CN108383923A - Phephorbide a-lentinan ester and preparation method thereof - Google Patents
Phephorbide a-lentinan ester and preparation method thereof Download PDFInfo
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- CN108383923A CN108383923A CN201810496118.6A CN201810496118A CN108383923A CN 108383923 A CN108383923 A CN 108383923A CN 201810496118 A CN201810496118 A CN 201810496118A CN 108383923 A CN108383923 A CN 108383923A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
- A61K41/0033—Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- 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
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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Abstract
The Phephorbide a lentinan ester of the present invention occurs esterification with Phephorbide a by lentinan and is prepared, lentinan is as the polar end for being dissolved in water, so that Phephorbide a lentinan ester is dissolved in water, solves the problems, such as Phephorbide a poorly water-soluble, with Phephorbide a and the dual antitumor action of lentinan, belong to light, sound dynamic therapy drug, can be used for preparing the drug for the treatment of skin disease, malignant tumour or cancerous thoracoascites.
Description
Technical field
The present invention relates to light, sound dynamic therapy drugs, specifically Phephorbide a-lentinan ester.
Background technology
Phephorbide a has certain light sensitivity and thermal sensitivity, thus Phephorbide a is both a kind of photosensitizer,
It is a kind of very promising sound sensitiser.It can generate more ROS（Reactive oxygen species）, and nontoxic, tumor tissues high selection
Property and nonneoplastic tissue clearance rate it is high, it is also smaller to the side reaction of skin, therefore suitable for tumour light, sound dynamic therapy.But
It is Phephorbide a poorly water-soluble, therefore limits it in clinical development and application.
Lentinan (lentinan, LNT) is the effective active composition extracted from high quality mushroom fruiting body, is to have
β-(1-3)-D- glucans of branch, main chain are made of the glucosyl group of β-(1-3)-connections, by β-along main chain random distribution
The glucosyl group of (1-6) connection is in pectinate texture.
Clinic shows that lentinan is a kind of host immune reinforcing agent (host defense with pharmacological research
Potentiator, HDP), have the effects that antiviral and antitumor, adjust immune function and stimulation interferon formation.Function master
It controls：It cannot perform the operation or Recurrent Gastric Carcinoma, liver cancer, carcinoma of urinary bladder, can alleviate symptom using this product, improve patient's immune function, correct
Disorder of tracelements.Lentinan plus radiotherapy, chemotherapeutic treatment Small Cell Lung Cancer, breast cancer, malignant lymphoma etc..It can also be used for carcinous
The treatment of Pleural effusions.
Lentinan is pale powder, is mostly acidic polysaccharose, is dissolved in water, diluted alkaline, is especially soluble in hot water, does not dissolve in
The organic solvents such as ethyl alcohol, acetone, ethyl acetate, ether, the transparent sticky shape of aqueous solution.Lentinan has no normal body
Immunologic enhancement, but lotus knurl formula or the immune response of metainfective body can be made to be improved.Lentinan has antitumor
Effect, it does not have the toxic side effect of chemotherapeutics.Lentinan is used with chemotherapeutic agent, there is attenuation, synergy.Mushroom
Polysaccharide can also make the blood vessel dilatation and bleeding of tumor locus, lead to tumour hemorrhagic necrosis and degenerate completely.
Have no the report that lentinan is combined with Phephorbide a.
Invention content
The advantages of in order to integrate lentinan and Phephorbide a, exploitation is preferably for light, the medicine of sound dynamic therapy
Object, the present invention provide Phephorbide a-lentinan ester.
The structure of Phephorbide a-lentinan ester such as following formula：
Esterification occurs with Phephorbide a by lentinan to be prepared.
The preparation method of Phephorbide a-lentinan ester, includes the following steps：
1）, in protective gas and under the conditions of be protected from light, lentinan is esterified with Phephorbide a；
2）, centrifugation, supernatant is with deionized water dialysis, freeze-drying.
3）, dried object detached with silica gel column chromatography, eluant, eluent is the mixed of the methylene chloride/methanol that volume ratio is 3/7 ~ 7/3
Close solution；
4）, fling to methylene chloride/methanol after, dissolved with methanol or acetonitrile, with reversed phase column chromatography polishing purification, eluant, eluent is first
Alcohol/water mixed liquid or acetonitrile/water mixed liquor；The filler that the reversed-phase column uses is C18；The methanol/water mixed liquor or acetonitrile/
The volume ratio of water mixed liquid is 3/7 ~ 7/3；
5）, gained refined solution be concentrated to dryness, then concentrate be dried in vacuo 24 ~ 36h or freeze-drying, obtain target product.
The application of Phephorbide a-lentinan ester is to prepare treatment skin disease, malignant tumour or cancerous thoracoascites
Drug, the skin disease includes：Condyloma acuminatum, flat wart, acne, nevus flammeus, capillary hemangioma, the malignant tumour packet
It includes：The cancer of the esophagus, lung cancer, brain tumor, head and neck neoplasm, Eye tumor, pharynx cancer, tumor of chest wall, breast cancer, mesothelioma of pleura, abdominal cavity meat
Tumor, carcinoma of urinary bladder, gynecological tumor, the carcinoma of the rectum, Kaposi sarcomas, cutaneum carcinoma, carcinoma of mouth, laryngocarcinoma, cervical carcinoma, carcinoma of vagina, carcinoma of vulva,
Carcinoma of penis, liver cancer, cholangiocarcinoma, gastric cancer, Small Cell Lung Cancer, malignant lymphoma, leukaemia.
Phephorbide a-lentinan ester of the present invention has the advantages that following main：
1）, lentinan is as the polar end for being dissolved in water so that Phephorbide a-lentinan ester is dissolved in water, solves Ce6
The problem of poorly water-soluble.
2）, have Phephorbide a and the dual antitumor action of lentinan.
3）, lentinan can also make the blood vessel dilatation and bleeding of tumor locus, lead to tumour hemorrhagic necrosis and degenerate completely.
And in the present invention, this blood vessel dilatation and bleeding are exactly the ROS of Phephorbide a generation to provide directly effect tumour thin
The beneficial way of born of the same parents, thus Phephorbide a-lentinan ester of the present invention has better antitumous effect.
Description of the drawings
Fig. 1 is the H of 1 target product of embodiment1- NMR schemes.
Fig. 2 is the C of 1 target product of embodiment13- NMR schemes.
Specific implementation mode
Embodiment 1
Under the conditions of protective gas is with being protected from light, Phephorbide a is dissolved in ethyl alcohol, is A.Lentinan is dissolved in 50 ~ 80 degree of hot water
Afterwards, A is added, 30 DEG C of conditions stir lower reaction 48h；Wherein Phephorbide a and lentinan are equimolar amounts.
Centrifugation, supernatant is with deionized water dialysis, freeze-drying.
Dried object is detached with silica gel column chromatography, and eluant, eluent is that the mixing for the methylene chloride/methanol that volume ratio is 3/7 ~ 7/3 is molten
Liquid；
After flinging to methylene chloride/methanol, dissolved with methanol or acetonitrile, with reversed phase column chromatography polishing purification, eluant, eluent is methanol/water
Mixed liquor or acetonitrile/water mixed liquor；The filler that the reversed-phase column uses is C18；The methanol/water mixed liquor or acetonitrile/water mixing
The volume ratio of liquid is 3/7 ~ 7/3；
Gained refined solution is concentrated to dryness, then concentrate is dried in vacuo 24 ~ 36h or freeze-drying, and it is green to obtain target product de-magging leaf
Sour a- lentinan esters.
Purity reaches HPLC and is more than 95%, and yield is more than 68%.
The H of Phephorbide a-lentinan ester1-NMR、C13- NMR such as Fig. 1,2.Structure known to analysis is confirmed.
The water-soluble solubility of Phephorbide a-lentinan ester is：28.6.
Application examples 1
Anticancer Activity in vitro is evaluated：
Photodynamic activity：HepG2 liver cancer cells, the absorbing wavelength of 663nm, light source height are 20cm, measure IC50/μm：
36.7。
Sound photodynamic activity：HepG2 liver cancer cells are surveyed away from ultrasonic vocalization probe 2cm, ultrasonic excitation (2MHz, 2W) 2min
Obtain IC50/μm：92.4.
Claims (3)
1. such as Phephorbide a-lentinan ester of following formula：
Esterification occurs with Phephorbide a by lentinan to be prepared.
2. the preparation method of Phephorbide a-lentinan ester described in claim 1, includes the following steps：
1）, in protective gas and under the conditions of be protected from light, lentinan is esterified with Phephorbide a；
2）, centrifugation, supernatant is with deionized water dialysis, freeze-drying；
3）, dried object detached with silica gel column chromatography, eluant, eluent be volume ratio be 3/7~7/3 methylene chloride/methanol mixing it is molten
Liquid；
4）, fling to methylene chloride/methanol after, dissolved with methanol or acetonitrile, with reversed phase column chromatography polishing purification, eluant, eluent is first
Alcohol/water mixed liquid or acetonitrile/water mixed liquor；The filler that the reversed-phase column uses is C18；The methanol/water mixed liquor or acetonitrile/
The volume ratio of water mixed liquid is 3/7~7/3；
5）, gained refined solution be concentrated to dryness, then concentrate be dried in vacuo 24~36h or freeze-drying, obtain target product.
3. the application of Phephorbide a-lentinan ester described in claim 1 is to prepare treatment skin disease, malignant tumour
Or the drug of cancerous thoracoascites, the skin disease include：Condyloma acuminatum, flat wart, acne, nevus flammeus, capillary hemangioma, institute
Stating malignant tumour includes：Between the cancer of the esophagus, lung cancer, brain tumor, head and neck neoplasm, Eye tumor, pharynx cancer, tumor of chest wall, breast cancer, pleura
Rind gall, abdominal cavity sarcoma, carcinoma of urinary bladder, gynecological tumor, the carcinoma of the rectum, Kaposi sarcomas, cutaneum carcinoma, carcinoma of mouth, laryngocarcinoma, cervical carcinoma, the moon
Road cancer, carcinoma of vulva, carcinoma of penis, liver cancer, cholangiocarcinoma, gastric cancer, Small Cell Lung Cancer, malignant lymphoma, leukaemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810496118.6A CN108383923A (en) | 2018-05-22 | 2018-05-22 | Phephorbide a-lentinan ester and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810496118.6A CN108383923A (en) | 2018-05-22 | 2018-05-22 | Phephorbide a-lentinan ester and preparation method thereof |
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| CN108383923A true CN108383923A (en) | 2018-08-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201810496118.6A Withdrawn CN108383923A (en) | 2018-05-22 | 2018-05-22 | Phephorbide a-lentinan ester and preparation method thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302949A (en) * | 2011-06-02 | 2012-01-04 | 西安建筑科技大学 | Novel photocatalytic sensitizer and preparation method thereof |
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2018
- 2018-05-22 CN CN201810496118.6A patent/CN108383923A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302949A (en) * | 2011-06-02 | 2012-01-04 | 西安建筑科技大学 | Novel photocatalytic sensitizer and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| LI LI ET AL.: ""GSH-mediated photoactivity of pheophorbide a-conjugated heparin/gold nanoparticle for photodynamic therapy"", 《JOURNAL OF CONTROLLED RELEASE》 * |
| LI LI ET AL.: ""Self-quenchable biofunctional nanoparticles of heparin–folate-photosensitizer conjugates for photodynamic therapy"", 《CARBOHYDRATE POLYMERS》 * |
| WOORAM PARK ET AL.: ""A highly tumor-specific light-triggerable drug carrier responds to hypoxic tumor conditions for effective tumor treatment"", 《BIOMATERIALS》 * |
| 姜锡瑞等: "《生物发酵产业技术（第1版）》", 31 May 2016, 中国轻工业出版社 * |
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