CN107235947B - Novel 5, 7-dihydroxy-6, 8-bis (1-methylpiperazine) -4H-chromen-4-one compounds and antitumor application thereof - Google Patents
Novel 5, 7-dihydroxy-6, 8-bis (1-methylpiperazine) -4H-chromen-4-one compounds and antitumor application thereof Download PDFInfo
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- CN107235947B CN107235947B CN201710541722.1A CN201710541722A CN107235947B CN 107235947 B CN107235947 B CN 107235947B CN 201710541722 A CN201710541722 A CN 201710541722A CN 107235947 B CN107235947 B CN 107235947B
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- China
- Prior art keywords
- compounds
- gastric cancer
- methylpiperazine
- bis
- cancer cells
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- -1 (1-methylpiperazine) -4H-chromen-4-one compounds Chemical class 0.000 title claims description 6
- 230000000259 anti-tumor effect Effects 0.000 title description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 16
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 16
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 abstract description 10
- 238000012216 screening Methods 0.000 abstract description 7
- 230000035755 proliferation Effects 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 abstract 1
- 230000009036 growth inhibition Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 19
- 230000002401 inhibitory effect Effects 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 231100000002 MTT assay Toxicity 0.000 description 2
- 238000000134 MTT assay Methods 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000009643 clonogenic assay Methods 0.000 description 2
- 231100000096 clonogenic assay Toxicity 0.000 description 2
- 230000005757 colony formation Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 1
- 238000002738 Giemsa staining Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000009950 gastric cancer growth Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
Abstract
The invention newly discovers a class of 5, 7-dihydroxyl-6, 8-bis (1-methylpiperazine) -4H-chromene-4-ketone compounds, and in vitro screening shows that the compounds have stronger inhibition effect on various gastric cancer cells (BGC-823 and MGC-803), and then growth inhibition experiments prove that the compounds can inhibit the in vitro proliferation of gastric cancer cells (BGC-823 and MGC-803). The novel compounds can be applied as antitumor drugs.
Description
Technical Field
The invention discovers a novel compound of 5, 7-dihydroxyl-6, 8-bis (1-methylpiperazine) -4H-chromen-4-one, which can inhibit the proliferation of gastric cancer cells in vitro. The invention discovers the application of the compounds in preparing antitumor drugs, and belongs to the technical field of medicines.
Background
The invention discovers a novel 5, 7-dihydroxy-6, 8-bis (1-methylpiperazine) -4H-chromen-4-one compound through screening a compound library, and the compound can obviously inhibit the in vitro proliferation of gastric cancer cells.
Disclosure of Invention
The invention searches lead compounds on the in vitro cell level, discovers a compound with a novel structure of 5, 7-dihydroxy-6, 8-bis (1-methylpiperazine) -4H-chromen-4-one, and proves that the compound can inhibit the in vitro proliferation of tumor cells through cytology experiments. The invention can provide lead compounds for the development of antitumor drugs.
The technical scheme of the invention is as follows: firstly, performing primary screening and secondary screening on the cellular level, and finding out a compound capable of inhibiting tumor cells in vitro; subsequently, the effect of inhibiting gastric cancer cell proliferation was confirmed by MTT assay and clonogenic assay.
Drawings
Fig. 1: bar graph of sample No. 1 inhibiting the in vitro growth of two gastric cancer cells (n=3);
fig. 2: sample No. 1 inhibits the clonogenic assay of two gastric cancer cells (representative graph);
fig. 3: sample No. 1 clones form a statistical plot of the experiment (n=3).
The specific embodiment is as follows:
the following description is made with reference to the accompanying drawings
MTT assay
(1) Taking one bottle of human gastric cancer cells in exponential growth phase, counting after digestion, inoculating 180 μl of cell suspension onto 96-well plate, and inoculating 2-4×10 3 Constant temperature CO is placed in each hole 2 Culturing in an incubator for 24 hours.
(2) The next day fresh culture medium (containing 10% serum) was changed, and samples of different concentrations were added and incubation continued for 72 hours.
(3) MTT reagent was added to the 96-well plate, 20. Mu.l/well, and the reaction was performed in an incubator for 4 hours.
(4) The supernatant was aspirated, DMSO was added, 150. Mu.l/well, and shaken on a plate shaker for 5 minutes. The absorbance of each well was measured at a wavelength of 570nm using an enzyme-linked immunosorbent assay, and cell inhibition was calculated.
2. Cloning formation experiments
Taking gastric cancer cells in logarithmic growth phase, counting 1000 cells after digestion, adding the gastric cancer cells into a 3.5cm cell culture dish, and adhering overnight; the next day fresh culture medium 2ml is replaced, the tested medicines with different concentrations are added, and constant temperature CO is added 2 The incubator was continuously cultured for 7 days. The colonies containing more than 50 cells were counted under a dissecting microscope by giemsa staining.
Experimental results
1. The structural general formula of the compound obtained by screening is as follows:
| compounds of formula (I) | R1 | R2 | R3 |
| 1 | F | A | A |
| 2 | F | B | B |
| 3 | F | C | C |
| 4 | F | D | D |
| 5 | F | E | E |
| 6 | F | F | F |
| 7 | F | K | K |
| 8 | F | L | L |
| 9 | E | A | A |
| 10 | G | A | A |
| 11 | H | A | A |
| 12 | I | A | A |
| 13 | I | B | B |
| 14 | J | A | A |
| 15 | K | A | A |
| 16 | L | A | A |
Wherein, the liquid crystal display device comprises a liquid crystal display device,
A：-H；
B：-CH2-CH3；
C：-O-CH3；
D：-CH2OH；
the inhibition rate (72 h,%) of the gastric cancer cells by the sample of 2.10 μg/ml is as follows:
3. inhibition of gastric cancer cells and IC (integrated circuit) by sample 50 Value (72 h)
According to the primary screening result, the sample No. 1 with the best effect is selected for re-screening, and a bar graph of the sample for inhibiting the growth of gastric cancer cells is produced (figure 1). IC of sample No. 1 to gastric cancer BGC-823 and MGC-803 cells 50 The values were 11.27.+ -. 0.67. Mu.M and 7.31.+ -. 0.53. Mu.M, respectively.
4. Sample for inhibiting in vitro proliferation of gastric cancer cells
The inhibition of BGC-823 and MGC-803 in vitro proliferation was studied in sample No. 1. Three groups of doses, high (5. Mu.M), medium (3. Mu.M) and low (1. Mu.M), were administered to BGC-823 and MGC-803 cells, at constant temperature CO 2 The incubator was continuously cultured for 7 days. After the completion of the experiment, the cells were stained with giemsa and observed under a dissecting microscope for colony formation. The results are shown in FIG. 2 and the statistical results are shown in FIG. 3. It can be seen that sample No. 1 has a significant inhibitory effect on colony formation of both gastric cancer cells and exhibits a significant dose dependency.
Claims (1)
1. The application of 5, 7-dihydroxy-6, 8-bis (1-methylpiperazine) -4H-chromen-4-one compounds in preparing medicines for treating gastric cancer is disclosed, wherein the compounds have the following structures:
the structure of the compound is specifically as follows:
Wherein B is-CH 2 CH 3 ；
E is
F is
I is
K is
L is
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710541722.1A CN107235947B (en) | 2017-06-29 | 2017-06-29 | Novel 5, 7-dihydroxy-6, 8-bis (1-methylpiperazine) -4H-chromen-4-one compounds and antitumor application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710541722.1A CN107235947B (en) | 2017-06-29 | 2017-06-29 | Novel 5, 7-dihydroxy-6, 8-bis (1-methylpiperazine) -4H-chromen-4-one compounds and antitumor application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107235947A CN107235947A (en) | 2017-10-10 |
| CN107235947B true CN107235947B (en) | 2023-10-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710541722.1A Active CN107235947B (en) | 2017-06-29 | 2017-06-29 | Novel 5, 7-dihydroxy-6, 8-bis (1-methylpiperazine) -4H-chromen-4-one compounds and antitumor application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107235947B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113549044B (en) * | 2021-07-23 | 2024-01-23 | 中国药科大学 | 8-azacyclo-substituted chromone derivative and preparation method and pharmaceutical application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997042949A1 (en) * | 1996-05-10 | 1997-11-20 | Bristol-Myers Squibb Company | 2-thio or 2-oxo flavopiridol analogs |
-
2017
- 2017-06-29 CN CN201710541722.1A patent/CN107235947B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997042949A1 (en) * | 1996-05-10 | 1997-11-20 | Bristol-Myers Squibb Company | 2-thio or 2-oxo flavopiridol analogs |
Non-Patent Citations (5)
| Title |
|---|
| "Nitrogen-containing flavonoid analogues as CDK1/cyclin B inhibitors: Synthesis,SAR analysis, and biological activity";Shixuan Zhang et al.;《Bioorganic & Medicinal Chemistry》;20080703;第16卷;第7127-7132页 * |
| "Nitrogen-containing flavonoids as CDK1/Cyclin B inhibitors: Design, synthesis, and biological evaluation";Tao Liu et al.;《Bioorganic & Medicinal Chemistry Letters》;20061107;第17卷;第278-281页 * |
| "SYNTHESIS OF AMINOMETHYL DERIVATIVES OF CHRYSIN";S. P. Bondarenko et al.;《Chemistry of Natural Compounds》;20131130;第49卷(第5期);第841-844页 * |
| "Synthesis of kaempferide Mannich base derivatives and their antiproliferative activity on three human cancer cell lines";Van-Son Nguyen et al.;《ACTA BIOCHIMICA POLONICA》;20150908;第62卷(第3期);第547-552页 * |
| 余元勋."细胞周期转化抑制剂".《中国分子胃癌学》.安徽科学技术出版社,2016,第391页. * |
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| Publication number | Publication date |
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| CN107235947A (en) | 2017-10-10 |
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