CN113662944B - Duck alkaloid ketone derivative - Google Patents
Duck alkaloid ketone derivative Download PDFInfo
- Publication number
- CN113662944B CN113662944B CN202111127277.7A CN202111127277A CN113662944B CN 113662944 B CN113662944 B CN 113662944B CN 202111127277 A CN202111127277 A CN 202111127277A CN 113662944 B CN113662944 B CN 113662944B
- Authority
- CN
- China
- Prior art keywords
- added
- cells
- alkaloid
- mmol
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E10/00—Energy generation through renewable energy sources
- Y02E10/50—Photovoltaic [PV] energy
- Y02E10/549—Organic PV cells
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a novel anti-tumor drug structure represented by a structural general formula 1, wherein the combination type of R1 and R2 is R1 is Br, R2 is H or R1 is F, R2 is H or R1 is F, R is Br; r3, R4 and R5 are respectively selected from H, OH and H. The medicine has simple synthesis method, contains a duckbill alkaloid ketone structural unit in the molecule, and can effectively inhibit proliferation of gastric adenocarcinoma cells (SGC-7901) and human myelogenous leukemia cells (HL-60) and prostate cancer cells (PC-3).
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a duckbill alkaloid ketone derivative.
Background
Malignant tumors, also known as cancers, are common and frequently occurring diseases that seriously harm human health, and about 700 tens of thousands of people die from cancer every year worldwide, accounting for about one-fourth of the total deaths. Gastric cancer is a common malignant tumor in China, the death rate of the gastric cancer accounts for the first place of various malignant tumors in the world, and the incidence rate of leukemia in China is 2.76/10 ten thousand. Leukemia is the 6 th (male) and 8 th (female) in the mortality rate of malignant tumors, and the 1 st in children and adults under 35 years old, which seriously affects the health of residents in China.
Drug therapy has become an effective and universally applicable treatment for malignant tumors, and the sales of antitumor drugs worldwide in 2020 has exceeded $800 billion.
The variety of antitumor drugs applied clinically is various, and currently, the common 1, antimetabolite, namely, the fluorouracil of the methoprene; 2. medicines interfering with protein synthesis and function, vincristine, vinblastine, paclitaxel; 3. drugs that interfere with the transcription process: doxorubicin and daunorubicin. 4. Affecting protein structure and function: alkylating agents (nitrogen mustard, cyclophosphamide) platinum complexes cisplatin carboplatin oxaliplatin; hormones: tamoxifen and medroxyprogesterone. Antibiotics: mitomycin, pingyangmycin, bleomycin, and the like.
At present, the existing antitumor drugs generally have the problems of poor selectivity, toxic and side effects, drug resistance and the like, and the search for the antitumor drugs with high efficiency and low degree is still an important subject faced by pharmaceutical chemists. The invention provides a structure of the duckbill alkaloid ketone medicine with anti-tumor activity, and has important development and application prospects.
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description summary and in the title of the application, to avoid obscuring the purpose of this section, the description summary and the title of the invention, which should not be used to limit the scope of the invention.
The invention aims to provide a novel anti-tumor drug structure of a duckbill alkaloid ketone, and the compound has obvious inhibition effect on gastric adenocarcinoma cells (SGC-7901) and human myelogenous leukemia cells (HL-60) and prostate cancer cells (PC-3).
In order to solve the technical problems, according to one aspect of the present invention, the following technical solutions are provided:
the application of the duckbill alkaloid ketone derivative in preparing medicaments for resisting gastric adenocarcinoma cells, human promyelocytic leukemia cells and prostatic cancer cells is selected from the following compounds in the general formula 1, and the compounds have the following structural expression:
R1-R5 are independently selected from H, OH, OMe, iPr and halogen.
Compared with the prior art, the invention has the beneficial effects that: can be added with one or more drug carriers or excipients to prepare into tablet, capsule, granule or emulsion. The in vitro pharmacodynamics experiment proves that: the compound has obvious inhibition effect on gastric adenocarcinoma cells (SGC-7901) and human myelogenous leukemia cells (HL-60), and prostate cancer cells (PC-3), and has good anti-tumor activity and good drug resistance.
Detailed Description
The following detailed description of the present invention will provide further details in order to make the above-mentioned objects, features and advantages of the present invention more comprehensible.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below. .
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in further detail below.
The general formula of the medicine is as follows:
R1-R5 are independentlyVertical is selected from H, OH, OMe, iPr and halogen; one preferred embodiment is that three substituents of R1-R5 are hydrogen, one is halogen and the other is OH, for example: r1 is Br, R2, R3 and R5 are H, and R4 is OH. Another preferred embodiment is where three substituents in R1-R5 are H, one is halogen and the other is OMe, for example: r1 is F, R2, R3 and R5 are H, and R4 is OMe. The halogen is Br or F. Most preferred is a scheme wherein R1 is Br, R2 is F, R3 and R5 are H, and R4 is OH.
The synthesis of the compound takes pyridine boric acid substituted by R1-R5, anthranilic acid and 3-bromo-2-pyrrolidone as raw materials for condensation reaction, and the specific synthetic route is as follows:
according to the synthetic route, the following structural drugs can be obtained: />
The following are pharmacological tests and data for some of the compounds of the invention:
1. anti-tumor cell proliferation Sulfonyl Rhodamine B (SRB) assay
The specific operation is as follows: collecting gastric adenocarcinoma cells (SGC-7901), human myelogenous leukemia cells (HL-60), and prostate cancer cells (PC-3) with RPMI1640 medium or MEM medium and 10% fresh calf serum at 37deg.C, CO 2 The cells were incubated in a 5% cell incubator, and tumor cells were inoculated into 96-well plates according to 10000 cells/well, respectively, and incubated in the cell incubator for 24 hours. A certain drug concentration and a blank control are set, and 3 parallel compound holes are set in each group. Detecting the cell staining condition by using a full-wavelength enzyme-labeling instrument according to the standard procedure of staining reading at the time of T0 and 48 hours respectively to obtain the chemical combinationInhibition of cancer proliferating cells by the agent.
The test results are shown in Table 1
Wherein, the compound 1-7 is a compound EKB-569 developed by Huisha corporation, and is a positive medicament with better activity. From the data, it can be seen that the compounds of the present invention have a certain antitumor effect, and some compounds have better activity than the control for certain cancers.
Test for inhibitory Activity of Compounds against cellular nitric oxide synthase
Determination of the inhibitory Activity of the synthesized Compounds on NO production by determining the amount of NO production in mouse macrophages
The test adopts a nitric oxide synthase detection kit to detect, cells used in the test are ANA-1 mouse macrophages with higher expression level of iNOS, the test cells are incubated by adopting RPMI1640 culture solution, then are connected into a 96-well plate, buffer solution and LPS are added, after incubation for 24 hours, the test cells are respectively dosed according to the test requirements, after 30 minutes, centrifugation is carried out, supernatant is sucked, PBS is used for cleaning for 2 times, the reaction result is measured by using a Varioskan full-wavelength fluoroenzyme-labeled instrument, the relative activity of iNOS enzyme is calculated by using the measured fluorescence value, and then the compound IC50 value is calculated by using a LOGIT method. The test results are shown in Table 2.
Wherein, the compounds 1-7 are positive control drugs L-Canavanine with better activity, which are publicly reported, and the data can find that the compounds contained in the patent reach the order of activity reported by the prior positive drugs.
Example 1
Synthesis method of compound 1-1
1.39g (10 mmol) of 4-hydroxy-2-pyridine boric acid and 1.63g (10 mmol) of 3-bromo-2-pyrrolidone are added into a 100mL round bottom double-mouth bottle, 35mL of absolute ethyl alcohol, 200mg of potassium carbonate and 30mg of palladium chloride catalyst are added for reaction at room temperature for 8h, 2.15g (10 mmol) of 4-bromo-2-aminobenzoic acid is added for reaction for 3h, 50mL of dichloromethane is added, filtration is carried out, the filtrate is directly concentrated and dried, and the mixture of ethyl acetate and petroleum ether is recrystallized to obtain 3.07g of target product with the yield of 85.9%.
1 H-NMR(400M, DMSO-d6):2.04-2.21(m, 2H), 3.13-3.34(m, 3H), 6.26-6.27(m, 1H), 7.24-7.37(m, 3H), 7.88-7.91(m, 2H), 9.45(s, 1H).
Example 2
Synthesis method of compound 1-2
1.39g (10 mmol) of 4-hydroxy-2-pyridine boric acid and 1.63g (10 mmol) of 3-bromo-2-pyrrolidone are added into a 100mL round bottom double-mouth bottle, 35mL of absolute ethyl alcohol, 200mg of potassium carbonate and 30mg of palladium chloride catalyst are added for reaction at room temperature for 8h, 1.55g (10 mmol) of 4-fluoro-2-aminobenzoic acid is added for reaction for 3h, 50mL of dichloromethane is added, filtration is carried out, the filtrate is directly concentrated and dried, and the mixture of ethyl acetate and petroleum ether is recrystallized to obtain 1.89g of target product with the yield of 63.4%.
1 H-NMR(400M, DMSO-d6):2.03-2.20(m, 2H), 3.14-3.31(m, 3H), 6.27-6.29(m, 1H), 7.21-7.36(m, 3H), 7.84-7.90(m, 2H), 9.47(s, 1H).
Example 3
Synthesis method of compounds 1-3
1.39g (10 mmol) of 4-hydroxy-2-pyridine boric acid and 1.63g (10 mmol) of 3-bromo-2-pyrrolidone are added into a 100mL round bottom double-mouth bottle, 35mL of absolute ethyl alcohol, 200mg of potassium carbonate and 30mg of palladium chloride catalyst are added for reaction at room temperature for 8h, 2.32g (10 mmol) of 4-fluoro-5-bromo-2-aminobenzoic acid is added, 50mL of dichloromethane is added after reaction for 3h, filtration, direct concentration and spin-drying of filtrate, ethyl acetate and stone are carried outRecrystallizing the mixed solution of the oil and the ether to obtain 3.11g of target product with the yield of 82.9 percent.
1 H-NMR(400M, DMSO-d6):2.09-2.22(m, 2H), 3.13-3.35(m, 3H), 6.16-6.21(m, 1H), 7.04-7.27(m, 2H), 7.68-7.81(m, 2H), 9.38(s, 1H).
Example 4
Synthesis method of compounds 1-4
1.53g (10 mmol) of 4-methoxy-2-pyridine boric acid and 1.63g (10 mmol) of 3-bromo-2-pyrrolidone are added into a 100mL round bottom double-mouth bottle, 35mL of absolute ethyl alcohol, 200mg of potassium carbonate and 30mg of palladium chloride catalyst are added for reaction at room temperature for 8h, 2.32g (10 mmol) of 4-fluoro-5-bromo-2-aminobenzoic acid is added for reaction for 3h, 50mL of dichloromethane is added, filtration is carried out, the filtrate is directly concentrated and dried, and the mixture of ethyl acetate and petroleum ether is recrystallized to obtain 3.31g of target product with the yield of 85.1%.
1 H-NMR(400M, DMSO-d6):2.07-2.21(m, 2H), 3.16-3.24(m, 3H),3.45(s, 3H) 6.18-6.20(m, 1H), 7.26-7.34(m, 3H), 7.80-7.89(m, 1H).
Example 5
Synthesis method of compounds 1-5
1.53g (10 mmol) of 4-methoxy-2-pyridine boric acid and 1.63g (10 mmol) of 3-bromo-2-pyrrolidone are added into a 100mL round bottom double-mouth bottle, 35mL of absolute ethyl alcohol, 200mg of potassium carbonate and 30mg of palladium chloride catalyst are added for reaction at room temperature for 8h, 1.37g (10 mmol) of 2-aminobenzoic acid is added for reaction for 3h, 50mL of dichloromethane is added, filtration is carried out, the filtrate is directly concentrated and dried, and the mixed solution of ethyl acetate and petroleum ether is recrystallized to obtain 2.16g of a target product, and the yield is 73.7%.
1 H-NMR(400M, DMSO-d6):2.10-2.17(m, 2H), 3.10-3.14(m, 3H),3.47(s, 3H) 6.19-6.23(m, 2H), 7.19-7.21(m, 4H), 7.73-7.81(m, 1H).
Example 6
Synthesis method of compounds 1-6
1.23g (10 mmol) of 2-pyridine boric acid and 1.63g (10 mmol) of 3-bromo-2-pyrrolidone are added into a 100mL round bottom double-mouth bottle, 35mL of absolute ethyl alcohol, 200mg of potassium carbonate and 30mg of palladium chloride catalyst are added for reaction at room temperature for 8h, 1.73g (10 mmol) of 4, 5-difluoro-2-aminobenzoic acid is added for reaction for 3h, 50mL of dichloromethane is added, filtration is carried out, the filtrate is directly concentrated and dried, and the mixed solution of ethyl acetate and petroleum ether is recrystallized to obtain 2.63g of target product, and the yield is 87.9%.
1 H-NMR(400M, DMSO-d6):2.11-2.19(m, 2H), 3.08-3.12(m, 3H), 6.34-6.38(m, 2H), 7.25-7.31(m, 3H), 7.69-7.74(m, 1H)。
Although the invention has been described hereinabove with reference to embodiments, various modifications thereof may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In particular, the features of the disclosed embodiments may be combined with each other in any manner as long as there is no structural conflict, and the exhaustive description of these combinations is not given in this specification merely for the sake of omitting the descriptions and saving resources. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed, but that the invention will include all embodiments falling within the scope of the appended claims. .
Claims (1)
1. A duckbill alkali ketone derivative characterized in that: a compound selected from the following structural formulae, in particular:
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111127277.7A CN113662944B (en) | 2021-09-26 | 2021-09-26 | Duck alkaloid ketone derivative |
| ZA2022/07565A ZA202207565B (en) | 2021-09-26 | 2022-07-08 | Vasicinone derivative as well as preparation method and anti-tumor application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111127277.7A CN113662944B (en) | 2021-09-26 | 2021-09-26 | Duck alkaloid ketone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113662944A CN113662944A (en) | 2021-11-19 |
| CN113662944B true CN113662944B (en) | 2023-06-09 |
Family
ID=78550140
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111127277.7A Active CN113662944B (en) | 2021-09-26 | 2021-09-26 | Duck alkaloid ketone derivative |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN113662944B (en) |
| ZA (1) | ZA202207565B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103417536B (en) * | 2012-05-17 | 2015-08-26 | 复旦大学 | The application in antitumor drug prepared by harmol |
| CN106518879B (en) * | 2016-09-21 | 2018-12-07 | 西安交通大学 | A kind of 2,3- lactam nucleus condenses quinazoline -4 (3H) -one derivative and its preparation method and application |
-
2021
- 2021-09-26 CN CN202111127277.7A patent/CN113662944B/en active Active
-
2022
- 2022-07-08 ZA ZA2022/07565A patent/ZA202207565B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| 刘玮.《授权前STN补充检索》. * |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA202207565B (en) | 2022-10-26 |
| CN113662944A (en) | 2021-11-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Immel et al. | Synthesis and X-ray structure analysis of a heptacoordinate titanium (IV)-bis-chelate with enhanced in vivo antitumor efficacy | |
| CN113072588B (en) | Tetravalent platinum complex containing artesunate and preparation method and application thereof | |
| US9233995B2 (en) | Quinazoline derivatives and quinazoline complex protein kinase inhibitor for inhibiting multiplication of tumor cells and preparation method thereof | |
| Monim-ul-Mehboob et al. | Synthesis, spectroscopic characterization and anti-cancer properties of new gold (III)–alkanediamine complexes against gastric, prostate and ovarian cancer cells; crystal structure of [Au2 (pn) 2 (Cl) 2] Cl2· H2O | |
| CN110002987A (en) | Phenyl acrol cyclohexenone derivates and preparation method and purposes | |
| CN102942595A (en) | Ruthenium complexes, preparation method thereof and application | |
| CN113662944B (en) | Duck alkaloid ketone derivative | |
| CN117024413B (en) | 3-aminopyrazine-2-formamide targeted proteolytic chimera, and preparation method, pharmaceutical composition and application thereof | |
| CN113698435B (en) | Tetravalent platinum complex containing p53-MDM2 inhibitor and preparation method and application thereof | |
| CN103382182A (en) | Phenylurea coupling quinazoline compound, and preparation method, pharmaceutical composition and pharmaceutical use thereof | |
| CN103554188B (en) | 6-(nitrogen heterocyclic replacement) anthraquinone platinum dichloride title complex and its preparation method and application | |
| Yan et al. | Synthesis, characterization and cytotoxicity of platinum (II) complexes containing reduced amino acid ester Schiff bases | |
| CN110922415A (en) | Synthesis and application of novel anti-tumor active compound | |
| CN102643247A (en) | Disulfide compound as well as preparation method and application thereof | |
| CN106188089B (en) | Mangostin derivative A, preparation method and its anti-tumor application | |
| CN111704634B (en) | Metal complex containing tridentate ligand and xanthine derivative ligand as well as preparation method and medical application of metal complex | |
| CN113773325A (en) | Isoquinoline and vasicine ketone mixed alkaloid analogue and application thereof in anti-tumor | |
| CN110156816A (en) | Tetrahydropyrazolopiperazine compound and preparation method and application thereof | |
| Xing et al. | Synthesis and cytotoxicity of diam (m) ineplatinum (II) complexes with 2, 2-bis (hydroxymethyl) malonate as the leaving group | |
| CN110105260B (en) | Aromatic ring ureido indole derivative and preparation method and application thereof | |
| CN104693189B (en) | A kind of pyrimidine compound and its preparation method and application | |
| RU2792567C1 (en) | Method for obtaining (3br*,7ar*,10br*,14ar*-cis-14c,14d)-2,9-bis(pyridin-3-ylmethyl)octadecahydro-1h,8h-2,3a,7b,9,10a, 14b-hexaazadibenzo[fg,op]tetracene and its use as an agent with cytotoxic activity | |
| CN114933599B (en) | Double beta-carboline compound and medicinal salt, preparation method and application thereof | |
| US11203608B2 (en) | Platinum-containing compounds, and related compositions and uses thereof | |
| EP3596054B1 (en) | 5-carboxamide-2-thiobarbituric acids and use thereof as medicaments |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |