CN102125549A - Dihydroporphin photosensitizer as well as preparation method and application thereof - Google Patents
Dihydroporphin photosensitizer as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a dihydroporphin photosensitizer as well as a preparation method and an application thereof. The dihydroporphin photosensitizer is meso-4(3-N,N-diethylaminemethyl)-4-metoxyphenyl)-dihydroporphin, and the chemical structural formula thereof is provided. The photosensitizer is prepared by the following steps: reducing meso-4(3-N,N-diethylaminemethyl)-4-metoxyphenyl)-dihydroporphin through a reducer in the presence of nitrogen gas and eluting through silica gel column chromatography. The dihydroporphin photosensitizer provided by the invention is used for preparing medicines for treating tumors and photoactivated insecticides. The preparation method is simple. The dihydroporphin photosensitizer can be made into hydrochloride injections to use, and has wide application prospects.
Description
Technical field
The invention belongs to photosensitizer and preparation thereof and application, particularly relate to a kind of dihydro porphin photosensitizer and preparation thereof and application.
Background technology
Photodynamic therapy is nearly 20 years a kind of one of the most promising new techniques that grow up.Since 20th century, entered clinical research the seventies, on tumor treatment, obtained and broken through progress, photodynamic therapy not only is confined to the treatment of malignant tumor at present, also shows good prospect in other multiple treatment of diseases.
In optical dynamic therapy, photosensitizer is as the bridge of carrier of energy, reaction and decisive role.First generation photosensitizer is to be representative with first photosensitizer photofrin II in Holland listing in 1993, and it is a mixture of forming complicated hematoporphyrin derivative, and its indication is a tumor; Second filial generation photosensitizer is based on the porphyrin analog derivative, the chemical constitution of this compounds is clear and definite, higher purity is arranged, photo and thermal stability preferably, the absorption of red light district is stronger, by can regulate the hydrophobic partition coefficient of photosensitizer to the chemical modification of porphyrin ring, helping absorption and the accumulation of photosensitizer at pathological tissues simultaneously, is the comparatively desirable photosensitizer that gets.One of another emphasis that develops in the secondary photosensitizer is the chlorin compounds.This compounds mainly comprises chlorins and porphine of bacterium, is the product after the two keys on pyrrole ring are reduced in the porphyrin structure.This compounds has good photophysical property, and is strong in visual field absorbing wavelength length and absorption.From point of theory, this compounds has shown the characteristic of suitable PDT medicine, has the great potential that is developed to the PDT medicine.The dihydro porphin photo-dynamical medicine that has gone on the market at present mainly contains Temoporfin and Talaporfin, and they are widely used in the treatment of various tumor diseases, and application prospect is very considerable.
Zhang Zhoupeng etc. (SCI, 1989,10 (11): 1136-1138) synthesized porphyrin compound as follows:
Bonnet etc. (Bonnet et al, Biochem.J., 1989,261:277-280) reported following chemical compound:
The Zhang Zhoupeng institute female ring of synthetic chemical compound is a porphin, in short wavelength (400-450nm) district absorption is more by force arranged, but absorb weak (long wavelength light tissue penetration ability is stronger) in long wavelength (500-750nm) district, influenced its optical dynamic therapy effect deep tumor and larger-diameter tumor.It is littler than chemical compound Temoporfin polarity that the advantage of this chemical compound is that periphery contains substituent group polarity, can distribute at hydrophobicity lesion tissue position (as skin carcinoma), thereby the shallow tumor of his-and-hers watches has photodynamics preferably.And this chemical compound periphery contains 4 tertiary amine groups, can be made hydrochlorate easily, uses thereby be made into injection, and stability is strong.
Temoporfin is strong at long wavelength (500-750nm) district absorptance porphin, and deep tumor and larger-diameter tumor are also had the optical dynamic therapy effect.The shortcoming of this chemical compound is that peripheral substituted radical is a phenol, easy oxidized destruction, and owing to contain 4 hydroxyls, polarity is bigger, it is less to distribute at hydrophobicity lesion tissue position (as skin carcinoma), influences the optical dynamic therapy effect.
Summary of the invention
Technical problem to be solved by this invention provides a kind of new dihydro porphin photosensitizer and preparation and application, this photosensitizer has absorption more by force at the visible light long wavelength region, and polar phase is to less, the tumor treatment that both can be used for deep tumor and larger volume can be used for showing shallow tumor treatment again; The synthetic method of this chemical compound is simple, can be made into hydrochlorate, use thereby both be easy to be made into injection, but enhanced stability again.
A kind of chlorin photosensitizer, name is called intermediary-four (3-(N, N dimethylamine ylmethyl)-4-methoxyphenyl) chlorin chemical compound, and its chemical structural formula is:
The preparation of a kind of dihydro porphin photosensitizer of the present invention comprises:
Intermediary-four (3-(N, N dimethylamine ylmethyl)-4-methoxyphenyl) porphin is reduced through Reducing agent, remove and desolvate, residue is collected product and is obtained the chlorin compounds through the silica gel column chromatography eluting, and its synthetic route is:
Concrete steps are:
Add the 1.047mmol-1.055mmol (3-(N of intermediary-four in the 250ml container; the N dimethylamine ylmethyl)-and the 4-methoxyphenyl) (press literature method prepares porphin: Zhang Zhoupeng etc.; SCI, 1989,10 (11): 1136-1138); add the 1.696mmol-1.72mmol Reducing agent; and adding 7.080mmol-7.2mmol Anhydrous potassium carbonate, evacuation, inflated with nitrogen; add the 48mL pyridine; stir, under the nitrogen protection, in oil bath, keep reflux; reaction finishes postcooling; stirring at room 12-24h adds 90-110mL ethyl acetate, 40-60mL water afterwards in reactant liquor; in oil bath, keep 100 ℃ of reactions 1 hour; cooling, organic facies washes with water repeatedly, drying; sucking filtration; concentrate; through the silica gel column chromatography eluting, promptly.
Reducing agent is unifor or hydrazine hydrate in the described step, wherein preferentially selects unifor.
Dihydro porphin photosensitizer of the present invention can be used for preparation treatment tumor class disease medicament or photoactivation insecticide.
By photosensitizer of the present invention the light dynamic test of colon cancer cell is found, when illumination is arranged, the propagation of photosensitizer energy obvious suppression colon cancer cell; By to synthetic this photosensitizer to mice S
180The light dynamic test of sarcoma finds that this photosensitizer can obviously suppress mice S
180Sarcoma has significant lethal effect to tumor, has the prospect that becomes light power antitumor drug; By light power activation toxicity test, find that this chemical compound is a class photoactivation insecticide preferably to the fruit bat that fills the stomach.
Beneficial effect
1, dihydro porphin photosensitizer of the present invention originally has absorption more by force at the visible light long wavelength region, and long wavelength light tissue penetration ability is strong, can be used for the tumor treatment of deep tumor and larger volume;
2, dihydro porphin photosensitizer polar phase of the present invention can be distributed in the shallow pathological tissues of table to less, therefore also can be used for showing shallow tumor treatment;
3, preparation method of the present invention is simple, can be made into the hydrochlorate enhanced stability, and injection is used.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
Intermediary-four (3-(N, N dimethylamine ylmethyl)-4-methoxyphenyl) chlorin (meso-tetra[3-(N, N-diethylaminomethyl)-4-methoxyphenyl] chlorine) synthetic:
Add 1184g (1.047mmol) intermediary-four (3-(N, N dimethylamine ylmethyl)-4-methoxyphenyl) porphin in the 250mL there-necked flask, add 0.318g (1.696mmol) unifor, and add 0.977g (7.080mmol) Anhydrous potassium carbonate.Evacuation, inflated with nitrogen.In there-necked flask, add the 48mL pyridine at last, stir, under the nitrogen protection, in oil bath, keep reflux, when the 2nd, 4,6,8 hour of reaction, add 0.318g (1.696mmol) unifor, TLC detection reaction.After reaction finishes, stop heating, natural cooling.Room temperature (25 ℃) stirs and spends the night then.Add the 90mL ethyl acetate afterwards in reactant liquor, 40mL water keeps 100 ℃ of reactions 1 hour in oil bath.Cooling, organic facies washes with water repeatedly, uses anhydrous sodium sulfate drying, filter, concentrate, plate layer chromatography separated 2 times, with methylene chloride-methanol-triethylamine (20: 1: 0.2, v/v) do developing solvent, (methylene chloride-methanol-triethylamine=20: 1: 0.2 v/v), is collected the aubergine colour band to last column chromatography, obtain purple solid 0.409g, yield is 36.3%.
ESI-MS(m/z)：1078.1(M+1)；
1H-NMR(400MHz，δ，CDCl
3，ppm)：-1.48(s，2H)，0.95～1.00(m，24H)，1.26～1.30(m，16H)，1.45(m，16H)，2.53～2.63(m，16H)，3.73～3.74(s，4H)，3.77(s，4H)，3.91(s，6H)，3.95(s，6H)，4.05(s，4H)，6.97～6.99(m，2H)，7.03～7.05(m，2H)，7.54(m，2H)，7.81～7.83(m，4H)，8.05(s，2H)，8.10(d，J＝4.72Hz，2H)，8.36(s，2H)，8.50(s，2H)；
UV/Visλmax(CH
2Cl
2)nm：421(soret)，524，552，598，652.
Embodiment 2
Intermediary-four (3-(N, N dimethylamine ylmethyl)-4-methoxyphenyl) chlorin (meso-tetra[3-(N, N-diethylaminomethyl)-4-methoxyphenyl] chlorine) synthetic:
Add 1193g (1.055mmol) intermediary-four (3-(N, N dimethylamine ylmethyl)-4-methoxyphenyl) porphin in the 250mL there-necked flask, add 0.087g (1.72mmol) hydrazine hydrate, and add 0.994g (7.200mmol) Anhydrous potassium carbonate.Evacuation, inflated with nitrogen.In there-necked flask, add the 48mL pyridine at last, stir, under the nitrogen protection, in oil bath, keep reflux, when the 2nd, 4,6,8 hour of reaction, add 0.087g (1.72mmol) hydrazine hydrate, TLC detection reaction.After reaction finishes, stop heating, natural cooling.Room temperature (25 ℃) stirs and spends the night then.Add the 110mL ethyl acetate afterwards in reactant liquor, 60mL water keeps 100 ℃ of reactions 1 hour in oil bath.Cooling, organic facies washes with water repeatedly, uses anhydrous sodium sulfate drying, filter, concentrate, plate layer chromatography separated 2 times, with methylene chloride-methanol-triethylamine (20: 1: 0.2, v/v) do developing solvent, (methylene chloride-methanol-triethylamine=20: 1: 0.2 v/v), is collected the aubergine colour band to last column chromatography, obtain purple solid 0.348g, yield is 30.9%.
Embodiment 3
Photosensitizer is to the light power antiproliferative experiment of colon cancer SW480 cell
Subject cell: colon cancer cell SW480
Be subjected to the reagent thing: photosensitizer, hematoporphyrin derivative HpD (Beijing Pharmaceutical Ind. Inst.'s production).
Light source: MTZ-1 type pulse laser cancer therapy machine; SD2490 type laser power measurement instrument.
Light power anti-tumour cell proliferative effect experiment: the cell that will be in exponential phase with trypsinization after, the resuspended one-tenth cell suspension of complete medium is inoculated in it 96 orifice plates thereupon, every hole 100 μ l place 37 ℃ of 5%CO
2Incubator is cultivated, and adds two kinds of different photosensitizer of same concentrations behind the 24h; 48h changes fresh culture into, carries out illumination (XD-635AB type light power PDT laser therapeutic apparatus, power 15mW/cm then
2, wavelength 630mm, irradiated cell 20min, light dosage 18J/cm
2); Carrying out MTT during 72h detects.Cultivate and stop the MTT that preceding 4h adds 10 μ l 5mg/ml, add 100 μ l DMSO cessation reactions after culture fluid is abandoned in suction, microplate reader 570nm detects the OD value.The experiment triplicate.Experimental result sees Table 1, found that this kind photosensitizer has antiproliferative effect to colon cancer cell.
The IC50 value of HpD and photosensitizer 1 is respectively 1.572 and 4.2 μ mol/L..
1 pair of SW480 colon cancer cell of table 1 photosensitizer inhibited proliferation
The photosensitizer half-light is learned toxotest: the cell that will be in exponential phase with trypsinization after, the resuspended one-tenth cell suspension of complete medium is inoculated in it 96 orifice plates thereupon, every hole 100 μ l place 37 ℃ of 5%CO
2The incubator lucifuge is cultivated, and adds two kinds of different photosensitizer of same concentrations behind the 24h; 48h changes fresh culture into: carry out MTT during 72h and detect.Cultivate and stop the MTT that preceding 4h adds 10 μ l 5mg/ml, add 100 μ l DMSO cessation reactions after culture fluid is abandoned in suction, microplate reader 570nm detects the OD value.The experiment triplicate.Experimental result sees Table 2, found that this kind photosensitizer does not have half-light and learns toxicity.
1 pair of SW480 colon cancer cell of table 2 photosensitizer half-light is learned toxicity
Embodiment 4
Photosensitizer is to mice S
180The optical dynamic therapy experiment of sarcoma
Animal subject: outbreeding Kunming strain mice average weight 18～24g, S180 sarcoma kind Mus (Chinese Academy of Sciences institute of materia medica provides)
Be subjected to the reagent thing: photosensitizer 1, the normal saline that under aseptic condition said medicine is dissolved in the minimum tween 80 is diluted to the 0.5mg/mL solution for standby, hematoporphyrin derivative HpD (Beijing Pharmaceutical Ind. Inst.'s production).
Light source: MTZ-1 type pulse laser cancer therapy machine; SD2490 type laser power measurement instrument.
Mice S180 sarcoma light power injury experiment: under the aseptic condition in mice anterior part of chest subcutaneous vaccination S180 sarcoma, when treating that tumor is grown to diameter 4～6mm, choose the mice of well-grown, the hemispherical single tumor of no ulcer tool, by brood with the sex random packet, every group 8, the mouse peritoneal drug administration by injection, and with drug solvent as blank, HpD is made into same concentrations solution as positive control, and the 2h power density is 220mW/cm after the administration
2Copper steam-dye laser (wavelength 630mm) radiation tumor 20min (light dosage 150J/cm
2); After the illumination 5 days, put to death mice, peel off tumor, weigh, and with matched group suppression ratio relatively.
Experimental result sees Table 3, and 1 pair of tumor of photosensitizer has the obvious suppression effect.
The inhibition effect of 1 pair of tumor of table 3 photosensitizer
* compare with blank P＜0.05
Embodiment 5
Photosensitizer is to the photodynamics experiment of the fruit bat that fills the stomach
Select to sprout wings the fruit bat examination worm that fills the stomach in a week with etherization grouping (being regardless of male and female), is put into and contains in (0.5,1.0,2.0 g/L) culture tube that variable concentrations is subjected to the reagent sample, and 20 of every pipes tightly cover mouth with the nylon yarn fabric width.Handle for every kind and repeat 3 times.Culture tube is placed the dark place, simulate the 48h that takes food in the dark, shift then in the basal medium, 20cm evenly is subjected to according to (tube wall temperature is no more than 35 degree during illumination) after a period of time under the electric filament lamp of different illumination intensity, be transferred to dark place and regularly observe dead number, calculate mortality rate.
Experimental result sees Table 4, finds that photosensitizer 1 shows photoactivation insecticidal activity preferably.
The photoactivation toxicity test of 1 pair of fruit bat that fills the stomach of table 4 photosensitizer
Claims (4)
1. dihydro porphin photosensitizer, name is called intermediary-four (3-(N, N dimethylamine ylmethyl)-4-methoxyphenyl) chlorin chemical compound, and its chemical structural formula is:
2. the preparation method of a dihydro porphin photosensitizer comprises:
With (3-(the N of 1.047mmol-1.055mmol intermediary-four; the N dimethylamine ylmethyl)-and the 4-methoxyphenyl) porphin; 1.696mmol-1.72mmol Reducing agent, after the 7.080mmol-7.2mmol Anhydrous potassium carbonate mixes, evacuation; inflated with nitrogen; add the 48mL pyridine, after stirring, reflux under the nitrogen protection; reaction finishes postcooling; stirring at room 12-24h adds 90-110mL ethyl acetate, 40-60mL water afterwards in reactant liquor; 100 ℃ were reacted 1 hour; cooling, organic facies washes with water, drying, sucking filtration, concentrated; through the silica gel column chromatography eluting, promptly.
3. the preparation method of a kind of dihydro porphin photosensitizer according to claim 2, it is characterized in that: the Reducing agent in the described step is unifor or hydrazine hydrate.
4. the application of dihydro porphin photosensitizer in preparation treatment tumor class disease medicament or photoactivation insecticide.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113754672A (en) * | 2021-10-27 | 2021-12-07 | 上海先辉医药科技有限公司 | Novel tetrapyrrole compound and application thereof |
| CN114516879A (en) * | 2022-02-28 | 2022-05-20 | 上海先辉医药科技有限公司 | Novel intermediate tetraphenyl naphthoporphin derivative and application thereof in medical field |
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Non-Patent Citations (3)
| Title |
|---|
| 《医学综述》 20081130 邵红霞等 光敏剂在光动力疗法中的作用 3404-07 1-4 第14卷, 第22期 2 * |
| 《药学进展》 20071231 张丹萍 光动力药物的研究与开发 529-535 1-4 第31卷, 第12期 2 * |
| 《高等学校化学学报》 19891130 张洲鹏 7种中位-四取代苯基卟啉化合物的合成 1136-38 1-4 第10卷, 第11期 2 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113754672A (en) * | 2021-10-27 | 2021-12-07 | 上海先辉医药科技有限公司 | Novel tetrapyrrole compound and application thereof |
| CN113754672B (en) * | 2021-10-27 | 2024-05-03 | 上海先辉医药科技有限公司 | Novel tetrapyrrole compounds and application thereof |
| CN114516879A (en) * | 2022-02-28 | 2022-05-20 | 上海先辉医药科技有限公司 | Novel intermediate tetraphenyl naphthoporphin derivative and application thereof in medical field |
| CN114516879B (en) * | 2022-02-28 | 2024-05-03 | 上海先辉医药科技有限公司 | Novel intermediate tetraphenyl naphthoporphin derivative and application thereof in medicine field |
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