CN102125549B - 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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- CN102125549B CN102125549B CN2010106005231A CN201010600523A CN102125549B CN 102125549 B CN102125549 B CN 102125549B CN 2010106005231 A CN2010106005231 A CN 2010106005231A CN 201010600523 A CN201010600523 A CN 201010600523A CN 102125549 B CN102125549 B CN 102125549B
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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
PDT is nearly 20 years a kind of one of the most promising new techniques that grow up.Since 20th century, got into clinical research the seventies, on tumor treatment, obtained and broken through progress, PDT not only is confined to the treatment of malignant tumor at present, in other multiple treatment of diseases, also shows good prospect.
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 main with the porphyrin analog derivative; The chemical constitution of this compounds is clear and definite, and higher purity is arranged, preferably photo and thermal stability; The absorption of red light district is stronger; Through 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 absorbing wavelength length and absorption are strong in the visual field.Say that from point of theory this compounds has shown the characteristic of suitable PDT medicine, have 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 (like 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 processed hydrochlorate easily, uses thereby be made into injection, and stability is strong.
The absorptance porphin is strong in long wavelength (500-750nm) district for Temoporfin, 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 (like 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, TMSDEA N diethylamine 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, TMSDEA N diethylamine 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:
(pressing literature method prepares: Zhang Zhoupeng etc., SCI, 1989 to add 1.047mmol-1.055mmol intermediary-four (3-(N, TMSDEA N diethylamine ylmethyl)-4-methoxyphenyl) porphin in the 250ml container; 10 (11): 1136-1138), add the 1.696mmol-1.72mmol Reducing agent, and add 7.080mmol-7.2mmol Anhydrous potassium carbonate, evacuation; Inflated with nitrogen adds the 48mL pyridine, stirs, under the nitrogen protection; In oil bath, keep reflux, reaction finishes postcooling, and stirring at room 12-24h adds the 90-110mL ethyl acetate afterwards in reactant liquor; 40-60mL water keeps 100 ℃ of reactions 1 hour in oil bath, cooling, and organic facies is with water washing repeatedly; Drying, sucking filtration, concentrated through the silica gel column chromatography eluting, promptly get.
Reducing agent is unifor or hydrazine hydrate in the said 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.
Through photosensitizer of the present invention the light dynamic test of colon cancer cell is found, when illumination is arranged, the propagation of photosensitizer ability obvious suppression colon cancer cell; Through 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; Through light power activation toxicity test, find that this chemical compound is one type of 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, method for preparing 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 the restriction scope of the present invention.Should be understood that in addition those skilled in the art can do various changes or modification to 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, TMSDEA N diethylamine ylmethyl)-4-methoxyphenyl) chlorin (meso-tetra [3-(N, N-diethylaminomethyl)-4-methoxyphenyl] chlorine) synthetic:
Add 1184g (1.047mmol) intermediary-four (3-(N, TMSDEA N diethylamine 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 ℃) stirred overnight then.In reactant liquor, add the 90mL ethyl acetate afterwards, 40mL water keeps 100 ℃ of reactions 1 hour in oil bath.Cooling, organic facies with water washing is repeatedly used anhydrous sodium sulfate drying, filters; Concentrate, plate layer chromatography separated 2 times, with methylene chloride-methanol-triethylamine (20: 1: 0.2; V/v) do developing solvent, and last column chromatography (methylene chloride-methanol-triethylamine=20: 1: 0.2, v/v); Collect the aubergine colour band, 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, TMSDEA N diethylamine ylmethyl)-4-methoxyphenyl) chlorin (meso-tetra [3-(N, N-diethylaminomethyl)-4-methoxyphenyl] chlorine) synthetic:
Add 1193g (1.055mmol) intermediary-four (3-(N, TMSDEA N diethylamine 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 ℃) stirred overnight then.In reactant liquor, add the 110mL ethyl acetate afterwards, 60mL water keeps 100 ℃ of reactions 1 hour in oil bath.Cooling, organic facies with water washing is repeatedly used anhydrous sodium sulfate drying, filters; Concentrate, plate layer chromatography separated 2 times, with methylene chloride-methanol-triethylamine (20: 1: 0.2; V/v) do developing solvent, and last column chromatography (methylene chloride-methanol-triethylamine=20: 1: 0.2, v/v); Collect the aubergine colour band, 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
Receive 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 appearance.
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 96 orifice plates with it 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, ELIASA 570nm detects the OD value.The experiment triplicate.Experimental result is seen table 1, and the result finds 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 96 orifice plates with it 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, ELIASA 570nm detects the OD value.The experiment triplicate.Experimental result is seen table 2, and the result finds 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)
Receive 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 appearance.
Mice S180 sarcoma light power injury experiment: 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 under the aseptic condition; 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 2h uses power density to be 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.
In
formula, T: the average tumor of administration group is heavy; C: the average tumor of matched group is heavy
Experimental result is seen 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 divide into groups (being regardless of male and female), being put into and contains in (0.5,1.0,2.0 g/L) culture tube that variable concentrations receives reagent appearance, and 20 of every pipes tightly cover mouth with the nylon yarn fabric width.Handle repetition 3 times for every kind.Culture tube is placed the dark place; Simulate the 48h that takes food in the dark, shift then in the basal medium, 20cm evenly receives 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 is seen 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, TMSDEA N diethylamine ylmethyl)-4-methoxyphenyl) chlorin chemical compound, and its chemical structural formula is:
2. the method for preparing of a dihydro porphin photosensitizer comprises:
With 1.047mmol-1.055mmol intermediary-four (3-(N, TMSDEA N diethylamine ylmethyl)-4-methoxyphenyl) porphin, the 1.696mmol-1.72mmol Reducing agent is after the 7.080mmol-7.2mmol Anhydrous potassium carbonate mixes; Evacuation, inflated with nitrogen adds the 48mL pyridine, after stirring; Reflux under the nitrogen protection, reaction finishes postcooling, and stirring at room 12-24h adds the 90-110mL ethyl acetate afterwards in reactant liquor; 40-60mL water, 100 ℃ were reacted 1 hour, cooling, organic facies is used water washing; Drying, sucking filtration, concentrated through the silica gel column chromatography eluting, promptly get.
3. the method for preparing of a kind of dihydro porphin photosensitizer according to claim 2, it is characterized in that: the Reducing agent in the said step is unifor or hydrazine hydrate.
4. the application of a kind of dihydro porphin photosensitizer as claimed in claim 1 in preparation treatment tumor class disease medicament or photoactivation insecticide.
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Non-Patent Citations (3)
| Title |
|---|
| 张丹萍.光动力药物的研究与开发.《药学进展》.2007,第31卷(第12期),529-535. * |
| 张洲鹏.7种中位-四取代苯基卟啉化合物的合成.《高等学校化学学报》.1989,第10卷(第11期),1136-38. * |
| 邵红霞等.光敏剂在光动力疗法中的作用.《医学综述》.2008,第14卷(第22期),3404-07. * |
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