CN107903258A - A kind of fat-soluble photosensitizer and its preparation method and application - Google Patents
A kind of fat-soluble photosensitizer and its preparation method and application Download PDFInfo
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- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
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- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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Abstract
The invention discloses a kind of fat-soluble photosensitizer and its preparation method and application.Vitamin e derivative and their inorganic salts and photosensitizer are combined the treatment for skin neoplasin by the present invention; while tumour cell can effectively be killed; by protective effect of the vitamin E to healthy skin, collagen fibers of skin reparation can be helped, greatly reduces drug side-effect.A kind of fat-soluble photosensitizer of the present invention, drug metabolic rate slow down, and drug effect is more lasting.Photosensitizer containing vitamin e derivative can produce more free radicals, and more efficiently quick to kill tumour cell, required dosage is far below 5 ALA of in the market, without antibiotic, does not produce drug resistance, is safe and non-toxic and economical and practical.
Description
Technical field
The present invention relates to a kind of fat-soluble photosensitizer and its preparation method and application, belongs to medical treatment and biomedical sector..
Background technology
Skin Squamous Cell Carcinoma is one kind of skin neoplasin.It is mainly characterized by：From the beginning of swelling lump for defect shape, substrate is hard, table
Face is coarse such as cauliflower-shaped, it is seen that telangiectasis, the cutin of the common sting sample in top.Skin Squamous Cell Carcinoma concurrent infection has sticky purulence
Liquid, with stench, pain.Its grade of malignancy is higher, is easier to shift, and common regional lymph nodes transfer, seriously affects patient's body and mind and be good for
Health.
The anticancer principle of photodynamic therapy (Photodynamic Therapy, PDT) is a kind of main influence destination organization,
Therapeutic modality with double selectivity.Its double selectivity be based on photosensitizer in normal structure and destination organization concentration
Difference, and make light to destination organization direct irradiation by way of limiting and focus on space.Photosensitizer is when injection 3-96 is small
After accumulate in destination organization, the specific time depends on photosensitizer used.During accumulation, with light direct irradiation destination organization with work
Change photosensitizer, the photosensitizer of activation transfers energy to ground state oxygen (3O2,3 ∑ g-) so as to form various forms of active oxygens, damages
Hinder the important 26S Proteasome Structure and Function of tumour cell, and then cause the destruction of tumor tissues.With the conventional therapy such as operation, chemotherapy, radiotherapy
Means are compared, and tumor photodynamic therapy has following important advantage：1) wound is small.2) toxicity is humble:Into the light power of tissue
Medicine, only reaches a certain concentration and is subject to sufficient light to irradiate, can just trigger phototoxic reaction killing tumor cell.3) selectivity
It is good.4) appearance and vitals function can be protected.
The side effect of existing photodynamic therapy is often photo sensitive reaction, at the same photodynamic reaction have certain hysteresis quality and
Uncontrollability, although targeting is high, its reaction speed is difficult to control with degree, causes side reaction more, curative effect is poor.Table
Now there is erythema or bubble, such as Chinese invention for local skin《Application of the photosensitizer in acne treatment》, application number：
201310097473.3, the photosensitizer of use occurs local temporary transient reactive edema for therapentic part after acne treatment,
And with pain, being due to that skin healing is bad causes.Secondly, aggregate concentration of the existing photosensitizer in skin neoplasin tissue
It need to be improved, such as Chinese invention《Photosensitizer chlorophyllin sodium salt derivative and its preparation method and application》, application number：
201210169784.1；The chlorophyllin sodium salt derivative of use is combined with traditional photosensitive agent, although water-soluble chlorophyllin sodium salt increases
The strong penetrating power of photosensitizer, but since its is not fat-soluble strong, makes photosensitizer enriched concentration and when retaining in tumor tissues
Between be just extremely restricted, be still difficult to reach good therapeutic effect.
To solve the above problems, the present invention designs the photosensitizer based on vitamin e derivative, vitamin E conduct first
A kind of powerful liposoluble vitamin, is widely used in skin makeup product, has the advantage that：1) can remove freely
Base, has antioxidation；2) enzymatic activity can be maintained, increases the function of mitochondria and biomembrane, makes cell membrane broken from oxidation
It is bad；3) the protein active structure of its energy stabilizing cell membrane, promotes the normal development of muscle and keeps the elasticity of skin；4) vitamin
E is fatsolvent, can skin care, improve local blood circulation and histotrophic nutrition situation, protect maintenance skin.The present invention is at the same time
Contain more oxygen atom using vitamin e derivative, there is bipolarity and skin healing can be promoted to repair, greatly
Photosensitizer is improved in tumor tissues enriched concentration and retention time, while realizing efficient optical dynamic therapy, also reduces light
The healing of infringement and promotion therapentic part skin of the power to surrounding healthy skin.
The content of the invention
For above-mentioned technical problem, it is an object of the invention to provide a kind of a kind of Small side effects, quick new
A kind of fat-soluble smooth power external preparation containing vitamin E fragment, pass through light power utilization oxidative stress treat skin squama
Cancer.
The technical scheme is that, there is provided a kind of fat-soluble photosensitizer, the structural formula of the fat-soluble photosensitizer are：
Wherein
R is K or Na.
The present invention also provides the preparation method of above-mentioned fat-soluble photosensitizer, comprise the following steps：
(1) by naphthalidine and chlorine-containing compoundReacted in 55 DEG C -60 DEG C of alcohol solvent, obtain centre
Product A, its reaction equation are：
By tetracarboxylic acid based compoundWith
KOH or NaOH solution reaction, obtain intermediate product B；
(2) intermediate product A and intermediate product B are pressed into 2-2.5：The molar ratio of 3-4 is reacted in alcohol solvent, obtains centre
Product C, reaction equation are：
(3) vitamin E and intermediate product C are reacted in acetone solvent, obtains fat-soluble photosensitizer, reaction equation is：
, in the reaction of step (1) synthetic mesophase product A, the molar ratio of naphthalidine and chloride is 1-2:2-2.5, instead
It is 4-5 minutes between seasonable.
Preferably, in the reaction of step (1) synthetic mesophase product B, using acetone or benzene as reaction dissolvent, temperature 45-50
℃。
Preferably, in step (2) synthetic mesophase product C reactions, reacted 20-30 minutes in 60-63 DEG C of alcohol solvent.
Preferably, in the reaction of step (3) synthesis fat-soluble photosensitizer, the molar ratio of intermediate product C and vitamin E is 1:1.
The present invention also provides application of the above-mentioned fat-soluble photosensitizer in terms of antitumor drug is prepared.
Preferably, in antitumor drug, the weight percentage of the fat-soluble photosensitizer for 0.0005%~
0.0020%.
Preferably, in antitumor drug, the weight percentage of the fat-soluble photosensitizer is 0.0015%.
Preferably, the antitumor drug is anti-skin neoplasin medicine, particularly anti-epithelial origin tumour medicine.
The dosage of the photosensitizer is 20~50mg/kg, and the weight percentage in the composition of photosensitizer is
0.0005%~0.0020%, preferably 0.0015%.The preparation includes liposoluble vitamin and pharmaceutically acceptable figuration
Agent or auxiliary material.The auxiliary material or excipient include but not limited to mannitol, sodium hydrogensulfite, starch, dextrine powder, absolute ethyl alcohol,
Any one or more in water for injection, Icing Sugar, lactose, hydroxypropyl methylcellulose, magnesium stearate, sucrose, PVP K30.
The light for the composition that the excitation includes photosensitizer is ultraviolet or visible light, preferably feux rouges.
Light source used in the light is：Ultrasonic irradiation generator, photoemitted electron pipe, electronic laser pipe, fuel laser,
One in daylight or white heat line source that halogen family metalized lamp, flash lamp, the fluorescent light source of machinery filtration, daylight or machinery filter
Kind is a variety of.
When light excitation includes the composition of this photosensitizer, optical wavelength is not limited, it is contemplated that penetrate effect, optimal wavelength
In the feux rouges of 380-780nm.Range of light intensities preferably 1~100J/cm2, optimum range is 1~20J/cm2。
In addition to exposure intensity, irradiation time is not also limited.It is good and to normal skin zero damage to reach effect
Condition, in addition to having optimal irradiation luminous intensity, irradiation equally also has an optimal irradiation time, optimal irradiation time for 10min~
15min, light irradiation number is 1 time.
The composition including photosensitizer is used in the form of liquid, semisolid, solid or aerosol.It is such as water-soluble
Either insoluble muddy suspension, solution, gel, emulsion (including cream), ointment, gel, slurries, suppository, tablet, capsule or thin
The forms such as micro- spray are used.
The skin neoplasin, it is mainly characterized by：From the beginning of swelling lump for defect shape, substrate is hard, rough surface such as cauliflower
Shape, it is seen that telangiectasis, the common sting sample cutin in top.
The photosensitiser composition including liposoluble vitamin E is intensified when light irradiates, by activate ERK, JNK and
P38 signal paths, promote tumour cell to produce oxidative stress inducing cell apoptosis, have the effect of fine to skin neoplasin.
The present invention has the beneficial effect that：Vitamin e derivative and their inorganic salts and photosensitizer are combined and swollen for skin
Knurl is treated, its therapeutic effect is notable, by protective effect of the vitamin E to healthy skin, collagen fibers of skin can be helped to repair
It is multiple, drug side-effect is greatly reduced, but normal cell is not damaged, the photosensitizer containing vitamin e derivative can produce more
More free radicals, reduces side effect and efficiently can quickly kill skin neoplasin with higher treatment concentration, more efficiently quickly kill
Dead tumour cell, dosage are far below the 5-ALA of in the market, without antibiotic, do not produce drug resistance, safe and non-toxic and economic reality
With.
Brief description of the drawings
Fig. 1 shows the chemical structural formula of fat-soluble photosensitizer.
Fig. 2 represents the hydrogen spectrogram of fat-soluble photosensitizer.
Fig. 3 represents the carbon spectrogram of fat-soluble photosensitizer.
Fig. 4 represents the influence that gradient concentration photosensitizer survives A431 squamous cell carcinomas.
Fig. 5 represents gradient concentration photosensitizer to A431 squamous cell carcinoma survival rate quantitative statistics figures.
Fig. 6 represents A431 squamous cell carcinoma fluidic cell result figures.
Fig. 7 represents apoptosis-related protein Western Blot result figures after photosensitizer processing.
Fig. 8 shows Caspase-3 and Bcl-2Western Blot result figures after photosensitizer processing.
Fig. 9 represents photosensitizer tumor tissue pathology's slice map before and after the processing.
Embodiment
With reference to embodiment, the invention will be further described.
Embodiment 1：The synthetic route of fat-soluble photosensitizer is as follows：
(1) by naphthalidine and chlorine-containing compoundReacted in 55 DEG C -60 DEG C of alcohol solvent, obtain centre
Product A, its reaction equation are：
By tetracarboxylic acid based compoundWith
KOH or NaOH solution reaction, obtain intermediate product B；
(2) intermediate product A and intermediate product B are pressed into 2-2.5：The molar ratio of 3-4 is reacted in alcohol solvent, obtains centre
Product C, reaction equation are：
(3) vitamin E and intermediate product C are reacted in acetone solvent, obtains fat-soluble photosensitizer (Fig. 1), reaction equation
For：
The hydrogen for end-product composes (Fig. 2) and carbon and composes (Fig. 3) below, it was demonstrated that the present invention successfully obtains above-mentioned target and produces
Thing.
Embodiment 2：Long-acting fat-soluble smooth power external preparation containing vitamin E fragment suppresses Skin Tumor Cells activity
Test
Mtt assay, is a kind of method for detecting cell survival and growth.Its testing principle is the amber in living cells mitochondria
Acidohydrogenase can make exogenous MTT be reduced to the bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) of water-insoluble and be deposited in cell,
And dead cell is without this function.Dimethyl sulfoxide (DMSO) (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, with enzyme-linked immunosorbent assay instrument in 490nm ripples
Strong point measures its absorbance value, can reflect living cells quantity indirectly.
(1) experimental method
Squamous cell carcinoma A-431 cell lines are incubated in the DMEM nutrient solutions of 10% calf serum, add the mould of 100IU/L
The streptomysin of element and 100mg/L, is placed in 37 DEG C, and cellar culture in the constant incubator of 5%CO2, after cell covers with bottom of bottle, is abandoned
Fall nutrient solution, PBS liquid rinses twice, then is digested 5 minutes with 0.25% pancreatin and 0.02% EDTA, then sub-bottle culture, 2 to
Once, growth period cell of taking the logarithm is used to test for passage in 3 days.
The A-431 cells in growth period of taking the logarithm are inoculated in after pancreatin digests in six well culture plates, are placed in 5%CO2 cultures
Case, 37 DEG C culture, it is to be grown to 80%~90% Fusion Strain when, be separately added into distilled water, 100nM, 200nM, 400nM,
The above-mentioned long-acting fat-soluble smooth power preparations containing vitamin E fragment of 600nM and 800nM, after being incubated 1h, use 20J/cm2It is red
Light irradiates 15min, detects the state of cell survival and growth after 16h with mtt assay.
(2) experimental result
MTT experiment is the results show that the long-acting fat-soluble smooth power preparation containing vitamin E fragment can substantially suppress A-431
Cytoactive, and the inhibition of cytoactive is increased with the increasing of dosage, in the long-acting fat containing vitamin E fragment
Inhibition can reach 76% (Fig. 4 and Fig. 5) during dissolubility light power preparation 800nM.
Embodiment 3：Long-acting fat-soluble smooth power preparation containing vitamin E fragment makes skin neoplasin produce apoptosis experiment
Annexin V are a kind of reagents for detecting Apoptosis, and in normal cell, phosphatidylserine is only distributed in carefully
The inner side of after birth double-layer of lipoid, apoptosis early stage, membrane phospholipid acyl serine (PS) in adipose membrane by turning on one's side laterally.Therefore
Annexin V are the sensitive indexes for detecting early apoptosis of cells.PI (propidium iodide) is a kind of nuclei dyeing that can be dyed to DNA
Color reagent, can be through damaged cell membrane and to nuclear staining although PI cannot be by living cells film.Therefore Annexin V
Being used in combination with PI can be at the same time to living cells and dead cell stain.
(1) experimental method
Squamous cell carcinoma A-431 cell lines are incubated in the DMEM nutrient solutions of 10% calf serum, add the mould of 100IU/L
The streptomysin of element and 100mg/L, is placed in 37 DEG C, and cellar culture in the constant incubator of 5%CO2, after cell covers with bottom of bottle, is abandoned
Fall nutrient solution, PBS liquid rinses twice, then is digested 5 minutes with 0.25% pancreatin and 0.02% EDTA, then sub-bottle culture, 2 to
Once, growth period cell of taking the logarithm is used to test for passage in 3 days.
The A-431 cells in growth period of taking the logarithm are inoculated in after pancreatin digests in six well culture plates, are placed in 5%CO2 cultures
Case, 37 DEG C culture, it is to be grown to 80%~90% Fusion Strain when, irradiation group is separately added into the above-mentioned fragments containing vitamin E of 400nM
Preparation, the above-mentioned preparation of fragment containing the vitamin E+NAC (acetylcysteine) of 400nM, the above-mentioned preparations of fragment containing vitamin E of 400nM+
GSH (glutathione), 100 μM of H2O2, 100 μM of H2O2+ NAC and 100 μM of H2O2After+GSH is incubated 1h, 20J/cm is used2Feux rouges
15min is irradiated, in addition irradiation group is not separately added into distilled water and the above-mentioned preparations of fragment containing vitamin E of 400nM, and irradiation is used after 16h
Group and not irradiation group are dyed with Annexin V-PI respectively, and cell is observed by FACSCalibur flow cytometer
The situation of apoptosis.
(2) experimental result
Flow cytometer detection the results show that the above-mentioned preparations of fragment containing vitamin E of 400nM irradiation is not thin not to A-431 to cell
Born of the same parents produce cytotoxicity.And the Apoptosis that 16h is produced after 400nM fragments containing vitamin E preparation-PDT processing is than empty
24% (Fig. 6) of white group increase, antioxidant NAC and GSH can substantially save the preparation-PDT of fragment containing vitamin E to A431 cells
Lethal effect, saves effect and reaches 4.83% and 12.55%.From interpretation of result, 400nM fragments containing vitamin E preparation-PDT energy
Obvious inducing cell produces apoptosis, and oxidative stress take part in killings of 400nM fragments containing the vitamin E preparation-PDT to cell
Effect.
Embodiment 4：The long-acting fat-soluble smooth power external preparation activation Skin Tumor Cells MAPK signals of fragment containing vitamin E
Promote cell apoptosis assay
MAPK signals participate in cell and the stress reactions such as radiation, osmotic pressure, temperature change, oxidative stress, regulating cell are increased
Grow, apoptosis and necrosis.Caspase-3 and Bcl-2 is the important indicator of Apoptosis, Caspase-3 expression increase and Bcl-2 tables
Suppression up to amount is the important symbol that cell produces apoptosis.
(1) experimental method
Squamous cell carcinoma A-431 cell lines are incubated in the DMEM nutrient solutions of 10% calf serum, add the mould of 100IU/L
The streptomysin of element and 100mg/L, is placed in 37 DEG C, and cellar culture in the constant incubator of 5%CO2, after cell covers with bottom of bottle, is abandoned
Fall nutrient solution, PBS liquid rinses twice, then is digested 5 minutes with 0.25% pancreatin and 0.02% EDTA, then sub-bottle culture, 2 to
Once, growth period cell of taking the logarithm is used to test for passage in 3 days.
The A-431 cells in growth period of taking the logarithm are inoculated in after pancreatin digests in six well culture plates, are placed in 5%CO2 cultures
Case, 37 DEG C culture, it is to be grown to 80%~90% Fusion Strain when, distilled water, 100 μM of H are separately added into every hole2O2,
400nM fragments containing vitamin E preparation and EGF, after being incubated 1h, use 20J/cm2Red light irradiation 15min, collected after half an hour thin
Born of the same parents extract the expression that total protein detects p-ERK, p-JNK and p-P38 in cell with Western Blot methods.
The A-431 cells in growth period of taking the logarithm are inoculated in culture dish after pancreatin digests, and are placed in 5%CO2 incubators, and 37
DEG C culture, it is to be grown to 80%~90% Fusion Strain when, irradiation group is separately added into 400nM fragments containing vitamin E preparation,
400nM fragments containing vitamin E preparation+NAC (acetylcysteine), 400nM fragments containing vitamin E preparation+GSH (gluathiones
Peptide), 100 μM of H2O2, 100 μM of H2O2+ NAC and 100 μM of H2O2After+GSH is incubated 1h, 20J/cm is used2Red light irradiation 15min,
Albumen is extracted after half an hour, in addition irradiation group is not separately added into distilled water and the 400nM preparation of fragment containing vitamin E, after half an hour
Albumen is extracted, detects the expression of p-ERK, p-JNK and p-P38 in cell with Western Blot methods respectively.
The A-431 cells in growth period of taking the logarithm are inoculated in culture dish after pancreatin digests, and are placed in 5%CO2 incubators, and 37
DEG C culture, it is to be grown to 80%~90% Fusion Strain when, irradiation group is separately added into 100nM, 200nM, 400nM and contains vitamin E
Fragment preparation, 100nM, 200nM, 400nM fragment containing vitamin E preparation+NAC (acetylcysteine), 100nM, 200nM,
400nM fragments containing vitamin E preparation+GSH (glutathione), 100 μM of H2O2, 100 μM of H2O2+ NAC and 100 μM of H2O2+GSH
After being incubated 1h, 20J/cm is used2Red light irradiation 15min, 16 it is small when after extract albumen, in addition irradiation group is not separately added into distilled water
With 400nM fragments containing vitamin E preparation, 16 it is small when after extract albumen, respectively with Western Blot methods detect cell in
The expression quantity of Caspase-3.
The A-431 cells in growth period of taking the logarithm are inoculated in after pancreatin digests in six well culture plates, are placed in 5%CO2 cultures
Case, 37 DEG C of cultures, it is to be grown to 80%~90% Fusion Strain when, add the 400nM preparations of fragment containing vitamin E medicaments incubation 1h
Afterwards, 20J/cm is used2Red light irradiation 15min, 16h after carries out immunofluorescence dyeing with collecting cell, observe cell Caspase-3
With the expression quantity of Bcl-2.
(2) experimental result
400nM fragments containing vitamin E preparation-PDT processing A-431 cells can substantially activate p-ERK, p-JNK and p-P38 letter
Number, its effect is better than 100 μM of H2O2(Fig. 7) represents that activation of the 400nM photosensitizers to apoptotic signal path is better than H2O2。
100nM, 200nM, 400nM fragment containing vitamin E preparation-PDT can substantially increase the expression of Caspase-3 at the same time.
Hydrogen peroxide substantially increases Caspase-3, and antioxidant NAC and GSH have inverted result.Antioxidant NAC and GSH is in different journeys
The Caspase-3 increases that the preparation of fragment containing vitamin E-PDT is induced are inhibited on degree.Immunofluorescence dyeing result equally explanation contains
Vitamin E fragment preparation-PDT is remarkably reinforced the expression of Caspase-3, while inhibits the expression (Fig. 8) of Bcl-2.Illustrate this
The apoptotic pathways of squamous carcinoma tumour cell can effectively be activated by inventing the photosensitizer containing vitamin E fragment being related to, from
And promote the death of cancer cell.Also, " Apoptosis " this procedural death process, is that cell is automatically dead, to week
The influence of side normal structure is very faint, and photodynamic side reaction is greatly reduced.
Embodiment 5：The preparation of fragment containing vitamin E-PDT treatment squamous carcinoma tumor-bearing mice experiments
(1) zoopery
Mouse squamous cytoma model, selects nude mice, male, 18-20g.During experiment, well-grown A-431 cells are taken,
With sterile saline by 1 after pancreatin digests:Tumor cell suspension is made after 10 dilution proportions, tumour is percutaneous on the left of nude mice
300 μM of preparations of fragment containing vitamin E of lower injection, right side tumor are not handled as control, use 20J/cm2Red light irradiation 15min,
Collect within the 7th day after processing tumor tissues and carry out histotomy observation tumor presence.
(2) experimental result
It can see within the 7th day after the 300 μM of preparation of fragment containing vitamin E-PDT processing, treatment group tumor tissue (500 μ
M-PDT it is) substantially smaller than control group (Ctrl), as a result illustrate that the preparation of fragment containing vitamin E-PDT can substantially remove tumor mass cell,
There is obvious therapeutic effect (Fig. 9) to Skin Squamous Cell Carcinoma.And tumor tissues and periphery health tissues are contrasted, compared to the control group
(Ctrl), after bright agent processing involved in the present invention, each level arrangement of newborn repair cell is closer, and cell growth is more prosperous
Contain, it is more clear with tumor tissues boundary, as a result illustrate that a kind of fat-soluble long-acting photosensitizer of the present invention kills tumor tissues
Hindering destruction effect has compared with high specific, and surrounding normal tissue injury is smaller after photodynamic reaction.And postnecrotic former tumor group
Also faster, outcome is more preferable for the reparation and healing of tissue region.
Claims (10)
1. a kind of fat-soluble photosensitizer, it is characterised in that the structural formula of the fat-soluble photosensitizer is：
Wherein R is K or Na.
2. the preparation method of the fat-soluble photosensitizer described in a kind of claim 1, it is characterised in that comprise the following steps：
(1) by naphthalidine and chlorine-containing compoundReacted in 55 DEG C -60 DEG C of alcohol solvent, obtain intermediate product
A, its reaction equation are：
By tetracarboxylic acid based compoundWith KOH or
NaOH solution is reacted, and obtains intermediate product B；
(2) intermediate product A and intermediate product B are pressed into 2-2.5：The molar ratio of 3-4 is reacted in alcohol solvent, obtains intermediate product
C, reaction equation are：
(3) vitamin E and intermediate product C are reacted in acetone solvent, obtains fat-soluble photosensitizer, reaction equation is：
3. preparation method as claimed in claim 2, it is characterised in that in the reaction of step (1) synthetic mesophase product A, 1- naphthalenes
The molar ratio of amine and chloride is 1-2:2-2.5, reaction time are 4-5 minutes.
4. preparation method as claimed in claim 2, it is characterised in that in the reaction of step (1) synthetic mesophase product B, with third
Ketone or benzene are reaction dissolvent, and temperature is 45-50 DEG C.
5. preparation method as claimed in claim 2, it is characterised in that in step (2) synthetic mesophase product C reactions, in 60-63
DEG C alcohol solvent in react 20-30 minutes.
6. preparation method as claimed in claim 2, it is characterised in that middle in step (3) synthesis fat-soluble photosensitizer reaction
The molar ratio of product C and vitamin E is 1:1.
7. application of the fat-soluble photosensitizer described in claim 1 in terms of antitumor drug is prepared.
8. application as claimed in claim 7, it is characterised in that in antitumor drug, the weight of the fat-soluble photosensitizer
Percentage composition is 0.0005%~0.0020%.
9. application as claimed in claim 7, it is characterised in that in antitumor drug, the weight of the fat-soluble photosensitizer
Percentage composition is 0.0015%.
10. such as claim 7-9 any one of them applications, it is characterised in that the antitumor drug swells for anti-epithelial origin
Tumor medicine.
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| CN115536608A (en) * | 2022-09-13 | 2022-12-30 | 温州医科大学 | Oxazine compound and preparation method and application thereof |
| CN115536608B (en) * | 2022-09-13 | 2023-12-15 | 温州医科大学 | Oxazine compound and preparation method and application thereof |
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