducing sulfonic group at the porphyrin periphery.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, provide to have excellent biological compatibility and water miscible diethylene-triamine pentaacetic acid or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin.
Second purpose of the present invention provides a kind of diethylene-triamine pentaacetic acid or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin preparation method.
The 3rd purpose of the present invention provides the purposes of diethylene-triamine pentaacetic acid or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin two.
Technical scheme of the present invention is summarized as follows:
Diethylene-triamine pentaacetic acid or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin have following structure:
Wherein M is H, Fe, Mn, Cu, Zn, Co, Pt or Mg;
R1＝-X-Y；
R2=-X-Y ,-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
R3=-X-Y ,-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
R4=-X-Y ,-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
N=2,3,4,5 or 6;
The preparation method of diethylene-triamine pentaacetic acid or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin, comprise the steps: in proportion, porphyrin (II a with 0.2-0.5g, II b or II c), 0.50-3.0g diethylene-triamine pentaacetic acid acid anhydride or ethylene diamine tetra-acetic anhydride or amine triacetic acid acid anhydride, 0.2.0-2.0mL triethylamine be dissolved in dimethyl sulfoxide (DMSO) or the N of 10-30ml, in dinethylformamide or the pyridine, 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room reaction 12-36h, add 10-40ml water, leave standstill, separate out precipitation, separate obtaining throw out, use ether, ethanol or ethyl acetate washing precipitation or use methylene dichloride successively, washing with alcohol is heavy rushes down, recrystallization or gel filtration chromatography obtain a kind of diethylene-triamine pentaacetic acid or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin (I a, I b or I c) pure product; The structural formula of described porphyrin (II a, II b or II c) is:
Wherein M is H, Fe, Mn, Cu, Zn, Co, Pt or Mg;
R1＝-X-H；
R2=-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
R3=-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
R4=-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
N=2,3,4,5 or 6.
Diethylene-triamine pentaacetic acid or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin (I a, I b or I c) are in the application of preparation optical dynamic therapy medicine.
Diethylene-triamine pentaacetic acid of the present invention or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin (I) good water solubility, good biocompatibility, this system has higher singlet oxygen generation behavior and stronger light absorpting ability, in fields such as optical dynamic therapy medicines significant effect is arranged, all confirmed this point based on cell and mouse test.The succinct easily row of preparation method of the present invention.
Description of drawings
Fig. 1 is the uv-spectrogram of diethylene-triamine pentaacetic acid modified porphyrin of the present invention;
Fig. 2 is the mass spectrum of diethylene-triamine pentaacetic acid modified porphyrin of the present invention;
Fig. 3 is cell survival rate and The compounds of this invention drug level graph of a relation;
Fig. 4 is the acute toxicity evaluation (the mouse body weight over time after the administration) of The compounds of this invention;
Fig. 5 estimates for the The compounds of this invention antitumous effect.
Embodiment
The present invention is further illustrated below in conjunction with specific embodiment.Following embodiment is used to illustrate the present invention, but does not limit the present invention, and the present invention can also enlarge the amount of getting raw materials used among the following embodiment or dwindle in proportion.
Embodiment 1
The preparation of diethylene-triamine pentaacetic acid modified porphyrin compound:
With 0.2g 5,10,15,20-four-[right-aminophenyl] porphyrin, 1.4g diethylene-triamine pentaacetic acid dicyclo acid anhydride, the triethylamine of 1.0ml is dissolved in the dimethyl sulfoxide (DMSO) of 15ml, at 3mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 12h, after reaction finishes, add 30mL water, leave standstill, separate out product, suction filtration obtains crude product; With washed with dichloromethane 3 times, washing with alcohol 3 times, drying, recrystallization, obtain the pure product of porphyrin compound that diethylene-triamine pentaacetic acid is modified, as follows formula.
The uv-spectrogram of the porphyrin that the product diethylene-triamine pentaacetic acid is modified is seen Fig. 1, and mass spectrum is seen Fig. 2, water-solublely sees Fig. 3
Wherein M is H
R1=R2=R3=R4=-X-Y, wherein
Embodiment 2
With 0.2g 5,10,15,20-four-[right-aminophenyl] chlorin, 1.4g ethylene diamine tetra-acetic anhydride, the triethylamine of 1.0ml are dissolved in the dimethyl sulfoxide (DMSO) of 15ml, at 2mg4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 12h, after reaction finishes, add 30mL water, leave standstill, separate out product, suction filtration obtains crude product; With washed with dichloromethane 3 times, washing with alcohol 3 times, drying, recrystallization, obtain the porphyrin compound that ethylenediamine tetraacetic acid (EDTA) is modified, as follows formula.
Wherein M is H
R1＝R2＝R3＝R4＝-X-Y
With 0.2g 5,10,15,20-four-[right-aminophenyl] tetrahydrochysene porphin phenol, 1.4g amine triacetic acid acid anhydride, 1.0ml triethylamine be dissolved in the dimethyl sulfoxide (DMSO) of 15ml, at 5mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 12h, after reaction finishes, add 30mL water, leave standstill, separate out product.Suction filtration obtains crude product, and with washed with dichloromethane 3 times, washing with alcohol 3 times, drying, recrystallization obtains amine triacetic acid modified porphyrin compound, as follows formula.
Wherein M is H
R1＝R2＝R3＝R4＝-X-Y、
Embodiment 4
(II a), the diethylene-triamine pentaacetic acid acid anhydride of 3.0g, the triethylamine of 2.0mL are dissolved in the 30ml dimethyl sulfoxide (DMSO) with the porphyrin of 0.5g, at 4mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 12h, add 10ml water, leave standstill, separate out precipitation, separate obtaining throw out, with ether washing 3 times, drying, recrystallization obtains the pure product of porphyrin compound that a kind of diethylene-triamine pentaacetic acid is modified.
(II is structural formula a), and wherein M is H for porphyrin; R1=R2=R3=R4=-X-H; Wherein:
Embodiment 5
(II a), the diethylene-triamine pentaacetic acid acid anhydride of 2.0g, the triethylamine of 1.0mL are dissolved in 20ml N, the dinethylformamide with the porphyrin of 0.3g, at 5mg4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 24h, add 40ml water, leave standstill, separate out precipitation, separate obtaining throw out, with 6ml ethyl acetate washing 3 times, drying, gel filtration chromatography obtains the pure product of porphyrin compound that a kind of diethylene-triamine pentaacetic acid is modified.
(II is structural formula a), and wherein M is H for porphyrin; R1=-X-H; Wherein:
R2=R3=R4=-H
With the porphyrin of 0.4g (II a), the diethylene-triamine pentaacetic acid acid anhydride of 2.5g, the triethylamine of 1.5mL is dissolved in the 25ml pyridine, at 3mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 36h, add 25ml water, leave standstill, separate out precipitation, separate obtaining throw out, with 5ml washing with alcohol 3 times, drying, recrystallization obtains the pure product of porphyrin compound that a kind of diethylene-triamine pentaacetic acid is modified.(II is structural formula a), wherein M Fe for porphyrin; R1=-X-H; Wherein:
N=2; R2=R3=R4=-OCH
3
Embodiment 7
(II a), the ethylene diamine tetra-acetic anhydride of 0.50g, the triethylamine of 0.2.0mL are dissolved in the 10ml dimethyl sulfoxide (DMSO) with the porphyrin of 0.2g, at 3mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 30h, add 10ml water, leave standstill, separate out precipitation, separate and obtain throw out, with 5ml washed with dichloromethane 3 times, 5ml washing with alcohol 3 times, drying, recrystallization obtains the pure product of porphyrin compound that a kind of ethylenediamine tetraacetic acid (EDTA) is modified.
(II is structural formula a), and wherein M is Mg for porphyrin; R1=-X-H; Wherein:
N=6; R2=R3=R4=-CH
3
Embodiment 8
(II a), the ethylene diamine tetra-acetic anhydride of 0.50g, the triethylamine of 0.2.0mL are dissolved in 10ml N, the dinethylformamide with the porphyrin of 0.2g, at 3mg4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 28h, add 10ml water, leave standstill, separate out precipitation, separate and obtain throw out, with 5ml washed with dichloromethane 3 times, 5ml washing with alcohol 3 times, drying, gel filtration chromatography obtains the pure product of porphyrin compound that a kind of ethylenediamine tetraacetic acid (EDTA) is modified.
(II is structural formula a), and wherein M is Mn for porphyrin; R1=-X-H; Wherein:
N=4; R2=R3=R4=-COOH.
Embodiment 9
(II a), the ethylene diamine tetra-acetic anhydride of 1.0g, the triethylamine of 1.0mL are dissolved in the 12ml pyridine with the porphyrin of 0.3g, at 3mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 16h, add 30ml water, leave standstill, separate out precipitation, separate and obtain throw out, with 5ml washed with dichloromethane 3 times, 5ml washing with alcohol 3 times, drying, gel filtration chromatography obtains the pure product of porphyrin compound that a kind of ethylenediamine tetraacetic acid (EDTA) is modified.
(II is structural formula a), and wherein M is Cu for porphyrin;
N=2.
Embodiment 10
(II a), the amine triacetic acid acid anhydride of 0.50g, the triethylamine of 0.5mL are dissolved in the 10ml dimethyl sulfoxide (DMSO) with the porphyrin of 0.2g, at 3mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 18h, add 15ml water, leave standstill, separate out precipitation, separate and obtain throw out, with 5ml washed with dichloromethane 3 times, 5ml washing with alcohol 3 times, drying, recrystallization obtains the pure product of a kind of amine triacetic acid modified porphyrin compound.
(II is structural formula a), and wherein M is Co for porphyrin; R1=-X-H; Wherein:
n＝5；R2＝R3＝R4＝-OCH
3
Embodiment 11
(II a), the amine triacetic acid acid anhydride of 0.25.0g, the triethylamine of 2.0mL are dissolved in 20ml N, the dinethylformamide with the porphyrin of 0.4g, at 3mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 30h, add 35ml water, leave standstill, separate out precipitation, separate and obtain throw out, with 5ml washed with dichloromethane 3 times, 5ml washing with alcohol 3 times, drying, recrystallization obtains the pure product of a kind of amine triacetic acid modified porphyrin compound.
(II is structural formula a), and wherein M is Zn:R1=-X-H for porphyrin; Wherein:
N=6; R2=R3=R4=-H
Embodiment 12
(II a), the amine triacetic acid acid anhydride of 3.0g, the triethylamine of 1.0mL are dissolved in the 30ml pyridine with the porphyrin of 0.5g, at 3mg4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 36h, add 40ml water, leave standstill, separate out precipitation, separate and obtain throw out, with 5ml washed with dichloromethane 3 times, 5ml washing with alcohol 3 times, drying, gel filtration chromatography obtains the pure product of a kind of amine triacetic acid modified porphyrin compound.
(II is structural formula a), and wherein M is Zn for porphyrin; R1=-X-H; Wherein:
N=6; R2=R3=R4=-H
Substituting group in the porphyrin ring of embodiment 4-11 on the phenyl is contraposition, also can select for use substituting group at the ortho position or the porphyrin compound of modifying for feedstock production of a position.
Embodiment 13
Step is with embodiment 4, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-X-H；R3＝-X-H；R4＝-X-H；
n＝2。
Embodiment 14
Step is with embodiment 4, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-X-H；R3＝-X-H；R4＝-X-H；
n＝6。
Embodiment 15
Step is with embodiment 4, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-X-H；R3＝-X-H；R4＝-X-H；
n＝3。
Substituting group in the porphyrin ring of embodiment 13-15 on the phenyl is contraposition, also can select for use substituting group at the ortho position or the porphyrin compound of modifying for feedstock production of a position.
Embodiment 16
Step is with embodiment 5, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-H；R3＝-H；R4＝-H；
n＝2。
Embodiment 17
Step is with embodiment 5, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-H；R3＝-H；R4＝-H；
n＝2。
Embodiment 18
Step is with embodiment 5, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-H；R3＝-H；R4＝-H；
n＝6。
Substituting group in the porphyrin ring of embodiment 16-18 on the phenyl is contraposition, also can select for use substituting group at the ortho position or the porphyrin compound of modifying for feedstock production of a position.
Embodiment 19
Step is with embodiment 6, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-OCH
3；R3＝-OCH
3；R4＝-OCH
3；
n＝2。
Step is with embodiment 6, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-OCH
3；R3＝-OCH
3；R4＝-OCH
3；
n＝4。
Embodiment 21
Step is with embodiment 6, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-OCH
3；R3＝-OCH
3；R4＝-OCH
3；
n＝6。
Substituting group in the porphyrin ring of embodiment 19-21 on the phenyl is contraposition, also can select for use substituting group at the ortho position or the porphyrin compound of modifying for feedstock production of a position.
Embodiment 22
Step is with embodiment 7, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-CH
3；R3＝-CH
3；R4＝-CH
3；
n＝2。
Embodiment 23
Step is with embodiment 7, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-CH
3；R3＝-CH
3；R4＝-CH
3；
n＝4。
Embodiment 24
Step is with embodiment 7, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-CH
3；R3＝-CH
3；R4＝-CH
3；
n＝6。
Substituting group in the porphyrin ring of embodiment 22-24 on the phenyl is contraposition, also can select for use substituting group at the ortho position or the porphyrin compound of modifying for feedstock production of a position.
Step is with embodiment 8, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-COOH；R3＝-COOH；R4＝-COOH；
n＝2。
Embodiment 26
Step is with embodiment 8, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-COOH；R3＝-COOH；R4＝-COOH；
n＝4。
Embodiment 27
Step is with embodiment 8, and the raw material porphyrin selects for use structural formula (II a) wherein: R1=-X-H; R2=-COOH; R3=-COOH; R4=-COOH;
N=6.
Substituting group in the porphyrin ring of embodiment 25-27 on the phenyl is contraposition, also can select for use substituting group at the ortho position or the porphyrin compound of modifying for feedstock production of a position.
Embodiment 28
Step is with embodiment 9, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-COOH；R3＝-COOH；R4＝-COOH；
n＝2。
Embodiment 29
Step is with embodiment 9, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-COOH；R3＝-COOH；R4＝-COOH；
n＝4。
Embodiment 30
Step is with embodiment 9, the raw material porphyrin select for use structural formula (II a) wherein:
R1＝-X-H；R2＝-COOH；R3＝-COOH；R4＝-COOH；
n＝6。
Substituting group in the porphyrin ring of embodiment 28-30 on the phenyl is contraposition, also can select for use substituting group at the ortho position or the porphyrin compound of modifying for feedstock production of a position.
Embodiment 31-embodiment 57, (II a), reaction conditions is identical with embodiment 4-30 successively with other raw material with raw material porphyrin (II b) alternative materials porphyrin.
Embodiment 58-embodiment 84, (II a), reaction conditions or other raw material are identical with embodiment 4-30 successively to substitute the raw material porphyrin with raw material porphyrin (II C).
Embodiment 85
The preparation of diethylene-triamine pentaacetic acid modified porphyrin compound:
With 0.2g 5,10,15-three [right-aminophenyl]-20-phenyl porphyrin, 1.4g diethylene-triamine pentaacetic acid dicyclo acid anhydride, the triethylamine of 1.0ml are dissolved in the dimethyl sulfoxide (DMSO) of 15ml, at 3mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 12h after reaction finishes, adds 30mL water, leave standstill, separate out product, suction filtration obtains crude product; With washed with dichloromethane 3 times, washing with alcohol 3 times, drying, recrystallization, obtain the pure product of porphyrin compound that diethylene-triamine pentaacetic acid is modified, as follows formula.
Wherein M is H
R1=R2=R3=-X-Y, R4=H, wherein
Embodiment 86
With 0.2g 5,10-two [right-aminophenyl]-15,20-phenylbenzene porphyrin, 1.4g diethylene-triamine pentaacetic acid dicyclo acid anhydride, the triethylamine of 1.0ml are dissolved in the dimethyl sulfoxide (DMSO) of 15ml, at 3mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 12h after reaction finishes, adds 30mL water, leave standstill, separate out product, suction filtration obtains crude product; With washed with dichloromethane 3 times, washing with alcohol 3 times, drying, recrystallization, obtain the pure product of porphyrin compound that diethylene-triamine pentaacetic acid is modified, as follows formula.
Wherein M is H
R3=R4=-X-Y, R3=R4=H, wherein
Embodiment 87
With 0.2g 5-[right-aminophenyl]-10,15,20-triphenyl porphyrin, 1.4g diethylene-triamine pentaacetic acid dicyclo acid anhydride, the triethylamine of 1.0ml are dissolved in the dimethyl sulfoxide (DMSO) of 15ml, at 3mg 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room 12h after reaction finishes, adds 30mL water, leave standstill, separate out product, suction filtration obtains crude product; With washed with dichloromethane 3 times, washing with alcohol 3 times, drying, recrystallization, obtain the pure product of porphyrin compound that diethylene-triamine pentaacetic acid is modified, as follows formula.
Wherein M is H
R1=-X-Y, R2=R3=R4=H, wherein
1. tumour cell bed board: the cancer cells that will be in the growth logarithmic phase with tryptic digestion after, be seeded in 96 orifice plates, bed board density is 1 * 10
4/ hole cell.This experiment establishes 12,5,6.25,3.125 altogether, five drug level groups of 1.5625,0.78 μ mol/L, and a negative control group and a blank group (only adding 180 μ L DMSO in the experiment final step) are established 4 secondary holes for every group.Behind the bed board 96 orifice plates are put into CO
2Overnight incubation in the incubator is treated cell attachment.
2. administration: behind the cell attachment, the nutrient solution that inclines, every hole adds the drug solution 200 μ L that Yi Bilie prepares successively, and concentration is followed successively by 12,5,6.25,3.125,1.5625,0.78 μ mol/L (negative control group replaces drug solution with nutrient solution).96 orifice plates are put into 37 ℃ of CO
2Hatched in the incubator in the incubator 24 hours.(note this whole process want lucifuge).
3. the capable photodynamic therapy of irradiation: 650nm laser excitation wavelength, 8J/cm
2, irradiation 20min.
4. add the MTT colour developing: irradiation continued in the incubator to hatch 3 hours after finishing, and every then hole adds the MTT20 μ L of 5mg/mL, hatches 1h in the incubator.(note this whole process want lucifuge).
5. absorbance detects: liquid in the hole of inclining, add 180 μ L DMSO in every hole, and immediately 96 orifice plates are put into microplate reader, shook 5 minutes.The OD value of each experimental port is detected at 490nm wavelength place.Calculate cell survival rate (%)=[(treatment group OD value-blank group OD value)/(negative control group OD value-blank group OD value)] * 100%.
Photo-dynamical medicine dosage is with Cytotoxic related (laser energy density is 8J/cm
2, light application time is 20 minutes, illumination wavelength is 650nm.Cell survival rate is by the mtt assay analysis, and test is the DMTM liver cancer cell with cell.)
The result shows that along with drug level increases, the drug toxicity of cell strengthens.
See Fig. 3 and table 1.
(among Fig. 3, compound 1 is embodiment 1 preparation, and compound 2 is embodiment 85 preparations, and compound 3 is embodiment 86 preparations, and compound 4 is embodiment 87 preparations.
Unit is (μ mol/L) (S represents the Survival survival rate, and the lower right corner numeral is a respective concentration)
Table 1
| ??Compound | 1 (modified porphyrin of embodiment 1 preparation) | 2 (modified porphyrins of embodiment 85 preparations) | 3 (modified porphyrins of embodiment 86 preparations) | 4 (modified porphyrins of embodiment 87 preparations) |
| ??S 0.78 | ??99.98％ | ??98.3224％ | ??92.9389％ | ??93.8838％ |
| ??S 1.56 | ??97.36％ | ??89.9877％ | ??96.822％ | ??95.4945％ |
| ??S 3.12 | ??75.7196％ | ??68.3456％ | ??71.2608％ | ??74.4839％ |
| ??Sl 6.25 | ??26.9625％ | ??28.4531％ | ??36.352％ | ??32.985％ |
| ??S 12.5 | ??19.9712％ | ??25.4808％ | ??35.124％ | ??28.106％ |
The compound of the present invention that experiment showed, the various embodiments of the present invention preparation is along with concentration increases, and the drug toxicity of cell all has enhancing in various degree.
The acute toxicity evaluation of embodiment 89 compounds
Sample to embodiment 1 preparation has carried out preliminary safety evaluation, and choosing body weight is 80 of 20～22g kunming mices, and male and female half and half are divided into 2 groups at random, blank group and experimental group, 40 every group.After the fasting 12 hours, it is the 1mM/L sample that experimental group is carried out tail vein injection concentration, and every injected in mice dosage is 200 μ l/20g.Observe and write down the physiological indexes situation of mouse in 2 weeks, result such as table 2, the result shows, in the blood routine examination, carry out in the The results of analysis of variance in indexs such as red corpuscle, white corpuscle, thrombocytes, experimental group is compared with the blank group, and comparing with the blank group at the 1st day, the 7th day except mean corpuscular volume (MCV) has certain reduction, and other indexs there is no significantly unusual.Find two groups of body weight change no significant differences in the mouse body weight change in experimental group and the blank group of observing in 15 days.See Fig. 4 (concentration is after the sample of embodiment 1 preparation of 1mmol/L is organized the tail intravenously administrable with blank, the body weight change situation in 15 days)
After table 2 concentration was sample (embodiment 1) the tail intravenously administrable of 1mmol/L, the routine blood test in 15 days changed
(wherein, being blank group data in the bracket, P≤0.05)
The compound that experiment showed, the various embodiments of the present invention preparation is compared two groups of body weight change no significant differences with the blank group.
Embodiment 90
The optical dynamic therapy purposes of diethylene-triamine pentaacetic acid modified porphyrin
Test method:
1. set up the foundation of rat liver cancer H-22 model: 1. mouse shank-feathering: cut off the long hair of mouse back earlier, utilize 8% sodium sulphite to take off the skin of about 2 * 2cm size then near afterbody, standby; 2. behind the 24h, get a well-grown mouse of liver cancer H-22 ascites, take out ascites 2-3ml, dilute cell concn about 10 in 1: 3 ratio
7/ ml is behind the conventional skin degerming, with the knurl liquid of every mouse behind shank-feathering district's subcutaneous vaccination of one milliliter of syringe 0.2ml.
2, administration: (size of mouse back knurl is about 0.5cm * 0.5cm) after inoculated tumour 5-7 days, (embodiment 1 in the beginning administration, embodiment 85, embodiment 86, embodiment 87 preparation) administration concentration is 20mg/kgw (0.2ml), in the knurl, topical (administration in the local subcutaneous of tumour and tumour).The mouse lucifuge is raised after the administration.
3, irradiation: behind 12h and the 24h, be the laser of 649nm with wavelength after the administration, optical density(OD) is 0.194w/cm
2Irradiation time 660s, radius 0.75cm, irradiation energy 72J/cm
24, put to death after 21 days, claim knurl heavy, calculate tumour inhibiting rate.(control group knurl weight-PDT group knurl is heavy)/heavy * 100% of control group knurl.The result shows, 1a (modified porphyrin of embodiment 1 preparation) combined PD T treatment back lotus liver cancer H-22 kunming mice has the obvious suppression effect, the most of tumour in treatment back is no longer bred, the mouse tumor that has almost disappears, the influence of combined PD T treatment lotus liver cancer H-22 kunming mice after 21 days, concrete outcome is seen Fig. 5 and table 3.
The modified porphyrin combined PD T treatment of the present invention of table 3:1 (embodiment 1 preparation), 2 (embodiment 85 preparations), 3 (embodiment 86 preparations) 4, (embodiment 87 preparations) after 21 days to the inhibiting rate of lotus liver cancer H-22 kunming mice
| Group | Inhibiting rate |
| Contrast | |
| ??1-PDT(10mg/kg) | ??48.56％ |
| Group | Inhibiting rate |
| ??1-PDT(20mg/kg) | ??69.12％ |
| ??1-PDT(40mg/kg) | ??73.35％ |
| ??2-PDT(10mg/kg) | ??45.56％ |
| ??2-PDT(20mg/kg) | ??51.02％ |
| ??2-PDT(40mg/kg) | ??62.35％ |
| ??3-PDT(10mg/kg) | ??38.56％ |
| ??3-PDT(20mg/kg) | ??42.32％ |
| ??3-PDT(40mg/kg) | ??58.62％ |
| ??4-PDT(10mg/kg) | ??40.06％ |
| ??4-PDT(20mg/kg) | ??48.62％ |
| ??4-PDT(40mg/kg) | ??6.62％ |
The modified porphyrin that experimental results show that each embodiment preparation of the present invention all has the effect that light power suppresses tumour.
Embodiment 91
Water-soluble mensuration:
The modified porphyrin water-soluble of embodiment 1 preparation: (6.31g/L)
The modified porphyrin water-soluble of embodiment 85 preparations: (1.78g/L)
The modified porphyrin water-soluble of embodiment 86 preparations: (1.450.76g/L)
The modified porphyrin water-soluble of embodiment 87 preparations: (0.9647g/L)
All water-soluble with the corresponding raw material of modified porphyrin that experimental results show that each embodiment preparation of the present invention is compared the increase that all has in various degree.
Claims (3)
1. diethylene-triamine pentaacetic acid or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin, its feature has following structure:
Wherein M is H, Fe, Mn, Cu, Zn, Co, Pt or Mg;
R1＝-X-Y；
R2=-X-Y ,-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
R3=-X-Y ,-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
R4=-X-Y ,-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
N=2,3,4,5 or 6;
2. the preparation method of the diethylene-triamine pentaacetic acid of claim 1 or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin, it is characterized in that comprising the steps: in proportion, porphyrin (II a with 0.2-0.5g, II b or II c), 0.50-3.0g diethylene-triamine pentaacetic acid acid anhydride or ethylene diamine tetra-acetic anhydride or amine triacetic acid acid anhydride, 0.2.0-2.0mL triethylamine be dissolved in dimethyl sulfoxide (DMSO) or the N of 10-30ml, in dinethylformamide or the pyridine, 4, under the catalysis of 4-Dimethylamino pyridine, stirring at room reaction 12-36h, add 10-40ml water, leave standstill, separate out precipitation, separate obtaining throw out, washing precipitation, recrystallization or gel filtration chromatography obtain a kind of diethylene-triamine pentaacetic acid or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin (I a, I b or I c) pure product; The structural formula of described porphyrin (II a, II b or II c) is:
Wherein M is H, Fe, Mn, Cu, Zn, Co, Pt or Mg;
R1＝-X-H；
R2=-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
R3=-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
R4=-X-H ,-H ,-OCH
3,-CH
3Or-COOH;
N=2,3,4,5 or 6.
3. the diethylene-triamine pentaacetic acid of claim 1 or ethylenediamine tetraacetic acid (EDTA) or amine triacetic acid modified porphyrin (I a, I b or I c) are in the application of preparation optical dynamic therapy medicine.
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