CN102526055A - Application of cyclohexanediamine hypocrelline B in photodynamic anti-tumor medicaments - Google Patents
Application of cyclohexanediamine hypocrelline B in photodynamic anti-tumor medicaments Download PDFInfo
- Publication number
- CN102526055A CN102526055A CN2010106063631A CN201010606363A CN102526055A CN 102526055 A CN102526055 A CN 102526055A CN 2010106063631 A CN2010106063631 A CN 2010106063631A CN 201010606363 A CN201010606363 A CN 201010606363A CN 102526055 A CN102526055 A CN 102526055A
- Authority
- CN
- China
- Prior art keywords
- hypocrellin
- cell
- ethylene diamine
- hypocrelline
- cyclohexanediamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to an application of cyclohexanediamine hypocrelline B in photodynamic anti-tumor medicaments as a photosencitizer, and the photodynamic anti-tumor medicaments comprise the medicaments for treating cervical cancer, breast cancer, lung cancer, stomach cancer, skin cancer and other malignancies. The detection proves that the IC50 dark toxicity of the cyclohexanediamine hypocrelline B against HeLa, MCF7, MCF7/Adr, A549, A549/DDP, H1299, MGC803, A875 and other tumor cells when the cyclohexanediamine hypocrelline B is placed away from light is greater than 160 mu M; the IC50 phototoxicity of the cyclohexanediamine hypocrelline B against the detected tumor cells when the dose of red light is 12J/cm<2> for irradiation is less than 0.3 mu M; and a light enhancement factor (IC50 dark toxicity/IC50 phototoxicity) is greater than 500 and even greater than 1600. Mitochondria are further proven to be important action target points for photodynamic killing of the tumor cells through the cyclohexanediamine hypocrelline B, and the tumor cells mainly die in an apoptosis way.
Description
Technical field
The present invention relates to the cyclic ethylene diamine group HB Hypocrellin B as the application of photosensitizer in light power antitumor drug.
Background technology
(photodynamic therapy PDT) is associating light and photosensitizer to optical dynamic therapy, the emerging therapy that the body pathology tissue is treated.Optical dynamic therapy goes through and success in the U.S., Japan and other countries, is used for the clinical treatment of malignant tumor such as the esophageal carcinoma, pulmonary carcinoma, oral cancer, hepatocarcinoma.Photosensitizer is a kind ofly can concentrate in pathogenic site and can produce photochemical reaction down and destroy the chemical substance of pathology target cell (or organizing) in the suitable optical excitation of wavelength.At present, development has the low and phototoxicity of dark toxicity to wait the novel photosensitive agent of premium properties by force is the key of field of photodynamic always.
(Hematoporphyrin derivative is the first generation photosensitizer for photodynamic therapy medicine HpD), also is the main optical dynamic therapy medicine of present clinical practice for Photofrin and hematoporphyrin derivative.It has better tissues selectivity and tumor cytotoxicity effect by the mixture that the porphyrin substance of different structure is formed.But their shortcoming is that chemical constituent is not single, and the skin phototoxicity time is long, requires patient behind injectable drug, to avoid 4 to 6 weeks of illumination.In addition, it is at long wave direction absorption difference, and a little less than the penetrance of tissue, not easy-to-use this photosensitizer of therefore bigger entity tumor is treated, and the laser of the 630nm that uses clinically can not be brought into play the maximum therapy effect.Therefore need the new photosensitizer of research and development to overcome these shortcomings.
Hypocrellin (Hypocrellin) is a kind of natural photosensitizer that extracts a kind of parasitical fungi Hypocrella bambusae (Bet Br). Sace (Hypocrellabambuas) on parasitizing the Yunnan Province of China Fargesia; belong in the awake analog derivative of perylene; Be divided into hypocrellin (Hypocrellin A; HA) (see structural formula I) and HB Hypocrellin B (Hypocrellin B HB) (sees structural formula II).
HpD compares with hematoporphyrin derivative; Hypocrellin has that raw material is easy to get, photosensitizer triplet quantum yield and the creating singlet oxygen by using quantum yield is high, high, the dark toxicity of phototoxicity is low, from advantages such as the eliminating speed of normal structure are fast; Its great advantage is to fix a point easily chemical modification, obtains highly purified monomer derived thing, is a kind of second filial generation optical dynamic therapy medicine (Science Bulletin that has application prospect; 1990,35:1608-1616; Science Bulletin, 1990,35:1681-1691).But as photosensitizer for photodynamic therapy, natural hypocrellin does not almost absorb at phototherapy window (600-900nm), has greatly limited its application clinically.In addition, natural hypocrellin is a lipophilic compound, and water solublity is bad, is not easy to process medicament.Therefore, need carry out structure of modification, to obtain having the photosensitizer for photodynamic therapy of strong absorption (being that red shift of wavelength is to cooperate the long wave laser therapy) and fat water compatible (being convenient to pharmaceutical preparation) at the phototherapy window to hypocrellin.
(English name is the cyclic ethylene diamine group HB Hypocrellin B: 2-demethoxy-2; 3-ethylene-diamino hypocrellin B; Abbreviation EDAHB) (seeing structural formula II I) is a kind of derivant of HB Hypocrellin B; This derivant is that the prosposition at parent HB Hypocrellin B molecule adds hydrophilic group reacting ethylenediamine gained.
Chinese patent CN1600771A (open day: on March 30th, 2005) disclose cyclic ethylene diamine group Preparation of Hypocrellin B method and the application aspect optical function material and device thereof; People such as Xu Shangjie are at (Bioorganic&MedicinalChemistry Letters; 2004; 14:1499-1501 and Photochemistry and Photobiology, 2004, reported the optical physics and the spectrochemical property of cyclic ethylene diamine group HB Hypocrellin B in 80:112-114).But, at present the cyclic ethylene diamine group HB Hypocrellin B is applied to not see bibliographical information as yet in the light power antitumor drug as photosensitizer.
Summary of the invention
The purpose of this invention is to provide the cyclic ethylene diamine group HB Hypocrellin B as the application of photosensitizer in light power antitumor drug.
Tumor described in the present invention is breast carcinoma, cervical cancer, pulmonary carcinoma, gastric cancer or skin carcinoma.
Preferred adenocarcinoma of breast of breast carcinoma described in the present invention or amycin drug resistance adenocarcinoma of breast.
The preferred adenocarcinoma of lung of pulmonary carcinoma described in the present invention, cisplatin resistance property adenocarcinoma of lung or non-small cell adenocarcinoma of lung.
The preferred adenocarcinoma of stomach of gastric cancer described in the present invention.
The preferred melanoma of skin carcinoma described in the present invention.
The present invention has detected the light power antitumous effect of cyclic ethylene diamine group HB Hypocrellin B, and used tumor cell comprises multiple malignant cell such as HeLa (cervical cancer tumer line), MCF7 (breast adenocarcinoma cell system), MCF7/Adr (amycin toleration breast adenocarcinoma cell system), A549 (lung adenocarcinoma cell system), A549/DDP (cisplatin toleration lung adenocarcinoma cell system), H1299 (non-small cell lung gland cell system), MGC803 (adenocarcinoma of stomach cell line) and A875 (K-1735) system.Experimental result shows: the cyclic ethylene diamine group HB Hypocrellin B when lucifuge to the IC50 of the different tumor cells that detected
Dark toxicityAll greater than 160 μ M; And HONGGUANG dosage is 12J/cm
2During irradiation, to the IC50 of detection tumor cell
PhototoxicityAll less than 0.3 μ M; Light enhancer (IC50
Dark toxicity/ IC50
Phototoxicity) all greater than 500 even greater than 1600.As contrast, parent photosensitizer HB Hypocrellin B to the light enhancer of these tumor cells only between 10 to 30, far below the light enhancer of cyclic ethylene diamine group HB Hypocrellin B.
Test finds that further the cyclic ethylene diamine group HB Hypocrellin B is in optical dynamic therapy kill tumor cell processes, and the main mode of death of neoplastic cells is apoptosis (apoptosis).Find that simultaneously the mitochondrion of cell receives remarkable damage in cyclic ethylene diamine group HB Hypocrellin B light power inducing cancer cell death process.This shows that mitochondrion is the important function target spot of cyclic ethylene diamine group HB Hypocrellin B light power inducing cancer cell death.
Cyclic ethylene diamine group HB Hypocrellin B of the present invention have composition single clear and definite, low when forming stable, lucifuge to the dark toxicity of histiocyte, light power anticancer effect is remarkable, anticancer spectrum is wide, action target spot is clear and definite and death of neoplastic cells is advantage such as to lead with the apoptosis.The present invention finds through the external smooth power antitumous effect of ethylenediamine base HB Hypocrellin B is detected; Ethylenediamine base HB Hypocrellin B can be applied to optical dynamic treatment of tumor as photosensitizer; Especially breast carcinoma, cervical cancer, pulmonary carcinoma, gastric cancer or skin carcinoma; And to the cancer such as the malignant tumor such as amycin toleration breast carcinoma, cisplatin toleration pulmonary carcinoma of chemotherapy tolerance, thereby has important application prospects.
Cyclic ethylene diamine group HB Hypocrellin B of the present invention can be prepared into conventional pharmaceutical dosage form as active constituents of medicine, for example, and injection etc.
Below further set forth antitumous effect of the present invention through Test Example.
Test Example 1:MTT method detects the action effect test of cyclic ethylene diamine group HB Hypocrellin B-optical dynamic therapy to tumor cell
(1) material
Cell line: HeLa, MCF7, MCF7/Adr, A549, A549/DDP, H1299, MGC803, A875 cell.
Reagent: RPMI 1640 culture medium and special top grade hyclone (U.S. GIBCO company); Dimethyl sulfoxide (DMSO), 3-(4,5-dimethylthiazole-2)-2,5-diphenyl tetrazole bromine salt (MTT) (U.S. Sigma company).
Equipment: KDH-150B red-light therapeutic instrument (Beijing Kedian Microwave Electronic Co., Ltd.); SPR-4001 spectroradiometer (Canadian Luzchem Research Inc.); Common inverted microscope (optical instrument factory, Chongqing); Biohazard Safety Equipment (U.S. BAKER company); ELIASA (U.S. Bio Rad company).
(2) method
Cell culture: cell is at 37 ℃, saturated humidity, 5%CO
2The conventional cultivation in the incubator, culture fluid are to contain the two anti-RPMI-1640 of 10% calf serum, 1% penicillin and streptomycin, change liquid and go down to posterity in per 2 days.
Mtt assay is measured: the logarithmic (log) phase cell of cultivating is used 0.25% trypsinization, process single cell suspension, the adjustment cell density is every milliliter 5 * 10
4Individual, obtained cell suspension is inoculated on 96 well culture plates, and every hole 200 μ L are at 5%CO
237 ℃ of overnight incubation in the incubator.The supernatant discarded culture fluid adds the photosensitizer working solution that does not have the variable concentrations of phenol red RPMI-1640 dilution preparation with serum-free by experimental design under the condition of strict lucifuge.At 5%CO
237 ℃ of lucifuges were hatched 1 hour in the incubator.Supernatant discarded, phosphate buffer PBS washes twice.For dark toxicity test, every hole adds the no phenol red RPMI-1640 culture medium that 200 μ L contain 10% hyclone, continues at 5%CO
237 ℃ of lucifuges were cultivated 24 hours in the incubator; For Phototoxicity experiment, every hole adds 200 μ L serum-frees does not have phenol red RPMI-1640, with the red light irradiation of various dose, recovers 10% hyclone for then the culture medium in every hole, continues at 5%CO
237 ℃ of lucifuges were cultivated 24 hours in the incubator.Discard culture fluid subsequently, the final concentration that every hole adds the new preparation of 200 μ L is the MTT solution of 0.5mg/mL, hatches 4 hours for 37 ℃.The careful suction abandoned liquid in the hole, and every hole adds 150 μ L DMSO, and vibration 10min dissolves until blue crystallization fully.Select the 595nm wavelength, on ELIASA, detect the absorbance value (A in each hole
595), do not add the blank well zeroing that cell only adds MTT with parallel with experimental port.
Cell survival rate=(test group A
595/ control group A
595) * 100%, wherein but matched group is meant and has absorbed photosensitizer the groups of cells of illumination not.
Light enhancer=IC50
Dark toxicity/ IC50
Phototoxicity, IC50 wherein
Dark toxicityFor (red light irradiation dosage is 0J/cm in the dark toxicity test
2) cell survival rate is 50% o'clock pairing photosensitizer concentration; IC50
PhototoxicityFor (HONGGUANG is 12J/cm according to dosage in the Phototoxicity experiment
2) cell survival rate is 50% o'clock pairing photosensitizer concentration.
Statistical method: adopt SPSS11.0 statistics software to carry out result treatment, continuous data adopts mean ± standard deviation
expression.
(3) result
This Test Example be with parent photosensitizer HB Hypocrellin B as reference, compared dark toxicity, phototoxicity and the light enhancer of cyclic ethylene diamine group HB Hypocrellin B and HB Hypocrellin B.
As shown in Figure 1, during not illumination, along with cyclic ethylene diamine group HB Hypocrellin B or HB Hypocrellin B are hatched the increase of concentration, the survival rate of HeLa cell all reduces gradually, shows that two kinds of photosensitizer pair cells all have certain dark toxicity.But; Compare with HB Hypocrellin B, the trend that the cyclic ethylene diamine group HB Hypocrellin B causes cell survival rate to reduce is slower, for example; When cyclic ethylene diamine group HB Hypocrellin B concentration is increased to 160 μ M; Cell survival rate still is about 80%, and HB Hypocrellin B concentration makes the HeLa cell survival rate just reduce to 50% when being increased to 120 μ M.Table 1 and table 2 have further been listed cyclic ethylene diamine group HB Hypocrellin B and the HB Hypocrellin B dark toxicity test result to the variety classes tumor cell respectively.As shown in table 1, when cyclic ethylene diamine group HB Hypocrellin B concentration was increased to 160 μ M, the survival rate of all cells to be detected was all about about 80%, and this shows, for all tumor cell lines to be detected, the IC50 of cyclic ethylene diamine group HB Hypocrellin B
Dark toxicityAll greater than 160 μ M; And as shown in table 2, for all tumor cell lines to be detected, the IC50 of HB Hypocrellin B concentration
Dark toxicityBe about respectively: 120 μ M (HeLa), 45 μ M (MCF7), 60 μ M (MCF7/Adr), 55 μ M (A549), 110 μ M (549/DDP), 40 μ M (H1299), 60 μ M (MGC803), 90 μ M (A875).Therefore, the dark toxicity to tumor cell of cyclic ethylene diamine group HB Hypocrellin B is lower than parent photosensitizer HB Hypocrellin B.
As shown in Figures 2 and 3, during red light irradiation, the photosensitizer of low concentration just can make cell survival rate significantly reduce, and shows that two kinds of photosensitizer pair cells all have higher phototoxicity.But, to compare with HB Hypocrellin B, the cyclic ethylene diamine group HB Hypocrellin B causes trend that cell survival rate reduces more hurry up, and for example, after HeLa cell and 0.2 μ M cyclic ethylene diamine group HB Hypocrellin B were hatched, giving dosage was 12J/cm
2Red light irradiation, just can make cell survival rate reduce to 50% (see figure 2); And after HeLa cell and 5 μ M HB Hypocrellin Bs hatched, giving dosage was 12J/cm
2Red light irradiation, make cell survival rate reduce to 50% (see figure 3).The cyclic ethylene diamine group HB Hypocrellin B further listed respectively by table 1 and table 2 and HB Hypocrellin B is measured the result to the phototoxicity of variety classes tumor cell.As shown in table 1, all tumor cells for to be detected give 12J/cm
2Red light irradiation the time, the IC50 of cyclic ethylene diamine group HB Hypocrellin B
PhototoxicityBe about 0.2 μ M (HeLa) respectively, 0.1 μ M (MCF7), 0.1 μ M (MCF7/Adr), 0.2 μ M (A549), 0.2 μ M (549/DDP), 0.2 μ M (H1299), 0.2 μ M (MGC803), 0.3 μ M (A875); And as shown in table 2, for all tumor cells to be detected, give 12J/cm
2Red light irradiation the time, the IC50 of HB Hypocrellin B
PhototoxicityBe about respectively: 5 μ M (HeLa), 4 μ M (MCF7), 4 μ M (MCF7/Adr), 4 μ M (A549), 4 μ M (A549/DDP), 3 μ M (H1299), 3 μ M (MGC803), 5 μ M (A875).Therefore, the phototoxicity to tumor cell of cyclic ethylene diamine group HB Hypocrellin B is higher than parent photosensitizer HB Hypocrellin B.
IC50 according to the photosensitizer pair cell
Dark toxicityAnd IC50
Dark toxicityAs a result, can calculate the light enhancer of two kinds of photosensitizer to different tumor cells.As shown in table 1, be 12J/cm at HONGGUANG dosage
2During irradiation, the cyclic ethylene diamine group HB Hypocrellin B to the light enhancer of tumor cell all greater than 500; And as shown in table 2, be 12J/cm at HONGGUANG dosage
2During irradiation, HB Hypocrellin B is about respectively the light enhancer of tumor cell: 24 (HeLa), 11 (MCF7), 15 (MCF7/Adr), 14 (A549), 27.5 (A549/DDP), 13 (H1299), 20 (MGC803), 18 (A875).Therefore, the light enhancer to tumor cell of cyclic ethylene diamine group HB Hypocrellin B is higher than parent photosensitizer HB Hypocrellin B.
Table 1 cyclic ethylene diamine group HB Hypocrellin B is measured the result to dark toxicity, phototoxicity and the light enhancer of different tumor cells
Table 2 HB Hypocrellin B is measured the result to dark toxicity, phototoxicity and the light enhancer of different tumor cells
The charged swimming test of Test Example 2:DNA ladder
(1) material
Cell line: HeLa and MCF7 cell.
Reagent: RPMI 1640 culture medium and special top grade hyclone (U.S. GIBCO company); DNA extraction agent box (Puli's lema gene technology company limited); Agarose (U.S. sigma company).
Equipment: KDH-150B red-light therapeutic instrument (Beijing Kedian Microwave Electronic Co., Ltd.); SPR-4001 spectroradiometer (Canadian Luzchem Research Inc); Common inverted microscope (optical instrument factory, Chongqing); Desk type high speed refrigerated centrifuger (German HERAEMS company); Biohazard Safety Equipment (U.S. BAKER company).
(2) method
Cell culture: HeLa and MCF7 cell are at 37 ℃, saturated humidity, 5%CO
2The conventional cultivation in the incubator, culture fluid are to contain the two anti-RPMI-1640 of 10% calf serum, 1% penicillin and streptomycin, change liquid and go down to posterity in per 2 days.
The electrophoretic test procedure of dna ladder band: the HeLa cell and the MCF7 cell that will be in exponential phase; Be divided into three groups respectively, under the condition of strict lucifuge, add the photosensitizer working solution that does not have 1 μ M of phenol red RPMI-1640 dilution preparation with serum-free respectively by experimental design.At 5%CO
237 ℃ of lucifuges were hatched 1 hour in the incubator.Supernatant discarded then, PBS washes twice, adds after serum-free do not have phenol red RPMI-1640, gives 0J/cm respectively to three groups of every kind of cell
2, 12J/cm
2Perhaps 18J/cm
2The red light irradiation of dosage recovers 10% hyclone in the culture medium.Cell continues lucifuge and cultivated 24 hours.Collecting cell (2 * 10
6/ mL), PBS washes cell once.Extract the operating procedure of test kit according to apoptosis DNA Ladder and extract cell DNA.The DNA sample is at 1.5% agarose gel electrophoresis, and 12.5V/cm electrophoresis 1 hour is observed under the uviol lamp and taken pictures.
(3) result
After cyclic ethylene diamine group HB Hypocrellin B-optical dynamic therapy is handled cell; Extract cell DNA; Carry out agarose gel electrophoresis and imaging, the result shows that the tumor cell that cyclic ethylene diamine group HB Hypocrellin B-optical dynamic therapy is handled has tangible dna ladder zoning (see figure 4).Because the dna ladder zoning is the features of apoptosis sign, therefore, this result of the test shows that cyclic ethylene diamine group HB Hypocrellin B-optical dynamic therapy causes apoptosis of tumor cells.
Test Example 3: mitochondrial membrane damage check test
(1) material
Cell line: HeLa cell.
Reagent: RPMI 1640 culture medium and special top grade hyclone (U.S. GIBCO company); Mitochondrion apoptosis detection kit (mitoCapt μ re
TMApoptosis detection kit) (U.S. Biovision company).
Equipment: KDH-150B red-light therapeutic instrument (Beijing Kedian Microwave Electronic Co., Ltd.); SPR-4001 spectroradiometer (Canadian Luzchem Research Inc); Common inverted microscope (optical instrument factory, Chongqing); Biohazard Safety Equipment (U.S. BAKER company); Laser confocal microscope (German Leica company).
(2) method
Cell culture adds in the special 35mm culture dish that posts coverslip in the bottom; Overnight incubation when cell is in exponential phase, hatched the cyclic ethylene diamine group HB Hypocrellin B working solution of cell and 1 μ M 1 hour; PBS give a baby a bath on the third day after its birth all over after, will not illumination or to give dosage be 12J/cm
2Red light irradiation, recover complete medium and continue lucifuge and cultivated 6 hours.Utilize test kit MitoCapt μ re again
TMApoptosis Detection Kit labeled mitochondria, laser confocal microscope is observed.
(3) result
Cellular uptake cyclic ethylene diamine group HB Hypocrellin B, but not illumination detect the cell mitochondrial of launching red fluorescence after 6 hours, its fluorescence is the area distribution of rule, no diffusing phenomenon, the very weak (see figure 5) of green fluorescence signal in the Cytoplasm; Behind the cellular uptake cyclic ethylene diamine group HB Hypocrellin B, give 12J/cm
2Red light irradiation, detect the cell mitochondrial of emission red fluorescence after 6 hours, distribute but its fluorescence is dispersivity, also detect the green fluorescence (see figure 6) that strong disperse shape distributes in the Cytoplasm simultaneously.Because dyestuff is easy to get in the Normocellular mitochondrion and with polymeric form and exists in the test kit, sends bright red fluorescence; And in apoptotic cell, because the mitochondrial membrane potential forfeiture, mitochondrial membrane damages and makes permeability become big, and dyestuff can't accumulate in the mitochondrion, can remain in the Cytoplasm with monomeric form, sends green fluorescence this moment.Therefore, can distinguish the cell mitochondrial of normal and damaged easily according to red green fluorescence.This result of the test shows that cyclic ethylene diamine group HB Hypocrellin B-optical dynamic therapy enlarges markedly the cell mitochondrial membrane permeability, and mitochondrial membrane is damaged.That is to say that mitochondrion is cyclic ethylene diamine group HB Hypocrellin B-important target spot of light power antineoplastic.
Description of drawings
Fig. 1: the dark toxicity figure of cyclic ethylene diamine group HB Hypocrellin B and HB Hypocrellin B pair cell, wherein the dark toxicity icon of cyclic ethylene diamine group HB Hypocrellin B does ●, the dark toxicity icon of HB Hypocrellin B is ■;
Fig. 2: the phototoxicity figure of cyclic ethylene diamine group HB Hypocrellin B pair cell;
Fig. 3: the phototoxicity figure of HB Hypocrellin B pair cell;
Fig. 4: dna ladder band electrophoretogram, wherein electrophoresis road 1 and 8 is the dna molecular standard reference, and electrophoresis road 2,3 and 4 is the DNA of HeLa cell, and electrophoresis road 5,6 and 7 is the DNA of MCF7 cell, and electrophoresis road 2 and 5 illumination dose are 0J/cm
2, electrophoresis road 3 and 6 illumination dose be 12J/cm
2, electrophoresis road 4 and 7 illumination dose be 18J/cm
2
Fig. 5: the cell mitochondrial membrane permeability detects figure, and wherein 1 is Cytoplasm (very weak green fluorescence), and the 2nd, mitochondrion (red fluorescence);
Fig. 6: the cell mitochondrial membrane permeability detects figure, and wherein 1 is Cytoplasm (green fluorescence), and the 2nd, mitochondrion (red fluorescence).
The specific embodiment
Embodiment 1: cyclic ethylene diamine group Preparation of Hypocrellin B and purification
According to the disclosed method preparation of CN1600771A.Take by weighing raw material HB Hypocrellin B 200 grams, be dissolved in 200ml and newly steam in the oxolane; Add 20 milliliters of ethylenediamines; 55 degrees centigrade of lucifuges stirred 12 hours, and distilling under reduced pressure removes and desolvates; With 200 milliliters of dissolved in chloroform depositions, extremely neutral with 1% dilute hydrochloric acid adjust pH; Boil off chloroform; With 200 gram re-crystallizing in ethyl acetate; Use thin layer chromatography purification residue then, obtain the cyclic ethylene diamine group HB Hypocrellin B, productive rate is 55%.With the purity of high speed liquid chromatography mensuration cyclic ethylene diamine group HB Hypocrellin B, purity is higher than 95%.
The above-mentioned cyclic ethylene diamine group HB Hypocrellin B that obtains is preserved with lyophilized form, be made into storage liquid with the DMSO dissolving during use, be diluted to the desired concn working solution with PBS or culture medium.
Embodiment 2: the preparation of injection
Get the lyophilized powder 1g of the cyclic ethylene diamine group HB Hypocrellin B of embodiment 1 preparation, adopt liposome, add pH regulator agent, osmotic pressure regulator, be prepared into injection.
Claims (6)
1. the cyclic ethylene diamine group HB Hypocrellin B is as the application of photosensitizer in light power antitumor drug.
2. application according to claim 1 is characterized in that described tumor is breast carcinoma, cervical cancer, pulmonary carcinoma, gastric cancer or skin carcinoma.
3. application according to claim 2 is characterized in that described breast carcinoma is adenocarcinoma of breast or amycin drug resistance adenocarcinoma of breast.
4. application according to claim 2 is characterized in that described pulmonary carcinoma is adenocarcinoma of lung, cisplatin resistance property adenocarcinoma of lung or non-small cell adenocarcinoma of lung.
5. application according to claim 2 is characterized in that described gastric cancer is adenocarcinoma of stomach.
6. application according to claim 2 is characterized in that described skin carcinoma is a melanoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010606363.1A CN102526055B (en) | 2010-12-24 | 2010-12-24 | Application of cyclohexanediamine hypocrelline B in photodynamic anti-tumor medicaments |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010606363.1A CN102526055B (en) | 2010-12-24 | 2010-12-24 | Application of cyclohexanediamine hypocrelline B in photodynamic anti-tumor medicaments |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102526055A true CN102526055A (en) | 2012-07-04 |
| CN102526055B CN102526055B (en) | 2014-01-01 |
Family
ID=46334881
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010606363.1A Expired - Fee Related CN102526055B (en) | 2010-12-24 | 2010-12-24 | Application of cyclohexanediamine hypocrelline B in photodynamic anti-tumor medicaments |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102526055B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106573054A (en) * | 2014-06-02 | 2017-04-19 | 利康公司 | Phthalocyanine probes and uses thereof |
| CN111825624A (en) * | 2016-10-13 | 2020-10-27 | 中国科学院理化技术研究所 | Ester-water amphiphilic hypocrellin derivative and preparation method and application thereof |
| CN116135831A (en) * | 2021-11-18 | 2023-05-19 | 中国科学院理化技术研究所 | 2-polyethylene glycol substituted water-soluble derivative of hypocrellin and application thereof in treating tumors |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1600780A (en) * | 2003-09-25 | 2005-03-30 | 中国科学院化学研究所 | Hypocrellin in cyclic ethylene diamine group, preparation method and usage |
-
2010
- 2010-12-24 CN CN201010606363.1A patent/CN102526055B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1600780A (en) * | 2003-09-25 | 2005-03-30 | 中国科学院化学研究所 | Hypocrellin in cyclic ethylene diamine group, preparation method and usage |
Non-Patent Citations (1)
| Title |
|---|
| 肖彩霞等: "竹红菌素及其衍生物抗肿瘤活性的研究进展", 《食品与药品》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106573054A (en) * | 2014-06-02 | 2017-04-19 | 利康公司 | Phthalocyanine probes and uses thereof |
| CN106573054B (en) * | 2014-06-02 | 2021-04-13 | 乐天医药生技股份有限公司 | Phthalocyanine probe and use thereof |
| CN111825624A (en) * | 2016-10-13 | 2020-10-27 | 中国科学院理化技术研究所 | Ester-water amphiphilic hypocrellin derivative and preparation method and application thereof |
| CN116135831A (en) * | 2021-11-18 | 2023-05-19 | 中国科学院理化技术研究所 | 2-polyethylene glycol substituted water-soluble derivative of hypocrellin and application thereof in treating tumors |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102526055B (en) | 2014-01-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102617610B (en) | Preparation method of porphyrin photosensitizer and anticarcinogen diad | |
| CN111053911A (en) | Reduction response type cross-linking agent and preparation and application of cross-linked hydroxyl drug molecule thereof | |
| CN102258788B (en) | Targeted transmission assembly of adriamycin anticancer medicine and preparation method thereof | |
| CN107619425A (en) | A kind of tail is connected to aryl ruthenium complex and its synthetic method and the application of machine guide molecule | |
| CN102526055B (en) | Application of cyclohexanediamine hypocrelline B in photodynamic anti-tumor medicaments | |
| CN101830897A (en) | Novel isoquinoline alkaloid derivatives and preparation method and application thereof | |
| CN113648401A (en) | Hybrid nano assembly for protease inhibition sensitization photodynamic therapy and preparation and application thereof | |
| CN111662250A (en) | Quaternized modified taxane derivative, pharmaceutical composition, synthetic route and application thereof | |
| CN103435639A (en) | Axial nucleoside asymmetrically-modified silicon phthalocyanine and preparation method and application thereof | |
| CN113599532A (en) | Drug and collagenase loaded albumin composite nanoparticles, preparation and application | |
| CN108836937A (en) | Cisplatin nano pharmaceutical preparation, preparation method and application | |
| CN106554497A (en) | Water-soluble Cabazitaxel anti-cancer drug compounds and its preparation method and application | |
| CN113384698B (en) | Self-assembled nano-medicament for synergetic chemotherapy/acousto-photodynamic therapy and application thereof | |
| CN111728981A (en) | Quercetin rare earth complex and preparation method thereof | |
| CN106177187A (en) | There is the tea polyphenol tea polysaccharide composition of efficacy enhancing and toxicity reducing antihepatocarcinoma effect | |
| CN108440602B (en) | Tetranuclear iridium complex and preparation method and application thereof | |
| US20230374043A1 (en) | Hexadeca Ammonium-Modified Phthalocyanine and Preparation Method and Use Thereof as Photodynamic Drug | |
| CN111393482B (en) | Platinum-iridium heteronuclear metal complex and preparation method and application thereof | |
| CN102503892A (en) | Co-containing sandwich heteropolyacid as well as synthesis method and application thereof | |
| CN100546590C (en) | Anti-cancer Tengli root extract and its production and use | |
| CN102827226B (en) | Silicon phthalocyanine modified by uridine derivatives and preparation method and application of silicon phthalocyanine | |
| CN111393465A (en) | Axial galactose/lactose modified silicon phthalocyanine and preparation method and application thereof | |
| CN112961337B (en) | Glycididazole sodium polyethylene glycol polyaspartic acid polymer and preparation method thereof | |
| CN114957340B (en) | Preparation method and application of binuclear iridium complex for inducing iron death | |
| CN105198934A (en) | Platinum compound with near-infrared absorbent photodynamics activity, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140101 Termination date: 20191224 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |