CN109293738B - Zinc phthalocyanine adriamycin conjugate with phototherapy and chemotherapy synergistic anticancer effect - Google Patents

Zinc phthalocyanine adriamycin conjugate with phototherapy and chemotherapy synergistic anticancer effect Download PDF

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CN109293738B
CN109293738B CN201811273230.XA CN201811273230A CN109293738B CN 109293738 B CN109293738 B CN 109293738B CN 201811273230 A CN201811273230 A CN 201811273230A CN 109293738 B CN109293738 B CN 109293738B
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黄剑东
柯美荣
陈少芳
郑碧远
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Fuzhou University
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Abstract

The invention discloses novel substituted zinc phthalocyanine and conjugates of the substituted zinc phthalocyanine and doxorubicin, and also discloses a preparation method and application of the substituted zinc phthalocyanine and the conjugates, belonging to the field of preparation of photosensitizers and drugs. The compound is a novel high-efficiency photosensitive drug, and the zinc phthalocyanine-adriamycin conjugate is an anticancer drug with double effects of photodynamic therapy and chemotherapy. In addition, the zinc phthalocyanine-adriamycin conjugate is connected through a substrate peptide segment which can be specifically recognized and hydrolyzed by tumor-related fibroblast activation protein, and can be used as an enzyme-targeted activated anticancer prodrug.

Description

Zinc phthalocyanine adriamycin conjugate with phototherapy and chemotherapy synergistic anticancer effect
This application is a divisional application based on the original application with application number 2016101335853.
Technical Field
The invention belongs to the field of medicine preparation, and particularly relates to a zinc phthalocyanine adriamycin conjugate with phototherapy and chemotherapy synergistic anticancer effects.
Background
Photodynamic therapy (or photodynamic therapy) is essentially the application of photosensitization reactions of photosensitizers (or photosensitizing drugs) in the medical field. The action process is that the photosensitizer is injected into the body, after a period of time (the waiting time is that the medicine is relatively enriched in the target body), the target body is irradiated by light with specific wavelength (the target in the body cavity can be introduced into the light source by means of optical fiber and other interventional techniques), and the photosensitizer enriched in the target body initiates a series of photophysical photochemical reactions under the excitation of light to produce active oxygen, so that the target body (such as cancer cell and cancer tissue) is damaged. The key to photodynamic therapy is the photosensitizer, which has been approved for clinical use, mainly hematoporphyrin derivative. Photofrin (formally approved by the FDA in the united states for the clinical treatment of cancer in 1995) is used in the united states, canada, germany, japan, etc., as a mixture of hematoporphyrin oligomers extracted from cow's blood and chemically modified. Hematoporphyrin derivatives show some efficacy, but also expose serious drawbacks: the maximum absorption wavelength (380-.
The phthalocyanine metal complex is highly regarded as the application of the novel photosensitizer due to the characteristics of the maximum absorption wavelength in a red light region which is easy to penetrate human tissues, low dark toxicity and the like. However, the phthalocyanine complex with bioactivity reported at present has defects, or lacks amphipathy, or has poor stability, or has complex synthetic route, or has poor biological selectivity, and the like, and further improvement is needed. On the other hand, due to the huge economic and social values of the photosensitizer and the photodynamic therapy, the large application range and the refinement of the treatment focus, the preparation of more phthalocyanine complexes with comparative advantages as candidate drugs is necessary.
On the other hand, the research in recent years shows that the combined use of the photodynamic therapy and the chemotherapy can not only effectively reduce the side effect of the chemotherapeutic drugs and reverse the multidrug resistance, but also can exert the dual anti-cancer curative effect of the light therapy and the chemotherapy, thereby having obvious clinical application prospect. However, there is still a lack of highly effective combination drugs, especially those with targeting function.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a zinc phthalocyanine-adriamycin conjugate with phototherapy and chemotherapy synergistic effects. The zinc phthalocyanine-adriamycin conjugate is connected through a substrate peptide segment which can be specifically recognized and hydrolyzed by tumor-related fibroblast activation protein, and can be used as an enzyme-targeted activated anticancer prodrug.
In order to achieve the purpose, the invention adopts the following technical scheme:
1. a terminal dipeptide-zinc phthalocyanine compound having the structural formula:
Figure 86238DEST_PATH_IMAGE001
（Ⅰ）。
2. a terminal tetrapeptide-zinc phthalocyanine compound has the following structural formula:
Figure 738323DEST_PATH_IMAGE002
(II) or
Figure 23811DEST_PATH_IMAGE003
（Ⅲ）。
3. A zinc phthalocyanine-doxorubicin conjugate having the following structural formula:
Figure 823140DEST_PATH_IMAGE004
(IV) or
Figure 674421DEST_PATH_IMAGE005
(V) or
Figure 166582DEST_PATH_IMAGE006
（Ⅵ）。
Phthalocyanine, the acronym of phthalocyanines, is an abbreviation for tetraphenyl porphyrazine. The compound shown in the formula (I) is characterized in that the peripheral monosubstituted tail end of zinc phthalocyanine contains glycine-proline dipeptide, and the compound shown in the formula (II) or the formula (III) is characterized in that the peripheral monosubstituted tail end of the zinc phthalocyanine contains threonine-serine-glycine-proline tetrapeptide, and the tail end carboxyl of the tetrapeptide can be combined with chemotherapeutic adriamycin; the compound shown in the formula (IV), the formula (V) or the formula (VI) is characterized in that zinc phthalocyanine and adriamycin are connected through a glycine-proline dipeptide chain or a threonine-serine-glycine-proline tetrapeptide chain, the connecting peptide segment can be specifically identified and hydrolyzed by fibroblast activation protein, so that a zinc phthalocyanine photosensitizer and adriamycin chemotherapeutic drug are released, and the fibroblast activation protein is a protein with high tumor tissue specificity expression.
4. A preparation method of a terminal dipeptide-zinc phthalocyanine compound (I) comprises the following steps:
(1) with 1- [4- (2-carboxyethyl) phenoxy group]Taking zinc phthalocyanine and N-hydroxysuccinimide as reactants in a feeding ratio of 1:1.5-3, taking N, N-dimethylformamide as a solvent and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride as a dehydrating agent, stirring and reacting for 1-2 hours at the temperature of-5-5 ℃ under the protection of nitrogen, moving to the temperature of 20-35 ℃, continuing stirring and reacting for 12-36 hours, and separating by column chromatography to obtain the carboxyl activating substance of the zinc phthalocyanine:
Figure 204946DEST_PATH_IMAGE007
(ii) a Wherein, the dosage of the 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride is 1.5-4mmol per mmol of zinc phthalocyanine reactant;
(2) taking the carboxyl activating substance of the zinc phthalocyanine prepared in the step (1) and glycine-proline dipeptide as reactants, wherein the feeding ratio of the carboxyl activating substance to the glycine-proline dipeptide is 1:1.5-2, taking N, N-dimethylformamide as a solvent and N, N-diisopropylethylamine as a condensing agent, stirring and reacting for 2-6 hours at 20-35 ℃ under the protection of nitrogen, and separating and purifying by column chromatography to obtain a compound (I); wherein, the dosage of the N, N-diisopropylethylamine is 1.5-3mmol per mmol of the carboxyl activating substance of the zinc phthalocyanine.
5. The preparation method of the terminal tetrapeptide-zinc phthalocyanine compound (II) comprises the following steps:
(1) with 1- [4- (2-carboxyethyl) phenoxy group]Taking zinc phthalocyanine and N-hydroxysuccinimide as reactants in a feeding ratio of 1:1.5-3, taking N, N-dimethylformamide as a solvent and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride as a dehydrating agent, stirring and reacting for 1-2 hours at the temperature of-5-5 ℃ under the protection of nitrogen, moving to the temperature of 20-35 ℃, continuing stirring and reacting for 12-36 hours, and separating by column chromatography to obtain the carboxyl activating substance of the zinc phthalocyanine:
Figure 135861DEST_PATH_IMAGE008
(ii) a Wherein, the dosage of the 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride is 1.5-4mmol per mmol of zinc phthalocyanine reactant;
(2) taking the carboxyl activating substance of the zinc phthalocyanine prepared in the step (1) and threonine-serine-glycine-proline tetrapeptide as reactants, wherein the feeding ratio of the carboxyl activating substance to the threonine-serine-glycine-proline tetrapeptide is 1:1.5-2, N-dimethylformamide as a solvent, N-diisopropylethylamine as a condensing agent, stirring and reacting for 2-6 hours at 20-35 ℃ under the protection of nitrogen, and separating and purifying by column chromatography to obtain a compound (II); wherein, the dosage of the N, N-diisopropylethylamine is 1.5-3mmol per mmol of the carboxyl activating substance of the zinc phthalocyanine.
6. A process for the preparation of compound (iii) comprising the steps of:
(1) to be provided with
Figure 104299DEST_PATH_IMAGE009
(VII) and N-hydroxysuccinimide are used as reactants, the feeding ratio of the two is 1:1.5-3, N-dimethylformamide is used as a solvent, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as a dehydrating agent, and the reaction is stirred for 1-2 hours at the temperature of-5-5 ℃ under the protection of nitrogenMoving to 20-35 ℃, continuing stirring for reaction for 12-36 hours, and separating by column chromatography to obtain a carboxyl activating substance of the zinc phthalocyanine; wherein, the dosage of the 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride is 1.5-4mmol per mmol of zinc phthalocyanine reactant;
(2) taking the carboxyl activating substance of the zinc phthalocyanine prepared in the step (1) and threonine-serine-glycine-proline tetrapeptide as reactants, wherein the feeding ratio of the carboxyl activating substance to the threonine-serine-glycine-proline tetrapeptide is 1:1.5-2, N-dimethylformamide as a solvent, N-diisopropylethylamine as a condensing agent, stirring and reacting for 2-6 hours at 20-35 ℃ under the protection of nitrogen, and separating and purifying by column chromatography to obtain a compound (III); wherein, the dosage of the N, N-diisopropylethylamine is 1.5-3mmol per mmol of the carboxyl activating substance of the zinc phthalocyanine.
7. The preparation method of the zinc phthalocyanine-adriamycin conjugate (IV) comprises the following steps:
a compound represented by the formula (I):
Figure 705044DEST_PATH_IMAGE010
and adriamycin hydrochloride are taken as reactants to prepare a compound (IV);
8. the preparation method of the zinc phthalocyanine-adriamycin conjugate (V) comprises the following steps:
with a compound (II):
Figure 479971DEST_PATH_IMAGE011
and doxorubicin hydrochloride as reactants to produce compound (v).
9. The preparation method of the zinc phthalocyanine-adriamycin conjugate (VI) comprises the following steps:
with a compound (III):
Figure 824365DEST_PATH_IMAGE012
and doxorubicin hydrochloride as reactants to produce compound (VI).
10. The more detailed preparation methods of the conjugate (IV), the conjugate (V) and the conjugate (VI) are as follows: the feeding molar ratio of the compound (I), the compound (II) or the compound (III) to the adriamycin hydrochloride is 1:1.2-1.5, N-dimethylformamide is used as a solvent, the mixture is stirred and reacted for 1-2 hours at the temperature of-5-5 ℃ in the presence of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and N-methylmorpholine under the protection of nitrogen, the mixture is moved to the temperature of 20-35 ℃ and is continuously stirred and reacted for 12-24 hours, and the corresponding compound is synthesized.
11. The application of a terminal dipeptide-zinc phthalocyanine compound or a terminal tetrapeptide-zinc phthalocyanine compound in the preparation of photodynamic medicaments or photosensitive medicaments.
12. The zinc phthalocyanine-adriamycin conjugate is applied to the preparation of medicines with double effects of photodynamic therapy and chemotherapy or targeted activatable antitumor medicines.
Photosensitizing agents, or simply photosensitizers, or photosensitizing pharmaceutical agents, also known as photodynamic agents. The prepared photodynamic medicament or photosensitive medicament can be used for photodynamic therapy, photodynamic diagnosis or photodynamic disinfection. The photodynamic therapy may be photodynamic therapy of malignant tumors, or photodynamic therapy of benign tumors, or extracorporeal photodynamic purification treatment of bone marrow of leukemia, or photodynamic therapy of non-cancer diseases. The non-cancer disease can be bacterial infection, oral disease, macular degeneration eye disease, arteriosclerosis, wound infection, skin disease or virus infection. The photodynamic disinfection can be photodynamic disinfection and purification of blood or blood derivatives, or photodynamic disinfection of water, or photodynamic disinfection of medical or living equipment.
The zinc phthalocyanine-adriamycin conjugate provided by the invention can be used for preparing medicines with photodynamic therapy-chemotherapy dual effects and can be used for preparing targeted activatable antitumor medicines. The zinc phthalocyanine-adriamycin conjugate provided by the invention is connected through a glycine-proline dipeptide chain or a threonine-serine-glycine-proline tetrapeptide chain, and the connecting peptide segment can be specifically identified and hydrolyzed by fibroblast activation protein, so that the fibroblast activation protein is a protein with high tumor tissue specificity expression. Compared with the independent adriamycin, the chemical treatment activity of the zinc phthalocyanine-adriamycin conjugate is obviously reduced under the condition of no light, but when the zinc phthalocyanine-adriamycin conjugate reaches tumor tissues, the fibroblast activation protein with high specific expression in the tumor tissues can hydrolyze the peptide segment to release the zinc phthalocyanine and the adriamycin, the chemical treatment anticancer effect of the adriamycin is recovered, and simultaneously, the zinc phthalocyanine generates photodynamic anticancer activity under the excitation of red light. Therefore, the zinc phthalocyanine-adriamycin conjugate provided by the invention is an enzyme activated targeted anticancer drug with photodynamic therapy-chemotherapy synergistic effect.
The method for preparing the photosensitive medicament or the medicine by using the compound of the invention comprises the following steps: dissolving the compound of the invention by using water or a mixed solution of water and other substances, wherein the mass fraction of the other substances is not higher than 10 percent, and using the mixed solution as a solvent to prepare a medicament containing a certain concentration, wherein the concentration of the compound of the invention is not higher than the saturated concentration; adding antioxidant, buffering agent and isotonic agent as additives to the prepared solution to maintain chemical stability and biocompatibility of the medicament; the other substances are one or a mixture of more of castor oil polyoxyethylene 35 ether, dimethyl sulfoxide, ethanol, glycerol, N-dimethylformamide, polyethylene glycol 300-3000, cyclodextrin, glucose, tween and polyethylene glycol monostearate.
The invention has the beneficial effects that:
(1) the novel zinc phthalocyanine provided by the invention is peripheral mono-substituted phthalocyanine, has excellent amphipathy and high cancer cell uptake rate;
(2) the maximum absorption wavelength of the novel zinc phthalocyanine provided by the invention is positioned near 675nm, and the molar absorption coefficient reaches 105Order of magnitude, ideal photophysical photochemical properties;
(3) the zinc phthalocyanine provided by the invention contains a glycine-proline dipeptide chain or a threonine-serine-glycine-proline tetrapeptide chain, the peptide segment can be specifically identified by fibroblast activation protein, and the fibroblast activation protein is a protein with high tumor tissue specificity expression, so that the terminal dipeptide or tetrapeptide provided by the invention can be used as a targeted photosensitizer to replace the zinc phthalocyanine;
(4) the terminal of the peripheral substituent of the novel zinc phthalocyanine is carboxyl, and the photosensitizer with special functions can be further conveniently constructed by utilizing the ester forming activity of the carboxyl and the carboxyl, for example, the photosensitizer targeted by an antibody is constructed by connecting an antibody, and the anti-cancer drug with phototherapy-chemotherapy dual effect is constructed by connecting chemotherapeutic drugs;
(5) the zinc phthalocyanine-adriamycin conjugate provided by the invention is an enzyme activated targeted anticancer drug with photodynamic therapy-chemotherapy dual effects. The zinc phthalocyanine-adriamycin conjugate provided by the invention is connected through a glycine-proline dipeptide chain or a threonine-serine-glycine-proline tetrapeptide chain, and the connecting peptide segment can be specifically identified and digested and hydrolyzed by fibroblast activation protein, so that the fibroblast activation protein is a protein with high tumor tissue specificity expression. Compared with the independent adriamycin, the toxicity of the zinc phthalocyanine-adriamycin conjugate is obviously reduced under the condition of no light, but when the zinc phthalocyanine-adriamycin conjugate reaches tumor tissues, the fibroblast activation protein with high specific expression in the tumor tissues can hydrolyze the peptide segment to release the zinc phthalocyanine and the adriamycin, so that the chemotherapeutic anticancer effect of the adriamycin is recovered, and simultaneously, the zinc phthalocyanine generates photodynamic anticancer activity under the excitation of red light. Therefore, the zinc phthalocyanine-adriamycin conjugate provided by the invention is an enzyme activated targeted anticancer drug with phototherapy-chemotherapy dual effects.
Detailed Description
1. A preparation method of a terminal dipeptide-zinc phthalocyanine compound (I) comprises the following steps:
(1) with 1- [4- (2-carboxyethyl) phenoxy group]Taking zinc phthalocyanine and N-hydroxysuccinimide as reactants in a feeding ratio of 1:1.5-3, taking N, N-dimethylformamide as a solvent and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride as a dehydrating agent, stirring and reacting for 1-2 hours at the temperature of-5-5 ℃ under the protection of nitrogen, moving to the temperature of 20-35 ℃, continuing stirring and reacting for 12-36 hours, and separating by column chromatography to obtain the carboxyl activating substance of the zinc phthalocyanine:
Figure 650238DEST_PATH_IMAGE008
(ii) a Wherein the amount of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride is per mm1.5-4mmol of the ol zinc phthalocyanine reactant is needed;
(2) taking the carboxyl activating substance of the zinc phthalocyanine prepared in the step (1) and glycine-proline dipeptide as reactants, wherein the feeding ratio of the carboxyl activating substance to the glycine-proline dipeptide is 1:1.5-2, taking N, N-dimethylformamide as a solvent and N, N-diisopropylethylamine as a condensing agent, stirring and reacting for 2-6 hours at 20-35 ℃ under the protection of nitrogen, and separating and purifying by column chromatography to obtain a compound (I); wherein, the dosage of the N, N-diisopropylethylamine is 1.5-3mmol per mmol of the carboxyl activating substance of the zinc phthalocyanine.
2. The preparation method of the terminal tetrapeptide-zinc phthalocyanine compound (II) comprises the following steps:
(1) with 1- [4- (2-carboxyethyl) phenoxy group]Taking zinc phthalocyanine and N-hydroxysuccinimide as reactants in a feeding ratio of 1:1.5-3, taking N, N-dimethylformamide as a solvent and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride as a dehydrating agent, stirring and reacting for 1-2 hours at the temperature of-5-5 ℃ under the protection of nitrogen, moving to the temperature of 20-35 ℃, continuing stirring and reacting for 12-36 hours, and separating by column chromatography to obtain the carboxyl activating substance of the zinc phthalocyanine:
Figure 815028DEST_PATH_IMAGE013
(ii) a Wherein, the dosage of the 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride is 1.5-4mmol per mmol of zinc phthalocyanine reactant;
(2) taking the carboxyl activating substance of the zinc phthalocyanine prepared in the step (1) and threonine-serine-glycine-proline tetrapeptide as reactants, wherein the feeding ratio of the carboxyl activating substance to the threonine-serine-glycine-proline tetrapeptide is 1:1.5-2, N-dimethylformamide as a solvent, N-diisopropylethylamine as a condensing agent, stirring and reacting for 2-6 hours at 20-35 ℃ under the protection of nitrogen, and separating and purifying by column chromatography to obtain a compound (II); wherein, the dosage of the N, N-diisopropylethylamine is 1.5-3mmol per mmol of the carboxyl activating substance of the zinc phthalocyanine.
3. A process for the preparation of compound (iii) comprising the steps of:
(1) to be provided with
Figure 296825DEST_PATH_IMAGE014
(VII) and N-Hydroxyl succinimide is used as a reactant, the feeding ratio of the hydroxyl succinimide to the N, N-dimethylformamide is 1:1.5-3, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as a solvent, the mixture is stirred and reacted for 1-2 hours at the temperature of-5-5 ℃ under the protection of nitrogen, the mixture is moved to the temperature of 20-35 ℃ and continuously stirred and reacted for 12-36 hours, and a carboxyl activating substance of zinc phthalocyanine is obtained by column chromatography separation; wherein, the dosage of the 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride is 1.5-4mmol per mmol of zinc phthalocyanine reactant;
(2) taking the carboxyl activating substance of the zinc phthalocyanine prepared in the step (1) and threonine-serine-glycine-proline tetrapeptide as reactants, wherein the feeding ratio of the carboxyl activating substance to the threonine-serine-glycine-proline tetrapeptide is 1:1.5-2, N-dimethylformamide as a solvent, N-diisopropylethylamine as a condensing agent, stirring and reacting for 2-6 hours at 20-35 ℃ under the protection of nitrogen, and separating and purifying by column chromatography to obtain a compound (III); wherein, the dosage of the N, N-diisopropylethylamine is 1.5-3mmol per mmol of the carboxyl activating substance of the zinc phthalocyanine.
4. The preparation method of the zinc phthalocyanine-adriamycin conjugate (IV) comprises the following steps:
a compound represented by the formula (I):
Figure 241647DEST_PATH_IMAGE010
and adriamycin hydrochloride are taken as reactants to prepare a compound (IV);
5. the preparation method of the zinc phthalocyanine-adriamycin conjugate (V) comprises the following steps:
with a compound (II):
Figure 656448DEST_PATH_IMAGE015
and adriamycin hydrochloride as reactants to prepare a compound (V);
6. the preparation method of the zinc phthalocyanine-adriamycin conjugate (VI) comprises the following steps:
with a compound (III):
Figure 661313DEST_PATH_IMAGE016
and doxorubicin hydrochloride as reactants to produce compound (VI).
The novel compound provided by the invention can be used for preparing photodynamic medicaments or photosensitive medicaments. The photosensitive agent, or simply referred to as photosensitizer, or photosensitive pharmaceutical preparation, is also referred to as photodynamic agent. The prepared photodynamic medicament or photosensitive medicament can be used for photodynamic therapy, photodynamic diagnosis or photodynamic disinfection. The photodynamic therapy may be photodynamic therapy of malignant tumors, or photodynamic therapy of benign tumors, or extracorporeal photodynamic purification treatment of bone marrow of leukemia, or photodynamic therapy of non-cancer diseases. The non-cancer disease can be bacterial infection, oral disease, macular degeneration eye disease, arteriosclerosis, wound infection, skin disease or virus infection. The photodynamic disinfection can be photodynamic disinfection and purification of blood or blood derivatives, or photodynamic disinfection of water, or photodynamic disinfection of medical or living equipment.
The zinc phthalocyanine-adriamycin conjugate provided by the invention can be used for preparing medicines with photodynamic therapy-chemotherapy dual effects and can be used for preparing targeted activatable antitumor medicines. The zinc phthalocyanine-adriamycin conjugate provided by the invention is connected through a glycine-proline dipeptide chain or a threonine-serine-glycine-proline tetrapeptide chain, and the connecting peptide segment can be specifically identified and hydrolyzed by fibroblast activation protein, so that the fibroblast activation protein is a protein with high tumor tissue specificity expression. Compared with the independent adriamycin, the chemical treatment activity of the zinc phthalocyanine-adriamycin conjugate is obviously reduced under the condition of no light, but when the zinc phthalocyanine-adriamycin conjugate reaches tumor tissues, the fibroblast activation protein with high specific expression in the tumor tissues can hydrolyze the peptide segment to release the zinc phthalocyanine and the adriamycin, the chemical treatment anticancer effect of the adriamycin is recovered, and simultaneously, the zinc phthalocyanine generates photodynamic anticancer activity under the excitation of red light. Therefore, the zinc phthalocyanine-adriamycin conjugate provided by the invention is an enzyme activated targeted anticancer drug with photodynamic therapy-chemotherapy dual effects.
The method for preparing the photosensitive medicament or the medicine by using the compound of the invention comprises the following steps: dissolving the compound of the invention by using water or a mixed solution of water and other substances, wherein the mass fraction of the other substances is not higher than 10 percent, and using the mixed solution as a solvent to prepare a medicament containing a certain concentration, wherein the concentration of the compound of the invention is not higher than the saturated concentration; adding antioxidant, buffering agent and isotonic agent as additives to the prepared solution to maintain chemical stability and biocompatibility of the medicament; the other substances are one or a mixture of more of castor oil polyoxyethylene 35 ether, dimethyl sulfoxide, ethanol, glycerol, N-dimethylformamide, polyethylene glycol 300-3000, cyclodextrin, glucose, tween and polyethylene glycol monostearate.
For the preparation for topical administration, the phthalocyanine compound of the present invention may be dissolved in an osmotic solvent, or may be injected into an ointment, lotion or gel. The penetrating solvent is preferably 5-35% (wt%) aqueous solution of dimethyl sulfoxide.
The application of the compound in photodynamic therapy, photodynamic diagnosis, photodynamic disinfection and photodynamic pollutant degradation needs to be matched with a proper light source, the proper light source can be provided by connecting a common light source with a proper optical filter or provided by a laser or an LED lamp with a specific wavelength or other light sources, and the wavelength range of the light source is 670-700 nm.
7. The structure of the 1- [4- (2-carboxyethyl) phenoxy ] zinc phthalocyanine used in the invention is shown as the following formula:
Figure 161565DEST_PATH_IMAGE017
。
the preparation method comprises the following steps:
(1) preparing 3- [4- (2-carboxyethyl) phenoxy ] phthalodinitrile having the structure shown in the following formula:
Figure 644499DEST_PATH_IMAGE018
the reaction was stirred for 24 to 96 hours at room temperature to 45 deg.C (preferably room temperature) in the presence of potassium carbonate (20 to 60mmol, preferably 45mmol) and under nitrogen atmosphere with p-hydroxyphenylpropionic acid (15 mmol) and 3-nitrophthalonitrile (15 to 45mmol, preferably 15 mmol) as reactants and anhydrous DMSO as solvent (15 to 30ml, preferably 30 ml), and the end point of the reaction was monitored by thin layer chromatography. And (2) carrying out suction filtration on the reaction mixture by using a sand core funnel, collecting filtrate, adding the filtrate into 500ml of ice-water mixed solution, adjusting the filtrate by using a 1M hydrochloric acid solution until the solution is acidic, precipitating a large amount of precipitate, standing, washing with a microporous organic filter membrane repeatedly for multiple times until the solution is neutral, collecting solid, freezing and drying to obtain white solid, and further carrying out recrystallization by using DMF (dimethyl formamide) -water to purify to obtain a white target product, wherein the yield is about 70%.
The characterization data of the product are as follows: IR (KBr, cm)-1): 3441(O-H); 3089(Ar-H); 2938(CH2); 2233(C≡N); 1710(C=O); 1575, 1471, 1458(Ar C=C); 1272, 1214, 1183, 1163(C-O-C). 1H NMR (400 MHz, d6-DMSO, ppm): 12.15 (s, 1H, COOH), 7.86-7.78 (m, 2H, Ar-H), 7.37 (d, J=8.4 Hz, 2H, Ar-H), 7.27-7.19 (m, 1H, Ar-H), 7.16 (d, J=8.4 Hz, 2H, Ar-H), 2.91-2.78 (m, 2H, CH2), 2.57 (t, J=7.6 Hz, 2H, CH2). MS (ESI): m/z291.3 (100%, [M-H]-).
(2) 3- [4- (2-carboxyethyl) phenoxy ] phthalodinitrile (1.5 mmol) and unsubstituted phthalodinitrile (7.5-9 mmol, preferably 7.5 mmol) obtained above were added to n-pentanol (15-45 ml, preferably 25 ml), purged with nitrogen, stirred and warmed to complete dissolution, and then anhydrous zinc acetate (5-8 mmol, preferably 5mmol) and DBU (0.3-0.7 ml, preferably 0.6 ml) were added, and the reaction was refluxed with stirring (the end point of the reaction was monitored by thin layer chromatography). Removing solvent by vacuum rotary evaporation, dissolving with a small amount of DMF, adding into ice water, adjusting with 1M hydrochloric acid solution until the solution is acidic, precipitating a large amount of precipitate, standing, washing with microporous organic filter membrane repeatedly until the solution is neutral, collecting solid, and freeze drying to obtain crude product blue powder. The crude product was purified by silica gel column, the first blue phthalocyanine band was washed with ethyl acetate, and further purified by silica gel column using ethyl acetate/DMF (10: 1 in volume) mixed solvent as eluent, and the objective product was collected. After spin-drying, a small amount of DMF was used to dissolve the mixture in a Bio-Beads S-X3 type gel column, the eluent was DMF, the first blue band was collected, evaporated to dryness and dried in vacuum to obtain blue powder with a yield of 3%.
The maximum absorption peak of the product in DMF was at 674nm and the maximum absorption wavelength in 1% aqueous solution of castor oil derivative (Cremophor EL, wt%) was at 678 nm.
The characterization data of the product are as follows: IR (KBr, cm)-1): 3424(O-H); 3053(Ar-H); 2922(CH2); 1727(C=O); 1580, 1483, 1455(Ar C=C); 1284, 1248, 1166, 1116(C-O-C); 975, 885, 775(Ar-H). MS (ESI): m/z 739.0 (65%, [M-H]-). 1H NMR (400 MHz, d6-DMSO, ppm): 12.11 (s, 1H, COOH), 9.22-8.96 (m, 6H, Pc-Hα), 8.75 (d, J = 7.2 Hz, 1H, Pc-Hα), 8.16-7.95 (m, 7H, Pc-Hβ), 7.70 (d, J = 7.6 Hz, 1H, Pc-Hβ), 7.52-7.34 (m, 4H, Ar-H), 2.90-2.74 (m, 4H, CH2).
8. The structure of the derivative of 1- [4- (2-carboxyethyl) phenoxy ] zinc phthalocyanine used in the invention is shown as the following formula:
Figure 176455DEST_PATH_IMAGE019
；
the preparation method comprises the following steps:
3- [2- (2- (2- (2-methoxyethoxy) ethoxy ] phthalonitrile, or 3- [2- (2-methoxyethoxy) ethoxy ] phthalonitrile can be obtained by using diethylene glycol monomethyl ether, or triethylene glycol monomethyl ether, or tetraethylene glycol monomethyl ether instead of p-hydroxyphenylpropionic acid in (7) or (1), respectively.
The phthalocyanine target product shown in the formula can be obtained by replacing the unsubstituted phthalonitrile in 7 (2) with 3- [2- (2- (2- (2-methoxyethoxy) ethoxy ] phthalonitrile, or 3- [2- (2-methoxyethoxy) ethoxy ] phthalonitrile. The maximum absorption peak of the product in DMF is located at 680-685nm, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, wt%) aqueous solution is located at 690-695 nm.
The invention is further illustrated by the following non-limiting examples.
Example 1
Compound (II)
Figure 86643DEST_PATH_IMAGE020
The preparation method comprises the following steps:
(1) firstly, preparing a carboxyl activator of zinc phthalocyanine with the structure shown as the following formula:
Figure 74190DEST_PATH_IMAGE021
；
with 1- [4- (2-carboxyethyl) phenoxy group]Zinc phthalocyanine (60. mu. mol) and N-hydroxysuccinimide (120. mu. mol) were used as reactants, DMF was used as a solvent (5 ml), and the reaction was stirred in the presence of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (180. mu. mol) under nitrogen protection at 5 ℃ for 1.5 hours, then the reaction mixture was moved to room temperature and stirred for another 20 hours, and the end point of the reaction was monitored by thin layer chromatography. After the reaction is completed, the reaction liquid is concentrated by rotary evaporation, passes through a silica gel column, a first blue color band is collected by using a mixed solvent of dichloromethane/tetrahydrofuran (the volume ratio is 15: 1) as an eluent, the first blue color band is dried by rotary evaporation after the collection, and blue powder is obtained after vacuum drying, wherein the yield is 78.2%. Characterization of carboxy activator as HRMS (ESI) m/z calculated C45H28N9O5Zn [M+H]+838.1505, found 838.1478.
(2) The carboxyl group activator (40. mu. mol) of zinc phthalocyanine and threonine-serine-glycine-proline tetrapeptide (60. mu. mol) collected above were used as raw materials, DMF (5 ml) was used as a solvent, and the reaction was stirred at room temperature for 4 hours in the presence of N, N-diisopropylethylamine (120. mu. mol) under nitrogen protection, and the end point of the reaction was monitored by thin layer chromatography. After the reaction is finished, 100 times of water is added into the reaction liquid, and HCl is added to acidify until solid is separated out. Filtering with microporous membrane. The filter cake was dried, dissolved in a small amount of DMF and passed through a Bio-Beads S-X3 gel column to collect the first bluish component which was rotary evaporated to dryness to give a blue powder in 62.3% yield after freeze drying.
The maximum absorption peak of the product in DMF is at 674nm, and the molar absorption coefficient is 1.86X 105 cm-1·mol-1L; the maximum absorption wavelength in a 1% aqueous solution of a castor oil derivative (Cremophor EL, wt%) is at 678 nm.
For polypeptide-modified compounds and some types of phthalocyanine compounds (especially those containing amino acid fragments), since HNMR signals overlap, the literature usually employs MS (or HRMS) in combination with HPLC purity analysis, and therefore this example uses the literature to perform characterization by conventional means, and the characterization data of the product are as follows: HRMS (-ESI):m/zcalculated value is C55H46N12O9Zn [M-H]-1081.2724, found 1081.2747. HPLC purity of the product:>98.0%。
example 2
Preparation of Compound (III):
Figure 360815DEST_PATH_IMAGE022
；
(1) to be provided with
Figure 750208DEST_PATH_IMAGE023
(VII) (60. mu. mol) and N-hydroxysuccinimide (120. mu. mol) as reactants, DMF as solvent (5 ml), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (180. mu. mol) in the presence of nitrogen at 5 ℃ for 1.5 hours with stirring, and then the reaction mixture was moved to room temperature to continue stirring for 20 hours, and the end point of the reaction was monitored by thin layer chromatography. After the reaction is completed, the reaction liquid is concentrated by rotary evaporation, passes through a silica gel column, a first blue color band is collected by using a mixed solvent of dichloromethane/tetrahydrofuran (the volume ratio is 15: 1) as an eluent, the first blue color band is dried by rotary evaporation after being collected, and blue powder is obtained after vacuum drying, wherein the yield is 70-80%.
(2) The carboxyl group activator (40. mu. mol) of zinc phthalocyanine and threonine-serine-glycine-proline tetrapeptide (60. mu. mol) collected above were used as raw materials, DMF (5 ml) was used as a solvent, and the reaction was stirred at room temperature for 4 hours in the presence of N, N-diisopropylethylamine (120. mu. mol) under nitrogen protection, and the end point of the reaction was monitored by thin layer chromatography. After the reaction is finished, 100 times of water is added into the reaction liquid, and HCl is added to acidify until solid is separated out. Filtering with microporous membrane. After drying the filter cake, dissolving with a small amount of DMF, passing through Bio-Beads S-X3 gel column, collecting the first blue component, rotary evaporating to dry, and freeze drying to obtain blue powder with yield of 60-70%.
The maximum absorption peak of the product in DMF is located at 680-690 nm; the maximum absorption wavelength in a 1% aqueous solution of a castor oil derivative (Cremophor EL, wt%) is located at 690-700 nm.
The characterization data of the product are as follows: ms (esi):m/z 1451.5[M-H]-（n=2）; 1583.5[M-H]-（n=3）; 1715.6 [M-H]-(n = 3). HPLC purity of the product:>97%。
example 3
Compound (I)
Figure 362455DEST_PATH_IMAGE024
The preparation method comprises the following steps:
(1) firstly, preparing a carboxyl activator of zinc phthalocyanine with the structure shown as the following formula:
Figure 837299DEST_PATH_IMAGE025
；
with 1- [4- (2-carboxyethyl) phenoxy group]Zinc phthalocyanine (60. mu. mol) and N-hydroxysuccinimide (120. mu. mol) were used as reactants, DMF was used as a solvent (5 ml), and the reaction was stirred in the presence of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (180. mu. mol) under nitrogen protection at 5 ℃ for 1.5 hours, then the reaction mixture was moved to room temperature and stirred for another 20 hours, and the end point of the reaction was monitored by thin layer chromatography. After the reaction is completed, the reaction liquid is concentrated by rotary evaporation, passes through a silica gel column, a first blue color band is collected by using a mixed solvent of dichloromethane/tetrahydrofuran (the volume ratio is 15: 1) as an eluent, the first blue color band is dried by rotary evaporation after the collection, and blue powder is obtained after vacuum drying, wherein the yield is 78.2%. Characterization of carboxy activators as calculated HRMS (ESI) m/zIs C45H28N9O5Zn [M+H]+838.1505, found 838.1478.
(2) Taking the carboxyl activating substance of the zinc phthalocyanine prepared in the step (1) and glycine-proline dipeptide as reactants, wherein the feeding ratio of the carboxyl activating substance to the glycine-proline dipeptide is 1:1.8, taking N, N-dimethylformamide as a solvent and N, N-diisopropylethylamine as a condensing agent, stirring and reacting for 4 hours at room temperature under the protection of nitrogen, and separating and purifying by column chromatography to obtain a compound (I); wherein, the dosage of the N, N-diisopropylethylamine is 2.0mmol per mol of carboxyl activating substance of the zinc phthalocyanine; the yield was 95%.
The maximum absorption peak of the product in DMF is at 672 nm, and the molar absorption coefficient is 2.13X 105 cm-1·mol-1L; the maximum absorption wavelength in a 1% aqueous solution of a castor oil derivative (Cremophor EL, wt%) is at 676 nm.
The characterization data of the product are as follows: HRMS (-ESI):m/zcalculated value is C48H34N10O5Zn [M-H]-893.1927, found 893.1915 HPLC purity of product:>99%。
example 4
Compound (V)
Figure 662035DEST_PATH_IMAGE026
The preparation steps are as follows:
dissolving compound (II) (30 mu mol), 1-hydroxybenzotriazole (90 mu mol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (90 mu mol) in DMF (5 ml), stirring and reacting at 5 ℃ for 10 minutes under the protection of nitrogen, adding adriamycin hydrochloride (36 mu mol) and N-methylmorpholine (90 mu mol) and continuing to react for 1.5 hours, then moving the reaction liquid to room temperature and stirring and reacting for 20 hours, and monitoring the reaction endpoint through thin-layer chromatography; after the reaction is completed, the reaction solution is slowly poured into 200ml of ice-water mixture, precipitates are separated out, the reaction solution is filtered by a microporous organic filter membrane, a filter cake is washed by 100ml of citric acid aqueous solution with pH =6 for three times, the solid is collected after the filter cake is washed by water for multiple times, and the solid is dried in vacuum to obtain blue-gray powder with the yield of 80%.
The maximum absorption peak of the product in DMF is at 676 nm, and the molar absorption coefficient is 1.54X 105 cm-1·mol-1L; the maximum absorption wavelength in a 1% aqueous solution of a castor oil derivative (Cremophor EL, wt%) is at 681 nm.
The characterization data of the product are as follows: HRMS (+ ESI):m/zcalculated value is C82H73N13O19Zn [M+H]+ 1608.4471, found 1608.4482 HPLC purity of product:>96%。
example 5
Compound (vi):
Figure 908864DEST_PATH_IMAGE027
the preparation of (1):
dissolving compound (III) (30 mu mol), 1-hydroxybenzotriazole (90 mu mol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (90 mu mol) in DMF (5 ml), stirring the mixture at 5 ℃ for 10 minutes under the protection of nitrogen, adding adriamycin hydrochloride (36 mu mol) and N-methylmorpholine (90 mu mol) to continue the reaction for 1.5 hours, moving the reaction solution to room temperature, stirring the reaction solution for 20 hours, and monitoring the end point of the reaction by thin layer chromatography; after the reaction is completed, slowly pouring the reaction solution into 200ml of ice-water mixture, precipitating, performing suction filtration by using a microporous organic filter membrane, washing a filter cake by using 100ml of citric acid aqueous solution with pH =6 for three times, washing by using water for multiple times, collecting a solid, and performing vacuum drying to obtain a product.
The maximum absorption peak of the product in DMF is positioned at 682-695 nm; the maximum absorption wavelength in a 1% aqueous solution of a castor oil derivative (Cremophor EL, wt%) is around 680 nm.
HPLC purity of the product:>95 percent. The characterization data of the product are as follows: ms (esi):m/z 1960.6[M-H]-（n=2）; 2092.7[M-H]-（n=3）; 2223.6 [M-H]-（n=3）。
example 6
Compound (iv):
Figure 426433DEST_PATH_IMAGE028
the preparation method comprises the following steps:
dissolving compound (I) (30 mu mol), 1-hydroxybenzotriazole (90 mu mol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (90 mu mol) in DMF (5 ml), stirring and reacting at 5 ℃ for 10 minutes under the protection of nitrogen, adding adriamycin hydrochloride (36 mu mol) and N-methylmorpholine (90 mu mol) and continuing to react for 1.5 hours, then moving the reaction liquid to room temperature and stirring and reacting for 20 hours, and monitoring the reaction endpoint through thin-layer chromatography; after the reaction is completed, the reaction solution is slowly poured into 200ml of ice-water mixture, precipitates are separated out, a microporous organic filter membrane is used for suction filtration, 100ml of citric acid aqueous solution with the pH =6 is used for washing a filter cake for three times, water is used for washing for multiple times, then solids are collected, and the product is obtained after vacuum drying, wherein the yield is 73%.
The maximum absorption peak of the product in DMF is at 675nm, and the molar absorption coefficient is 1.98X 105 cm-1·mol-1L; (ii) a The maximum absorption wavelength in a 1% aqueous solution of a castor oil derivative (Cremophor EL, wt%) is around 680 nm.
The characterization data of the product are as follows: HRMS (+ ESI): m/z calculated value is C75H61N11O15Zn [M+H]+1420.3718, found 1420.3722. HPLC purity of the product:>97%。
application example 1
Dissolving the compound (I), the compound (II), the compound (III), the compound (IV), the compound (V) and the compound (VI) in DMF to prepare 4 mu M photosensitive agent, and testing the singlet oxygen quantum yield of the photosensitive agent.
The singlet oxygen yield was determined by a steady-state method using DPBF (1, 3-diphenylisobenzofuran) as a probe. Preparing mixed solution of phthalocyanine compound (4 μ M) and DPBF (35 μ M), and using red light (15 mW/cm) with wavelength of 610nm or more2) Illuminating it, measuring different illumination times as the illumination time increasesThe change in the UV absorbance at 414nm of the lower DPBF was determined and the singlet oxygen yield was calculated using the unsubstituted zinc phthalocyanine as a reference. See Journal of Photochemistry and Photobiology A: Chemistry, 2009, 201 (1), 23-31 for specific experimental procedures.
The above-mentioned red light with wavelength greater than 610nm is provided by connecting a 500W halogen lamp with a heat-insulating water tank and a filter greater than 610 nm.
The results showed that the singlet oxygen quantum yields of the compound (II), the compound (III) and the compound (I) were 0.60 to 0.71, and it was found that the above compounds all had a high singlet quantum yield and were excellent photosensitizers.
The singlet oxygen quantum yield of the phthalocyanine-adriamycin conjugate bridged by dipeptide (Gly-Pro) or tetrapeptide (Thr-Ser-Gly-Pro) in the compound (IV), the compound (V) and the compound (VI) is 0.20-0.30, which is 2-3 times lower than that of the corresponding substituted zinc phthalocyanine compound, which shows that the introduction of the adriamycin in the compound reduces the photosensitization capability of phthalocyanine.
Application example 2
Dissolving the phthalocyanine-adriamycin conjugate, namely the compound (IV), the compound (V) or the compound (VI), in DMF to prepare 4mM mother liquor, taking 2.5 mu l of the mother liquor to disperse in 100 mu l of 1% castor oil derivative (Cremophor EL, wt%) aqueous solution, then diluting the solution to 2ml by using phosphate buffer solution with pH =7.4, finally preparing a 5 mu M conjugate solution, and testing the enzymolysis condition of Fibroblast Activation Protein (FAP) on the phthalocyanine-adriamycin conjugate.
The enzymolysis experiment is provided with two groups, wherein one group is an enzymolysis group and is added with 10 mug of FAP enzyme; the other group is blank group without FAP enzyme. And (3) detecting the condition that the phthalocyanine-adriamycin conjugate is decomposed into a corresponding phthalocyanine compound and adriamycin under the action of FAP by using High Performance Liquid Chromatography (HPLC).
Elution conditions for HPLC: the chromatographic column is merck LiChrospher 100 RP-18 endclamped (5 μm); the eluent was eluted using a binary gradient, phase A being SDS solution (sodium dodecyl sulfate 0.72g, 0.34ml phosphoric acid in 250ml water): acetonitrile: methanol = 250:250:30, phase B is DMF solution, and phase a/B volume ratio is 2: 3; the column temperature is 30 ℃; the flow rate was 1 ml/min.
The result shows that the compound (V) or the compound (VI) releases free phthalocyanine (i.e. the compound (II) and the compound (III)) and adriamycin by breaking peptide bonds between proline and adriamycin sugar amino under the action of FAP, and the enzymolysis release efficiency can reach 80-90%; in contrast, the enzymatic release efficiency of FAP from compound (iv) is significantly low.
Application example 3
The terminal dipeptide or tetrapeptide-phthalocyanine according to the invention, i.e. compound (II), compound (III) or compound (I), is dissolved in a 1% aqueous solution of a castor oil derivative (Cremophor EL, wt%) to form a 1mM or 0.5mM photosensitive agent. Testing them against human hepatoma cells HepG2Dark toxicity and photodynamic activity.
Diluting the photosensitive agent into cell culture solution to obtain cell culture solution containing phthalocyanine compounds with different concentrations. Cancer cells were cultured in culture solutions containing phthalocyanine compounds at different concentrations for 2 hours, respectively, and then the culture solution was discarded, and after washing the cells with PBS, a new culture solution (containing no phthalocyanine compound) was added. The light experiment group irradiates cells with red light (the exciting light source is red light with wavelength of more than 610nm, the irradiation time is 30 min, and the irradiation power is 15mw cm-2) (ii) a The group was left unlit and the cells were left in the dark for 20 minutes. After the cells were exposed to light or not, the survival rate of the cells was examined by the MTT method. The specific experimental procedures are described in Bioorganic& Medicinal Chemistry Letters》, 2006, 16，2450-2453。
The above-mentioned red light with wavelength greater than 610nm is provided by connecting a 500W halogen lamp with a heat-insulating water tank and a filter greater than 610 nm.
As a result, it was revealed that when the compound (II), the compound (III) or the compound (I) solution was diluted to a concentration of 0.001mM (i.e., 1X 10)-6 mol/L), if the light is not used, the human liver cancer cell HepG2 has no killing and growth inhibition effects, which shows that the cells have no dark toxicity; however, if red light irradiation is carried out, the compound (II) of the present inventionCompound (iii) and compound (i), all kill cancer cells at 100%. The compound (II), the compound (III) and the compound (I) protected by the invention have high photodynamic anticancer activity. According to the dose-effect relationship, the half lethal dose of the photodynamic inhibition human liver cancer cell HepG2 is 0.39 multiplied by 10 respectively-6 mol/L (compound (II)), 0.05-0.20X 10-6 mol/L (Compound (III)) and 0.45X 10-6 mol/L (Compound (I)).
The same experimental results were obtained by replacing the 1% aqueous solution of castor oil derivative (Cremophor EL, wt%) with a 1% aqueous solution of castor oil derivative (Cremophor EL, wt%) in Phosphate Buffered Saline (PBS) or 0.5% aqueous solution of castor oil derivative (Cremophor EL, wt%).
Application example 4
Doxorubicin and Compound (IV), Compound (V) and Compound (VI) were tested for human hepatoma cell HepG according to the method of application example 32Dark toxicity (chemotherapeutic activity) and photodynamic activity. The result shows that the chemotherapeutic activity of the zinc phthalocyanine-adriamycin is obviously less than that of adriamycin, and the adriamycin can inhibit HepG in the absence of illumination2Half-lethal concentration (IC)50) Is 2.7X 10-6 mol/L, while the compound (IV), the compound (V) and the compound (VI) inhibit HepG in the absence of illumination2IC of50The value is 6.4-10.8X 10-6 mol/L, which indicates that the chemotherapeutic activity of doxorubicin is inhibited when it is conjugated to phthalocyanine.
On the other hand, the phototherapy activity of the phthalocyanine-adriamycin is obviously smaller than that of the corresponding substituted zinc phthalocyanine compound, and the compound (V) inhibits HepG under the irradiation of red light2IC of50The value is 0.56X 10-6 mol/L, compound (VI) inhibits HepG under red light irradiation2IC of50The value is 0.2-0.5X 10-6 mol/L, compound (IV) inhibits HepG under red light irradiation2IC of50The value was 2.6X 10-6 mol/L is obviously smaller than that of corresponding free phthalocyanine compounds (compound (II), compound (III) and compound (I)).
This suggests that the compound (IV), the compound (V) and the compound (VI) are useful as prodrugs of not only the chemical drug doxorubicin but also the phototherapeutic drug phthalocyanine.
Application example 5
Phthalocyanine-doxorubicin conjugates bridged by dipeptides (Gly-Pro) or tetrapeptides (Thr-Ser-Gly-Pro), i.e., compound (IV), compound (V) and compound (VI), described in the present invention, in the presence of Fibroblast Activation Protein (FAP), human hepatoma cells HepG were tested2The photodynamic activity of (a). The phthalocyanine-doxorubicin conjugate was incubated with FAP for 24 hours (molar ratio of conjugate to FAP 100: 1), and then the anticancer activity under light was tested according to the method of application example 3.
The results show that the compound (V) shows high photodynamic anti-cancer activity and inhibits HepG in the presence of FAP2IC of50The value is 0.13X 10-6 mol/L. This demonstrates that the anti-cancer activity of the phthalocyanine-doxorubicin conjugate is significantly enhanced in the presence of FAP, which is significantly higher than the photodynamic activity of the phthalocyanine-doxorubicin conjugate in the absence of FAP, and also higher than the chemotherapeutic activity of doxorubicin and the photodynamic activity of the corresponding free phthalocyanine, showing a high synergistic effect of phototherapy and chemotherapy. Calculated according to literature methods (t.c. Chou,Pharmacol. Rev.2006, 58, 621-blood 681), compound (v) may achieve a synergistic effect of 0.39 in phototherapy and chemotherapy.
In the presence of FAP, the compound (VI) also shows similarly high photodynamic anti-cancer activity, inhibiting HepG2IC of50The value is 0.01-0.10X 10-6 mol/L, also shows high phototherapy and chemotherapy synergistic effects. Compound (iv) also shows dual anti-cancer effects of phototherapy and chemotherapy.
The fibroblast activation protein is a tumor tissue specific high-expression hydrolase protein, the compound (IV), the compound (V) and the compound (VI) are connected through a glycine-proline dipeptide chain or a threonine-serine-glycine-proline tetrapeptide chain, and the connecting peptide segment can be specifically identified and digested by FAP. Compared with the independent adriamycin, the toxicity of the zinc phthalocyanine-adriamycin conjugate is obviously reduced under the condition of no light, but when the zinc phthalocyanine-adriamycin conjugate reaches tumor tissues, the fibroblast activation protein with high specific expression in the tumor tissues can hydrolyze the peptide segment to release the zinc phthalocyanine and the adriamycin, so that the chemotherapeutic anticancer effect of the adriamycin is recovered, and simultaneously, the zinc phthalocyanine generates photodynamic anticancer activity under the excitation of red light. Therefore, the zinc phthalocyanine-adriamycin conjugate provided by the invention is an enzyme activated targeted anticancer drug with phototherapy-chemotherapy dual effects.
Application example 6
The method for preparing the photodynamic medicament (namely the photosensitive medicament) or the photodynamic-chemotherapy combined medicament by utilizing the silicon phthalocyanine and the adriamycin conjugate comprises the following steps: dissolving the phthalocyanine or the phthalocyanine-adriamycin conjugate by taking water or mixed solution of water and other substances as a solvent, wherein the mass fraction of the other substances is not higher than 10%, preparing a medicament with a certain concentration, and the concentration of the phthalocyanine silicon and the phthalocyanine-adriamycin conjugate is not higher than the saturation concentration; adding an antioxidant, a buffering agent and an isotonic agent as additives to the prepared solution to maintain the chemical stability and biocompatibility of the photosensitizer; the other substances are one or more of castor oil polyoxyethylene 35 ether, dimethyl sulfoxide, ethanol, glycerol, N-dimethylformamide, polyethylene glycol 300-3000, cyclodextrin, glucose, tween and polyethylene glycol monostearate.
The phthalocyanine and the adriamycin conjugate thereof are dissolved in 5-35 percent (wt percent) of dimethyl sulfoxide aqueous solution, and can be used as a preparation for local administration.
Application example 7
The application method of the photodynamic medicament or photosensitizer prepared by the invention in photodynamic therapy, photodynamic diagnosis or photodynamic disinfection is the same as the application method of the photodynamic medicament or photosensitizer prepared by the phthalocyanine or porphyrin compound which is not prepared by the prior art, but needs to be matched with a proper light source, the proper light source can be provided by connecting a common light source with a proper optical filter or by laser with a specific wavelength, and the wavelength range of the light source is 300-800nm, preferably 670-700 nm.

Claims (7)

1. A terminal tetrapeptide-zinc phthalocyanine compound characterized by: the structural formula is as follows:
Figure 799744DEST_PATH_IMAGE001
(II) or
Figure 513622DEST_PATH_IMAGE002
（Ⅲ）。
2. A zinc phthalocyanine-doxorubicin conjugate, characterized in that: the structural formula is as follows:
Figure 886834DEST_PATH_IMAGE003
(V) or
Figure 347290DEST_PATH_IMAGE004
（Ⅵ）。
3. A method of preparing the terminal tetrapeptide-zinc phthalocyanine compound of claim 1, wherein:
the synthesis of the compound (II) comprises the following steps:
(1) with 1- [4- (2-carboxyethyl) phenoxy group]The method comprises the steps of taking zinc phthalocyanine and N-hydroxysuccinimide as reactants in a feeding ratio of 1:1.5-3, taking N, N-dimethylformamide as a solvent, taking 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride as a dehydrating agent, and under the protection of nitrogen, taking-5~Stirring and reacting for 1-2 hours at 5 ℃, moving to 20-35 ℃, continuing stirring and reacting for 12-36 hours, and separating by column chromatography to obtain the carboxyl activating substance of the zinc phthalocyanine:
Figure 161663DEST_PATH_IMAGE005
；
(2) taking the carboxyl activating substance of the zinc phthalocyanine prepared in the step (1) and threonine-serine-glycine-proline tetrapeptide as reactants, wherein the feeding ratio of the carboxyl activating substance to the threonine-serine-glycine-proline tetrapeptide is 1:1.5-2, N-dimethylformamide is taken as a solvent, N-diisopropylethylamine is taken as a condensing agent, and the mixture is stirred and reacted for 2 hours at the temperature of 20-35 ℃ under the protection of nitrogen~Separating and purifying by column chromatography to obtain a compound (II) after 6 hours;
the synthesis of the compound (III) comprises the following steps:
(1) to be provided with
Figure 108759DEST_PATH_IMAGE006
(VII) and N-hydroxysuccinimide are used as reactants, the feeding ratio of the two is 1:1.5-3, N-dimethylformamide is used as a solvent, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as a dehydrating agent, and-5 under the protection of nitrogen~Stirring and reacting for 1-2 hours at 5 ℃, moving to 20-35 ℃, continuing stirring and reacting for 12-36 hours, and separating by column chromatography to obtain a carboxyl activating substance of zinc phthalocyanine;
(2) taking the carboxyl activating substance of the zinc phthalocyanine prepared in the step (1) and threonine-serine-glycine-proline tetrapeptide as reactants, wherein the feeding ratio of the carboxyl activating substance to the threonine-serine-glycine-proline tetrapeptide is 1:1.5-2, N-dimethylformamide is taken as a solvent, N-diisopropylethylamine is taken as a condensing agent, and the mixture is stirred and reacted for 2 hours at the temperature of 20-35 ℃ under the protection of nitrogen~After 6 hours, the compound (III) is isolated and purified by column chromatography.
4. A method of preparing the zinc phthalocyanine-doxorubicin conjugate of claim 2, wherein:
the synthesis of the compound (V) comprises the following steps:
with a compound (II):
Figure 641371DEST_PATH_IMAGE007
and adriamycin hydrochloride as reactants to prepare a compound (V);
the synthesis of the compound (VI) comprises the following steps:
with a compound (III):
Figure 902588DEST_PATH_IMAGE008
and doxorubicin hydrochloride as reactants to produce compound (VI).
5. The method of preparing a zinc phthalocyanine-doxorubicin conjugate according to claim 4, wherein: the feeding molar ratio of the compound (II) or the compound (III) to the adriamycin hydrochloride is 1:1.2-1.5, N-dimethylformamide is used as a solvent, and the mixture is subjected to-5 in the presence of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and N-methylmorpholine and under the protection of nitrogen~Stirring and reacting for 1-2 hours at 5 ℃, moving to 20-35 ℃, continuing stirring and reacting for 12-24 hours, and synthesizing to obtain the corresponding compound.
6. Use of a compound according to claim 1 for the preparation of a photodynamic medicament or photosensitizing agent.
7. Use of a conjugate according to claim 2 for the preparation of a medicament having the dual effect photodynamic therapy-chemotherapy or for the preparation of a targeted activatable antitumor medicament.
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