CN113527266A - FAP-targeted hydrogen peroxide-responsive prodrug and preparation method and application thereof - Google Patents
FAP-targeted hydrogen peroxide-responsive prodrug and preparation method and application thereof Download PDFInfo
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- 239000000126 substance Substances 0.000 claims description 26
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
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- 239000012071 phase Substances 0.000 claims description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 4
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a hydrogen peroxide-responsive prodrug targeting FAP, and a preparation method and application thereof. The prodrug mainly comprises three parts, including a unit (glycyl-2-cyano pyrrolidine compound) targeting FAP, a high-expression hydrogen peroxide response unit in tumor and an anti-tumor drug unit. The preparation method comprises the following steps: firstly, the hydrogen peroxide response part is connected to the anti-tumor drug through an amide group, and then the unit targeting FAP is connected to the anti-tumor drug modified by the hydrogen peroxide response unit. The prodrug of the FAP-targeted hydrogen peroxide response is effectively enriched at a tumor part by utilizing the function of the FAP-targeted hydrogen peroxide, and the thioketone bond is broken by the high-expression hydrogen peroxide in the tumor to release the antitumor drug, so that the antitumor function is realized. The prodrug can improve the enrichment amount of the antitumor drug in the tumor, and can release the antitumor drug into the tumor under the stimulation of high-expression hydrogen peroxide in the tumor to realize the antitumor function.
Description
Technical Field
The invention belongs to the technical field of prodrug preparation, and particularly relates to a hydrogen peroxide-responsive prodrug targeting FAP, and a preparation method and application thereof.
Background
At present, malignant tumor is one of the main causes of human death all over the world, and has become a serious disease which seriously harms human life and health and restricts the development of society and economy. The current treatment means mainly comprise traditional operations, chemotherapy, radiotherapy, emerging immunotherapy and the like. The treatment methods usually need to be supplemented with treatment reagents, and most of the treatment reagents are small molecular reagents, have high metabolic speed and nonspecific distribution, have large side effects, and are difficult to effectively and specifically enrich at tumor parts. Therefore, there are still many challenges to accurately and efficiently enrich these adjunctive therapeutic agents at the tumor site. The method of connecting an antibody with a targeting unit and the like is a main method for improving the enrichment of a therapeutic agent in a tumor region by delivering the agent to the tumor region in a specific targeting manner through the targeting property of the antibody and the like. However, this method has some problems, such as too large molecular weight of the antibody, which not only makes it difficult to attach a small molecule drug, but also makes it possible to inhibit the function of the small molecule drug. Therefore, designing and developing new small molecule drug delivery systems is a problem that still needs to be solved at present.
Tumor-associated fibroblasts (CAFs) are stromal cells important to the tumor microenvironment and are involved in the migration, proliferation and survival of tumor cells. While CAFs highly express a Fibroblast Activation Protein (FAP), which is not expressed in normal tissues and is a specific marker of the tumor microenvironment. Thus, tumor therapy targeting FAP has attracted widespread attention. A variety of anti-tumor agents targeting FAP (patent No. 201910425487.0) or imaging agents (patent No. 201880083520.X) have been developed. However, when a chemotherapeutic drug or imaging agent is linked to a targeted FAP agent, the function of the chemotherapeutic drug or FAP inhibitor is lost as a result of structural changes. Therefore, the construction of a novel prodrug targeting FAP and capable of keeping independent drug effect is of great significance.
Disclosure of Invention
Based on the technical current situation that a prodrug which targets FAP and can keep independent drug effect is absent in the prior art, the invention provides a hydrogen peroxide-responsive prodrug which targets FAP, and a preparation method and application thereof.
The purpose of the invention can be realized by the following technical scheme:
the invention firstly provides a hydrogen peroxide-responsive prodrug targeting FAP, which has the following structural formula:
wherein R is3Is an anti-tumor drug unit.
The prodrug of the FAP-targeted hydrogen peroxide response comprises three parts, namely a drug group part, a response group part and a FAP-targeted group part, wherein the parts are respectively shown as follows.
The FAP targeting group is a unit targeting FAP, specifically a glycyl-2-cyano pyrrolidine compound, the response group is a high-expression hydrogen peroxide response unit in a tumor, and the drug group is an anti-tumor drug unit.
In one embodiment of the present invention, the anti-tumor drug is selected from one or more of lapatinib, gefitinib, adriamycin, paclitaxel or hydroxycamptothecin.
The invention also provides a preparation method of the hydrogen peroxide-responsive prodrug targeting FAP, which is obtained by carrying out amide reaction and esterification reaction covalent bonding on a substance with an active targeting FAP group and an anti-tumor drug through a substance containing a hydrogen peroxide-responsive linking group.
In one embodiment of the invention, the substance with an actively targeted FAP group (referred to as FAPI) has the following structure:
the substance with the active targeting FAP group in the structure is glycyl-2-cyano pyrrolidine compound.
In one embodiment of the invention, the substance containing the hydrogen peroxide-responsive linker (referred to as TK) has the following structure:
in the substance containing the hydrogen peroxide response connecting group, the connecting group is a micromolecule connecting group containing thioketone.
In one embodiment of the invention, the synthesis method of the substance containing the hydrogen peroxide response linking group (called TK) is as follows:
A. preparing a mixed solution of acetone and thioglycollic acid with a molar ratio of 1-1: 2.5;
B. under the protection of nitrogen, slowly dripping trifluoroacetic acid with the volume of about 0-1mL, and reacting for 6-36 hours;
C. after the reaction is finished, filtering, and washing with petroleum ether and water respectively to obtain a product, namely the substance (TK) containing the hydrogen peroxide response connecting group.
In one embodiment of the invention, the antineoplastic drug (referred to as R)3) Is selected from one or more of lapatinib, gefitinib, adriamycin, paclitaxel or hydroxycamptothecin.
In one embodiment of the invention, the preparation method of the hydrogen peroxide-responsive prodrug targeting FAP comprises the following steps:
the anti-tumor drug reacts with the substance containing the hydrogen peroxide response connecting group, namely, the hydrogen peroxide response part is connected to the anti-tumor drug through the amide group,
the reaction product reacts with a substance with an active targeting FAP group to obtain a hydrogen peroxide-responsive prodrug targeting FAP.
In one embodiment of the invention, the antineoplastic agent is reacted with a substance containing a hydrogen peroxide-responsive linker (i.e., synthesis of R)3TK) as follows:
A. preparing a N, N-dimethylformamide solution of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) with a certain concentration;
B. preparing a dichloromethane solution of TK and N, N-diisopropylethylamine with a molar ratio of 1-1: 4;
C. slowly adding the solution B into the solution A, and reacting for 10-30 minutes at the temperature of 0-50 ℃;
D. preparing an antitumor drug (R)3) And DIPEA in dichloromethane at a molar ratio of 1-1: 4;
E. adding the solution D into the solution C, reacting for 12-36 hours, extracting the water phase for multiple times by using dichloromethane, combining the organic phases, and drying the organic phases by using anhydrous magnesium sulfate;
F. filtering the solution, removing filtrate, removing solvent under vacuum to obtain crude product, and performing thin layer chromatography to obtain pure product, i.e. R3-TK。
R3The structure of TK is shown below:
in one embodiment of the invention, the reaction product obtained by the reaction of the antitumor drug and the substance containing the hydrogen peroxide response connecting group reacts with the substance with the active targeting FAP group (i.e. synthesizing FAPI-R)3TK) by the following method,
A. preparing N, N-dimethylformamide solution of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate with certain concentration;
B. configuration R3-a solution of TK and N, N-diisopropylethylamine in dichloromethane in a molar ratio of 1-1: 4;
C. slowly adding the solution B into the solution A, and reacting for 10-30 minutes at the temperature of 0-50 ℃;
D. preparing a solution of FAPI and DIPEA in dichloromethane, wherein the molar ratio of the FAPI to the DIPEA is 1-1: 4;
E. adding the solution D into the solution C, reacting for 12-36 hours, extracting the water phase with dichloromethane for multiple times, combining the organic phases, and drying the organic phases with anhydrous magnesium sulfate.
F. And filtering the solution, removing filtrate, removing the solvent in vacuum to obtain a crude product, and performing thin-layer chromatography to obtain a pure product, namely the prodrug of the FAP-targeted hydrogen peroxide response.
In one embodiment of the invention, the route for the synthesis of a hydrogen peroxide-responsive prodrug targeting FAP is as follows:
the invention also provides application of the hydrogen peroxide-responsive prodrug targeting FAP, and application of the hydrogen peroxide-responsive prodrug targeting FAP in preparation of a medicament for accurately treating a tumor part.
The prodrug of the target FAP in hydrogen peroxide response can react with hydrogen peroxide in a tumor microenvironment to release a drug, so that tumor parts can be treated accurately.
The invention provides preparation and application of a hydrogen peroxide-responsive prodrug targeting FAP. The prodrug mainly comprises three parts, including a unit (glycyl-2-cyano pyrrolidine compound) targeting FAP, a high-expression hydrogen peroxide response unit in tumor and an anti-tumor drug unit. The preparation method comprises the following steps: firstly, the hydrogen peroxide response part is connected to the anti-tumor drug through an amide group, and then the unit targeting FAP is connected to the anti-tumor drug modified by the hydrogen peroxide response unit.
The prodrug of the FAP-targeted hydrogen peroxide response is effectively enriched at a tumor part by utilizing the function of the FAP-targeted hydrogen peroxide, and the thioketone bond is broken by the high-expression hydrogen peroxide in the tumor to release the antitumor drug, so that the antitumor function is realized. The prodrug can improve the enrichment amount of the antitumor drug in the tumor, and can release the antitumor drug into the tumor under the stimulation of high-expression hydrogen peroxide in the tumor to realize the antitumor function.
Compared with the prior art, the hydrogen peroxide-responsive prodrug targeting FAP provided by the invention has no activity in vitro, can target to a tumor region after entering an organism, and simultaneously reacts with hydrogen peroxide highly expressed in a tumor microenvironment to activate the activity of a medicament.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of TK prepared in example 1;
FIG. 2 is a nuclear magnetic hydrogen spectrum of JI-TK prepared in example 2;
FIG. 3 is a nuclear magnetic carbon spectrum of JI-TK prepared in example 2;
FIG. 4 is a nuclear magnetic hydrogen spectrum of JI-TK-FAPI prepared in example 3;
FIG. 5 is a nuclear magnetic carbon spectrum of JI-TK-FAPI prepared in example 3.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments.
In the following examples, the structure synthesis methods are as follows, and unless otherwise specified, it is indicated that the reagents used are all conventional commercial products or prepared by conventional techniques in the art.
The synthetic route for the hydrogen peroxide-responsive prodrug targeting FAP in the following examples is as follows:
example 1 Synthesis of TK
A mixed solution of acetone (2.9g,50mmol) and mercaptoacetic acid (11.44g,100mmol) was prepared in a molar ratio of 1:2, and trifluoroacetic acid (0.1 mL in volume) was slowly added dropwise under nitrogen protection to react for 12 hours. After the reaction is finished, filtering, and washing with petroleum ether and water respectively to obtain the product.
The nuclear magnetic hydrogen spectrum of the TK obtained is shown in figure 1.
Example 2 Synthesis of JI-TK
Preparing a solution of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (380mg, 1mmol) in N, N-dimethylformamide (2mL) to obtain a solution A. A solution of TK (224mg,1mmol) and N, N-diisopropylethylamine (0.2mL) in 10mL of dichloromethane was prepared as solution B. The solution B was slowly added to the solution A at room temperature, and reacted for 30 minutes. A solution of gefitinib (446mg,1mmol) and N, N-diisopropylethylamine (0.4mL) in dichloromethane was prepared to give solution C. The solution C was added to the mixed solution of A, B above, and after 12 hours of reaction, the aqueous phase was extracted several times with dichloromethane, and the organic phases were combined and dried over anhydrous magnesium sulfate. Filtering the solution, removing the filtrate, removing the solvent in vacuum to obtain a crude product, and performing thin-layer chromatography to obtain a pure product, namely JI-TK.
The nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the prepared JI-TK are shown in FIG. 2 and FIG. 3, respectively.
EXAMPLE 3 Synthesis of JI-TK-FAPI
Preparing a solution of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (380mg, 1mmol) in N, N-dimethylformamide (2mL) to obtain a solution A. A10 mL solution of JI-TK (224mg,1mmol) and N, N-diisopropylethylamine (0.2mL) in dichloromethane was prepared to obtain solution B. The solution B was slowly added to the solution A at room temperature, and reacted for 30 minutes. A solution of FAPI (446mg,1mmol) and N, N-diisopropylethylamine (0.4mL) in dichloromethane was prepared as solution C. The solution C was added to the mixed solution of A, B above, and after 12 hours of reaction, the aqueous phase was extracted several times with dichloromethane, and the organic phases were combined and dried over anhydrous magnesium sulfate. Filtering the solution, removing the filtrate, removing the solvent in vacuum to obtain a crude product, and performing thin-layer chromatography to obtain a pure product, namely JI-TK-FAPI.
The nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the prepared JI-TK-FAPI are shown in figure 4 and figure 5 respectively.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. A hydrogen peroxide-responsive prodrug targeting FAP, which has the following structural formula:
wherein R is3Is an anti-tumor drug unit.
2. The hydrogen peroxide-responsive prodrug targeted to FAP according to claim 1, wherein the antitumor drug is selected from one or more of lapatinib, gefitinib, doxorubicin, paclitaxel or hydroxycamptothecin.
3. The preparation method of the hydrogen peroxide-responsive prodrug targeting FAP as claimed in claim 1 or 2, which is characterized in that a substance with an active targeting FAP group and an anti-tumor drug are subjected to amide reaction and esterification reaction through a substance containing a hydrogen peroxide-responsive linking group to be covalently bonded to obtain the prodrug.
4. The method for preparing the hydrogen peroxide-responsive prodrug targeting FAP according to claim 3, wherein the substance with the active targeting FAP group has the following structure:
5. the method for preparing the hydrogen peroxide-responsive prodrug targeted to FAP according to claim 3, wherein the hydrogen peroxide-responsive linker-containing substance has the following structure:
6. the method for preparing the hydrogen peroxide-responsive prodrug targeted to FAP according to claim 5, wherein the synthesis method of the substance containing the hydrogen peroxide-responsive linker comprises the following steps:
A. preparing a mixed solution of acetone and thioglycollic acid with a molar ratio of 1-1: 2.5;
B. under the protection of nitrogen, slowly dripping trifluoroacetic acid, and reacting for 6-36 hours;
C. after the reaction is finished, filtering, and washing with petroleum ether and water respectively to obtain products, namely the substances containing the hydrogen peroxide response connecting group.
7. The method for preparing the hydrogen peroxide-responsive prodrug targeted to FAP of claim 3, comprising the steps of:
the antitumor drug reacts with the substance containing the hydrogen peroxide response connecting group,
the reaction product reacts with a substance with an active targeting FAP group to obtain a hydrogen peroxide-responsive prodrug targeting FAP.
8. The method for preparing the hydrogen peroxide-responsive prodrug targeting FAP according to claim 7, wherein the method for reacting the antitumor drug with the substance containing the hydrogen peroxide-responsive linker comprises the following steps:
A. preparing a N, N-dimethylformamide solution of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) with a certain concentration;
B. preparing a dichloromethane solution of TK and N, N-diisopropylethylamine with a molar ratio of 1-1: 4;
C. slowly adding the solution B into the solution A, and reacting for 10-30 minutes at the temperature of 0-50 ℃;
D. preparing an antitumor drug (R)3) And DIPEA in dichloromethane at a molar ratio of 1-1: 4;
E. adding the solution D into the solution C, reacting for 12-36 hours, extracting the water phase for multiple times by using dichloromethane, combining the organic phases, and drying the organic phases by using anhydrous magnesium sulfate;
F. filtering the solution, removing the filtrate, removing the solvent in vacuum to obtain a crude product, and performing thin-layer chromatography to obtain a pure product;
the structure of a reaction product after the antitumor drug and the substance containing the hydrogen peroxide response connecting group react is as follows:
9. the method for preparing the hydrogen peroxide-responsive prodrug targeting FAP according to claim 7, wherein a reaction product obtained by the reaction of an antitumor drug and a substance containing a hydrogen peroxide-responsive linker reacts with a substance having an active targeting FAP group,
A. preparing N, N-dimethylformamide solution of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate with certain concentration;
B. preparing a solution of a reaction product obtained after the reaction of the antitumor drug and a substance containing a hydrogen peroxide response connecting group and dichloromethane of N, N-diisopropylethylamine at a molar ratio of 1-1: 4;
C. slowly adding the solution B into the solution A, and reacting for 10-30 minutes at the temperature of 0-50 ℃;
D. preparing a solution of FAPI and DIPEA in dichloromethane, wherein the molar ratio of the FAPI to the DIPEA is 1-1: 4;
E. adding the solution D into the solution C, reacting for 12-36 hours, extracting the water phase for multiple times by using dichloromethane, combining the organic phases, and drying the organic phases by using anhydrous magnesium sulfate;
F. and filtering the solution, removing filtrate, removing the solvent in vacuum to obtain a crude product, and performing thin-layer chromatography to obtain a pure product, namely the prodrug of the FAP-targeted hydrogen peroxide response.
10. The use of the FAP-targeted hydrogen peroxide-responsive prodrug of claim 1 or 2, wherein the FAP-targeted hydrogen peroxide-responsive prodrug is used for the preparation of a medicament for the precise treatment of a tumor site.
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