CN113461708A - Ansamitocin P-3 derivative and application thereof in preparation of drugs for treating gastric cancer - Google Patents
Ansamitocin P-3 derivative and application thereof in preparation of drugs for treating gastric cancer Download PDFInfo
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- CN113461708A CN113461708A CN202110829626.3A CN202110829626A CN113461708A CN 113461708 A CN113461708 A CN 113461708A CN 202110829626 A CN202110829626 A CN 202110829626A CN 113461708 A CN113461708 A CN 113461708A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention belongs to the technical field of gastric cancer treatment medicines, and particularly relates to an ansamitocin P-3 derivative and application thereof in preparation of a gastric cancer treatment medicine, wherein the ansamitocin P-3 derivative is represented by a formula (A), and the ansamitocin P-3 derivative or pharmaceutically acceptable salt thereof is applied in preparation of a gastric cancer treatment medicine; the pharmaceutically acceptable salts are as defined in the specification;
Description
Technical Field
The invention belongs to the technical field of gastric cancer treatment medicines, and particularly relates to an ansamitocin P-3 derivative and application thereof in preparation of a medicine for treating gastric cancer.
Background
Gastric cancer (gastric carcinoma) is one of the most common malignancies worldwide. According to the latest cancer data, the number of new cases and deaths of gastric cancer in 2020 ranks fifth and fourth among all cancers, and reaches 109 ten thousand and 77 ten thousand respectively. In 2020, the number of new cases and deaths of gastric cancer in China is in the third place, 48 ten thousand and 37 ten thousand respectively, and both cases account for almost half of the world. Gastric cancer originates from gastric mucosal epithelium, mostly belongs to adenocarcinoma, has no obvious symptoms in the early stage, and is often similar to the symptoms of chronic diseases of the stomach, such as gastritis, gastric ulcer and the like. Therefore, the early diagnosis rate is low, and the optimal radical operation time is often delayed. A considerable part of patients with gastric cancer after radical operation or in late stage are matched with proper chemotherapy treatment. The commonly used gastric cancer chemotherapeutics include oral drugs (such as tegafur, efonidine, and fluocinolone), intravenous chemotherapeutics (such as fluorouracil, mitomycin, cisplatin, and adriamycin), and in recent years, the chemotherapeutics such as paclitaxel and platinum oxalate are also used for treating gastric cancer.
However, since the efficacy of these various chemotherapeutic agents is general and is often accompanied by drug resistance, chemotherapy for gastric cancer often has only limited short-term effects. Ansamitocin P-3(Ansamitocin-3) is a maytansinol-type macrolide antibiotic from microorganisms, and can characteristically inhibit mitosis of eukaryotic cells to generate strong antitumor activity. However, the toxic and side effects are huge, and the application of the traditional Chinese medicine in the aspect of gastric cancer treatment is limited.
Disclosure of Invention
In order to overcome the defects of the prior art, the technical problems to be solved by the invention are as follows: solves the problem of large toxic and side effect of ansamitocin P-3.
In order to solve the above technical problems, the present invention provides ansamitocin P-3 derivatives represented by formula (A);
further provided is the use of an ansamitocin P-3 derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of gastric cancer, said ansamitocin P-3 derivative being represented by formula (a);
wherein the pharmaceutically acceptable salt is a sodium salt.
Wherein, the medicine for treating gastric cancer is tablets, capsules, powder, granules, troches, injections or gels.
Wherein, the medicine for treating gastric cancer is carried out by oral administration or intravenous injection.
The medicine for treating gastric cancer comprises an effective amount of ansamitocin P-3 derivatives or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or diluent.
The invention has the beneficial effects that: the formula (A) represents an ansamitocin P-3 derivative, and the N element in the inner heterocyclic ring of the ansamitocin P-3 is replaced by the C element based on the principle of bioisostere to obtain the ansamitocin P-3 derivative, wherein the ansamitocin P-3 derivative has no increase in antitumor activity and synthesis cost compared with the ansamitocin P-3, but the toxic and side effects are greatly reduced; compared with chemotherapeutic drugs taxol and cytotoxin small molecule Colchicine, the curative effect is respectively improved by 15-30 times and more than 100 times, meanwhile, the ansamitocin P-3 derivative has lower production cost and equivalent effect with the same amount of taxol, and can be used for patients at low dose on the premise of higher anti-tumor effect, so that the economic burden of the patients is reduced to a certain extent.
Drawings
FIG. 1 is a graph showing the respective changes of cell activity and log (M) of AP-3/AP-3-D/Collinic/Paclitaxel in SGC-7901 antitumor drug efficacy assay for gastric cancer cells;
FIG. 2 is a graph showing the antitumor efficacy of AP-3, AP-3-D and a blank solvent in a mouse model (which contains a subcutaneously inoculated gastric cancer cell line SGC-7901) as a function of tumor volume change versus time of administration;
FIG. 3 is a graph showing the antitumor efficacy of AP-3, AP-3-D and a blank solvent in a mouse model (which contains a subcutaneously inoculated gastric cancer cell line SGC-7901) as a function of the change in body weight of nude mice and the time of administration.
Detailed Description
In order to explain technical contents, achieved objects, and effects of the present invention in detail, the following description is made with reference to the accompanying drawings in combination with the embodiments.
An ansamitocin P-3 derivative represented by formula (A);
use of an ansamitocin P-3 derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of gastric cancer, said ansamitocin P-3 derivative being represented by formula (a);
specifically, the compound represented by the formula (A) is designed based on the bioisosterism principle as an ansamitocin P-3 derivative on the basis of the prototype of ansamitocin P-3. The differences from the ansamitocin P-3 prototype are: one of the N elements in the heterocycle is replaced by the C element to obtain the ansamitocin P-3 derivative. The ansamitocin P-3 derivative obtained by atom replacement has equivalent anti-tumor activity with an ansamitocin P-3 prototype, but the toxic and side effects are greatly reduced, and the ansamitocin P-3 derivative has the potential of drug formation.
In this context, "pharmaceutically acceptable salts" particularly refer to acid addition salts or base salts which retain the biological effectiveness (especially anti-tumor activity herein) and properties of the compounds of formula (a), and which are not generally biologically or pharmaceutically undesirable salts.
The "toxic and side effects" refer to the side effects of emaciation, nausea, vomiting, hair loss and the like accompanying patients in the treatment process, such as tegafur, efonidine, fluocinolone, fluorouracil, mitomycin, cisplatin, adriamycin and the like, which are traditional cancer chemotherapeutics.
Optionally, the pharmaceutically acceptable salt is a sodium salt.
Further, the formulation of the gastric cancer treatment drug includes, but is not limited to, tablets, capsules, powders, granules, lozenges, injections or gels.
Further, the medicine for treating gastric cancer is taken orally or injected intravenously.
Further, the medicine for treating gastric cancer comprises an effective amount of ansamitocin P-3 derivative or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
Herein, "pharmaceutically acceptable carrier or diluent" specifically refers to a carrier or diluent that does not cause significant irritation to an organism, while not destroying the biological activity (referred to herein as antitumor activity) and properties of the administered compound (which is a compound represented by formula (a) herein).
In the following, the ansamitocin P-3 derivative is represented by AP-3-D; the ansamitocin P-3 prototype is denoted AP-3.
Detection example 1
AP-3-D antitumor drug efficacy assay was performed at the cellular level.
The test method comprises the following steps:
four groups of experiments are set, and the four groups of experiments respectively detect the substances to be detected, namely AP-3-D, AP-3, colchicine and paclitaxel; each group of experiments is respectively subjected to four parallel experiments, and specifically comprises an experiment group, a control group and a blank group.
Wherein the experimental group comprises a culture medium containing cells, CCK-8 and a substance to be detected, and is marked As;
the control group comprises a culture medium containing cells and no substances to be detected and CCK-8 which is marked as Ac;
the blank included medium without cells and without test substance and CCK-8, denoted Ab.
Wherein the cell is selected from gastric cancer cells (SGC-7901);
the culture medium is a cell culture medium such as 1640 or DMEM which does not contain serum.
The specific test method is as follows:
1. to the plates were added 50. mu.L of the test substances at different concentrations, 4 replicates per concentration.
Wherein the concentrations are respectively 10-13、10-12、10-11、10-10、10-9、10-8、10-7、10-6mol/L；
2. At 37 ℃ 5% CO2At a concentration of 50. mu.L in a 96-well plateCell suspension with cell number of 8X 103A hole;
3. observing the cell spreading degree by a microscope, after ensuring that the cells are spread uniformly, putting a 96-hole culture plate in a layer closest to water in a cell culture box, and culturing for 72 hours;
4. after 72 hours, preparing a culture medium and CCK-8 mixed solution, and preparing the mixed solution according to the calculation of 90 mu L of culture medium and 10 mu L of CCK-8 in each hole;
5. removing old culture medium by using a vacuum pump, and adding the mixed solution into a 96-well plate by using an 8-gang discharging gun, wherein each well contains 100 mu L of the mixed solution;
6. putting the 96-well plate in the step 5 into an incubator for incubation for 1-2 h;
7. testing the absorbance value of each hole at 450nm by using an enzyme-labeling instrument to obtain the absorbance value data of each hole;
8. and processing the absorbance value data, wherein the processing formula is as follows: the cell viability (cell viability) ═ As-Ab)/(Ac-Ab) ] × 100%, and the data processing results are shown in fig. 1.
As can be seen from FIG. 1, the pharmacological effects IC of AP-3-D and AP-3 on gastric cancer cell SGC-790150Are all at 10-11M, shows that the antitumor activity of AP-3-D is equivalent to that of AP-3; and the drug effect IC of colchicine50At 10-8M level, pharmacodynamic IC of paclitaxel50At 10-10The M level shows that the anti-gastric cancer activity of colchicine and paclitaxel is lower than AP-3-D and AP-31-2 orders of magnitude.
Example two
And (3) carrying out AP-3-D antitumor drug effect measurement on an animal model.
The test method comprises the following steps:
1. constructing a female nude mouse gastric cancer model, which specifically comprises the following steps: the gastric cancer cell SGC-7901 is added at a ratio of 5 × 106One/one female nude mouse was injected subcutaneously;
2. when the tumor grows to 100mm3The female nude mice are divided into groups at the left and the right, and each group comprises 8 mice;
3. respectively administering tail vein of each group of nude mouse model with dose of 0.5mg/kg for 1 time/week for four weeks;
wherein, the administration is specifically AP-3, AP-3-D and a blank solvent (control);
wherein the blank solvent is the same as the solvent for dissolving the AP-3 and the AP-3-D, and is specifically normal saline containing 10% of propylene glycol.
4. Tumor size and nude mouse model body weight were measured twice weekly and statistical results are shown in fig. 2 and 3.
As can be seen from FIG. 2, AP-3 and AP-3-D had tumor growth inhibitory effects (p < 0.05) in a nude mouse model in which gastric cancer cells (SGC-7901) were subcutaneously transplanted. And after stopping the administration, both AP-3 and AP-3-D were able to maintain tumor volume, showing that both AP-3-D and AP-3 had comparable antitumor activity and had tumor suppressive effect for a period of time after stopping the administration.
As can be seen from FIG. 3, AP-3 had a greater effect on the body weight of nude mice than the blank solvent at the same dose, and showed significant differences (p < 0.05 or p < 0.01) after the second dose, whereas AP-3-D had a close effect on the body weight of nude mice, with no limitation. It was shown that AP-3-D has lower toxic side effects than AP-3.
In conclusion, the invention provides application of the ansamitocin P-3 derivative or the pharmaceutically acceptable salt thereof in preparing a medicament for treating gastric cancer, and a medicinal composition consisting of the ansamitocin P-3 derivative or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. The compound of the formula (A) is used as an ansamitocin P-3 derivative, and an N element in an inner heterocyclic ring of the ansamitocin P-3 is replaced by a C element on the basis of a biological electronic isostere principle to obtain the ansamitocin P-3 derivative, wherein the ansamitocin P-3 derivative is not increased in antineoplastic activity and synthesis cost compared with the ansamitocin P-3, but the toxic and side effects are greatly reduced; compared with chemotherapeutic drugs taxol and cytotoxin small molecule Colchicine, the curative effect is respectively improved by 15-30 times and more than 100 times, meanwhile, the ansamitocin P-3 derivative has lower production cost and equivalent effect with the same amount of taxol, and can be used for patients at low dose on the premise of higher anti-tumor effect, so that the economic burden of the patients is reduced to a certain extent.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent changes made by using the contents of the present specification and the drawings, or applied directly or indirectly to the related technical fields, are included in the scope of the present invention.
Claims (6)
1. An ansamitocin P-3 derivative characterized by being represented by the formula (a);
2. use of an ansamitocin P-3 derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of gastric cancer, wherein the ansamitocin P-3 derivative is represented by formula (a);
3. the use according to claim 2, wherein the pharmaceutically acceptable salt is a sodium salt.
4. The use according to claim 2, wherein the gastric cancer treatment drug is a tablet, capsule, powder, granule, lozenge, injection or gel.
5. The use according to claim 2, wherein the medicament for the treatment of gastric cancer is administered orally or intravenously.
6. The use according to claim 2, wherein the medicament for treating gastric cancer comprises an effective amount of the ansamitocin P-3 derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
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| CN202110829626.3A CN113461708A (en) | 2021-07-22 | 2021-07-22 | Ansamitocin P-3 derivative and application thereof in preparation of drugs for treating gastric cancer |
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| CN202110829626.3A CN113461708A (en) | 2021-07-22 | 2021-07-22 | Ansamitocin P-3 derivative and application thereof in preparation of drugs for treating gastric cancer |
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4322348A (en) * | 1979-06-05 | 1982-03-30 | Takeda Chemical Industries, Ltd. | Maytansinoids |
| CN1490322A (en) * | 2003-08-13 | 2004-04-21 | 中国科学院昆明植物研究所 | Ansi glycoside compound and its medicinal composition, preparation and use |
| EP2103618A1 (en) * | 2008-03-20 | 2009-09-23 | Leibniz Universität Hannover | Novel ansamitocin derivatives |
| US20090258870A1 (en) * | 2008-03-20 | 2009-10-15 | Leibniz Universitat Hannover | Novel ansamitocin derivatives |
| CN103254213A (en) * | 2012-12-21 | 2013-08-21 | 百奥泰生物科技(广州)有限公司 | Preparation method of maytenin-like ester and composition used in method |
| CN103333179A (en) * | 2012-12-21 | 2013-10-02 | 百奥泰生物科技(广州)有限公司 | Maytansinoid derivatives, preparation method thereof and applications thereof |
| US20130323268A1 (en) * | 2010-11-03 | 2013-12-05 | Immunogen, Inc. | Cytotoxic agents comprising new ansamitocin derivatives |
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| WO2020180709A1 (en) * | 2019-03-01 | 2020-09-10 | Celgene Corporation | Preparation of maytansinol |
-
2021
- 2021-07-22 CN CN202110829626.3A patent/CN113461708A/en active Pending
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4322348A (en) * | 1979-06-05 | 1982-03-30 | Takeda Chemical Industries, Ltd. | Maytansinoids |
| CN1490322A (en) * | 2003-08-13 | 2004-04-21 | 中国科学院昆明植物研究所 | Ansi glycoside compound and its medicinal composition, preparation and use |
| EP2103618A1 (en) * | 2008-03-20 | 2009-09-23 | Leibniz Universität Hannover | Novel ansamitocin derivatives |
| US20090258870A1 (en) * | 2008-03-20 | 2009-10-15 | Leibniz Universitat Hannover | Novel ansamitocin derivatives |
| US20130323268A1 (en) * | 2010-11-03 | 2013-12-05 | Immunogen, Inc. | Cytotoxic agents comprising new ansamitocin derivatives |
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| WO2020180709A1 (en) * | 2019-03-01 | 2020-09-10 | Celgene Corporation | Preparation of maytansinol |
| CN111635418A (en) * | 2020-06-17 | 2020-09-08 | 山东大学 | Maytansinoid derivative and synthetic method and application thereof |
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