CN117050092A - Broad-spectrum anticancer drug MCPC1 and preparation method and application thereof - Google Patents
Broad-spectrum anticancer drug MCPC1 and preparation method and application thereof Download PDFInfo
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- CN117050092A CN117050092A CN202311022384.2A CN202311022384A CN117050092A CN 117050092 A CN117050092 A CN 117050092A CN 202311022384 A CN202311022384 A CN 202311022384A CN 117050092 A CN117050092 A CN 117050092A
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- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 24
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- PBLZLIFKVPJDCO-UHFFFAOYSA-N 12-aminododecanoic acid Chemical compound NCCCCCCCCCCCC(O)=O PBLZLIFKVPJDCO-UHFFFAOYSA-N 0.000 claims abstract description 20
- JAABVEXCGCXWRR-FBXFSONDSA-N rel-norcantharidin Chemical compound C1C[C@H]2[C@@H]3C(=O)OC(=O)[C@@H]3[C@@H]1O2 JAABVEXCGCXWRR-FBXFSONDSA-N 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 4
- 201000005202 lung cancer Diseases 0.000 claims abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 4
- 201000001441 melanoma Diseases 0.000 claims abstract description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 6
- 239000008055 phosphate buffer solution Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 239000002105 nanoparticle Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 5
- 239000003814 drug Substances 0.000 abstract description 15
- 230000001093 anti-cancer Effects 0.000 abstract description 11
- 230000003013 cytotoxicity Effects 0.000 abstract description 9
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 230000021615 conjugation Effects 0.000 abstract description 3
- 150000008065 acid anhydrides Chemical class 0.000 abstract description 2
- 201000011510 cancer Diseases 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 abstract description 2
- 231100000820 toxicity test Toxicity 0.000 abstract description 2
- JAABVEXCGCXWRR-UHFFFAOYSA-N norcantharidin Chemical compound C1CC2C3C(=O)OC(=O)C3C1O2 JAABVEXCGCXWRR-UHFFFAOYSA-N 0.000 abstract 2
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 10
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 5
- DHZBEENLJMYSHQ-XCVPVQRUSA-N cantharidin Chemical class C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)OC2=O DHZBEENLJMYSHQ-XCVPVQRUSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229940095758 cantharidin Drugs 0.000 description 2
- 229930008397 cantharidin Natural products 0.000 description 2
- DHZBEENLJMYSHQ-UHFFFAOYSA-N cantharidine Natural products O1C2CCC1C1(C)C2(C)C(=O)OC1=O DHZBEENLJMYSHQ-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 235000017858 Laurus nobilis Nutrition 0.000 description 1
- 235000005212 Terminalia tomentosa Nutrition 0.000 description 1
- 244000125380 Terminalia tomentosa Species 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- PKAHQJNJPDVTDP-UHFFFAOYSA-N methyl cyclopropanecarboxylate Chemical compound COC(=O)C1CC1 PKAHQJNJPDVTDP-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Nanotechnology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Biotechnology (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Animal Behavior & Ethology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a broad-spectrum anticancer drug MCPC1, a preparation method and application thereof. The broad-spectrum anticancer medicine of the invention is an anticancer medicine obtained by utilizing the conjugation reaction of norcantharidin NCTD and 12-aminododecanoic acid through acid anhydride and amino. The result of the anti-tumor activity and toxicity test experiment shows that the MCPC1 has spectrum anti-cancer activity, has an inhibiting effect on lung cancer (A549), melanoma (B16F 10-OVA) and pancreatic cancer (Panc-1), and has higher medicinal value and better clinical application prospect when the final concentration of the medicine is 25 mug/mL, at least half of various cancer cells are killed, and the broad spectrum anti-cancer medicine MCPC1 has lower cytotoxicity and reduces the cytotoxicity of norcantharidin NCTD.
Description
Technical Field
The invention relates to a broad-spectrum anticancer drug MCPC1, a preparation method and application thereof, belonging to the technical field of biological medicine.
Background
Norcantharidin (NCTD) is an artificially synthesized anticancer compound, namely cantharidin derivative, and is the product of the main anticancer component cantharidin of Chinese medicinal materials after dimethyl is removed by hydrolysis. Norcantharidin is easy to synthesize and has wider prospect in anticancer and other application fields than cantharidin. However, the composition has the defects of rapid elimination in vivo, low bioavailability, poor tumor targeting, biotoxicity to normal cells and the like, restricts the wide clinical application of the composition, and also influences the antitumor effect of the composition. Therefore, the synthesis of cantharidin derivatives based on the purpose of reducing toxicity and enhancing efficiency is always one of the hot spots for the development of new drugs.
Lauric acid, also known as dodecanoic acid, is a natural product and represents about 3% of the laurel oil content. 12-aminododecanoic acid is a derivative of lauric acid, and amino groups can be oxidized by related enzymes in vivo to be biologically metabolized. There is no report on the modification of NCTD with 12-aminododecanoic acid to reduce its cytotoxicity.
Disclosure of Invention
The purpose of the invention is that: aiming at the defects of high cytotoxicity, poor drug effect, poor targeting and the like of norcantharidin, the invention aims to provide a norcantharidin drug modified by 12-aminododecanoic acid, namely, the modified norcantharidin drug MCPC1 is obtained by the conjugation reaction of norcantharidin NCTD and 12-aminododecanoic acid through acid anhydride and amino, and has broad-spectrum anticancer activity and low cytotoxicity.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
in a first aspect of the present invention, there is provided a broad spectrum anticancer drug MCPC1 or a pharmaceutically acceptable salt thereof, said broad spectrum anticancer drug MCPC1 having the chemical structural formula shown below:
in a second aspect of the present invention, a preparation method of a broad-spectrum anticancer drug MCPC1 in the above technical solution is provided, including: adding norcantharidin and 12-aminododecanoic acid into polar solvent, adding organic base catalyst, heating to react, and separating and purifying to obtain the final product.
Preferably, the polar solvent is at least one of N, N-dimethylformamide and N-methylpyrrolidone; the organic base catalyst is at least one of pyridine, triethylamine and N, N-diisopropylethylamine.
Preferably, the temperature of the heating reaction is 50-70 ℃ and the time is 48-96 h.
Preferably, the specific steps of separation and purification include: after the reaction is finished, insoluble substances are removed by filtration, the filtrate is collected and added into pure water, the pH value of the solution is regulated to 5.5-6.5, and the product is obtained by filtration.
Preferably, the preparation method further comprises the step of self-assembling the obtained product into nanoparticles: and dissolving the filtered product into PBS (phosphate buffer solution) with the pH of 7.4 to prepare a mixed solution with the concentration of 0.1-0.25 mg/mL, and stirring the mixed solution at normal temperature for reaction and then self-assembling to obtain the nano particles.
In a third aspect of the present invention, there is provided an application of the broad-spectrum anticancer drug MCPC1 or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug in the above technical scheme.
Preferably, the tumor includes any one of lung cancer, melanoma and pancreatic cancer.
Compared with the prior art, the invention has the following beneficial effects:
the invention utilizes 12-aminododecanoic acid to reform norcantharidin, prepares a structured modified norcantharidin drug MCPC1 through one-step facilitated conjugation, and the drug has broad-spectrum anticancer activity, but has lower cytotoxicity to normal cells, and reduces the cytotoxicity of the norcantharidin; in addition, the nano-drug MCPC1 prepared by the invention has single molecular weight (382 g/mol), and is convenient for purification and separation and verification of clinical efficacy.
Drawings
FIG. 1 is a synthetic route of the broad-spectrum anticancer drug MCPC1 of the invention;
FIG. 2 is a hydrogen spectrum of the broad-spectrum anticancer drug MCPC1 of the invention;
FIG. 3 is a mass spectrum of the broad-spectrum anticancer drug MCPC1 of the invention;
fig. 4 is an assembly diagram of the broad-spectrum anticancer drug MCPC1 of the present invention in PBS7.4 (0.25 mg/mL, scale = 100 nm);
FIG. 5 is a broad-spectrum antitumor activity assay of the broad-spectrum anticancer drug MCPC1 of the invention;
FIG. 6 shows the low toxicity of the broad-spectrum anticancer drug MCPC1 of the invention to normal cells (293T).
Detailed Description
In order to make the invention more comprehensible, preferred embodiments accompanied with figures are described in detail below.
The test methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.
EXAMPLE 1 preparation of Decantharidin nano-drug MCPC1
The preparation route of the MCPC1 is shown in fig. 1, and the specific preparation method comprises the following steps: 1.68g of norcantharidin and 2.15g of 12-aminododecanoic acid are added into 100mL of DMF, triethylamine is used as a catalyst (2.8 mL), and the mixture is reacted for 72h at 60 ℃. After the reaction was completed, insoluble matter was removed by filtration. Adding the filtered DMF mixed solution into pure water, adjusting the pH value of the solution to 6.0, and filtering to obtain a product which is named MCPC1.
The MCPC1 was successfully prepared by characterization of nuclear magnetism (fig. 2) and mass spectrometry (fig. 3). We dissolved MCPC1 in PBS solution (pH 7.4) and found that at a concentration of 0.25mg/mL (too high a concentration would precipitate), MCPC1 could assemble into nanoparticles of about 50nm (see FIG. 4).
EXAMPLE 2 antitumor Activity and toxicity test of MCPC1
Broad-spectrum antitumor activity was the main objective of the MCPC1 study, and in this example, the inhibition of MCPC1 (PBS solution of MCPC 1) on lung cancer (A549), melanoma (B16F 10-OVA) and pancreatic cancer (Panc-1) was measured, and as a result, it was found that MCPC1 had broad-spectrum anticancer activity, and at a final drug concentration of 25. Mu.g/mL, at least half of various cancer cells were killed (see FIG. 5).
In addition to examining the broad-spectrum anticancer activity of MCPC1, it is also important to evaluate its toxicity to normal cells. In the experiment, the cytotoxicity of MCPC1 and NCTD on 293T cells under the condition of the same (original drug) concentration is measured by using normal cells 293T as model cells. As shown in FIG. 6, since MCPC1 can form stable nanostructures, about 60% of 293T cells survived at a final drug concentration of 25. Mu.g/mL. Whereas for NCTD treatment, only about 40% of the cells survived when the final concentration was 6.25. Mu.g/mL. It can be seen that the nano-drug formed by implantation of 12-aminododecanoic acid can effectively reduce cytotoxicity.
While the invention has been described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (8)
1. A broad-spectrum anticancer drug MCPC1 or a pharmaceutically acceptable salt thereof, wherein the broad-spectrum anticancer drug MCPC1 has a chemical structural formula shown below:
2. the method for preparing broad-spectrum anticancer drug MCPC1 of claim 1, comprising: adding norcantharidin and 12-aminododecanoic acid into polar solvent, adding organic base catalyst, heating to react, and separating and purifying to obtain the final product.
3. The method for preparing broad-spectrum anticancer drug MCPC1 according to claim 2, wherein the polar solvent is at least one of N, N-dimethylformamide and N-methylpyrrolidone; the organic base catalyst is at least one of pyridine, triethylamine and N, N-diisopropylethylamine.
4. The method for preparing broad-spectrum anticancer drug MCPC1 as claimed in claim 2, wherein the heating reaction is carried out at 50-70 ℃ for 48-96 hours.
5. The method for preparing broad-spectrum anticancer drug MCPC1 according to claim 2, wherein the specific steps of separation and purification include: after the reaction is finished, insoluble substances are removed by filtration, the filtrate is collected and added into pure water, the pH value of the solution is regulated to 5.5-6.5, and the product is obtained by filtration.
6. The method for preparing broad-spectrum anticancer drug MCPC1 according to any one of claims 2 to 5, further comprising a step of self-assembling the obtained product into nanoparticles: and dissolving the filtered product into PBS (phosphate buffer solution) with the pH of 7.4 to prepare a mixed solution with the concentration of 0.1-0.25 mg/mL, and stirring the mixed solution at normal temperature for reaction and then self-assembling to obtain the nano particles.
7. The use of broad-spectrum anticancer drug MCPC1 or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of an antitumor drug.
8. The use of claim 7, wherein the tumor comprises any one of lung cancer, melanoma, and pancreatic cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311022384.2A CN117050092A (en) | 2023-08-14 | 2023-08-14 | Broad-spectrum anticancer drug MCPC1 and preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311022384.2A CN117050092A (en) | 2023-08-14 | 2023-08-14 | Broad-spectrum anticancer drug MCPC1 and preparation method and application thereof |
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| CN117050092A true CN117050092A (en) | 2023-11-14 |
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| CN202311022384.2A Pending CN117050092A (en) | 2023-08-14 | 2023-08-14 | Broad-spectrum anticancer drug MCPC1 and preparation method and application thereof |
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| CN (1) | CN117050092A (en) |
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- 2023-08-14 CN CN202311022384.2A patent/CN117050092A/en active Pending
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