CN113801110B - 1,2, 4-oxadiazole heterocyclic compound and application thereof - Google Patents
1,2, 4-oxadiazole heterocyclic compound and application thereof Download PDFInfo
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
The invention relates to a1, 2, 4-oxadiazole heterocyclic compound and application thereof, belonging to the technical field of antitumor drugs. The technical problem solved by the invention is to provide a novel compound with an inhibition effect on tumor cells. The structural formula of the compound is shown in the formula I, wherein X is a carbon atom or a nitrogen atom, and R is selected from C1-C4 alkyl, C1-C4 alkoxy or halogen atoms. The invention synthesizes a series of novel compounds, discovers that the compounds have inhibition effect on the growth of tumor cells, in particular to liver cancer cells and breast cancer cells, has good inhibition effect, can be applied to anti-tumor drugs, and lays a foundation for the research and development of novel anti-tumor drugs.
Description
Technical Field
The invention relates to a1, 2, 4-oxadiazole heterocyclic compound and application thereof, belonging to the technical field of antitumor drugs.
Background
According to World Health Organization (WHO) statistics, 3/5 of people worldwide die from 4 major diseases, cancer, diabetes, cardiovascular disease, chronic respiratory disease, and cancer is one of the most prominent causes of death. At present, the treatment methods of cancer mainly comprise operation treatment, radiation treatment, chemotherapy, biological immunity treatment, microwave treatment, laser treatment and the like. Wherein, the chemical treatment mainly kills tumor cells by chemical drugs, inhibits the growth and propagation of the tumor cells and promotes the differentiation of the tumor cells, which is a systemic treatment means and has treatment effect on primary foci, metastasis and subclinical metastasis.
Cisplatin, also known as cis-diamminedichloroplatinum, is a platinum-containing anticancer drug that can cross-link with DNA strands and exhibits cytotoxic effects. After dissolution, the cell membrane can pass through the charged cell membrane without carrier transport in vivo. Because the concentration of chloride ions in cells is low, the chloride ions are replaced by water, the charge is positive, the double-functional group-like alkylating agent has the function of double-functional groups, can be combined with the basic groups of DNA in the cell nucleus to form three types of cross links, so that the DNA is damaged, the DNA replication and transcription are damaged, and the synthesis of RNA and protein is inhibited at high concentration. Cisplatin has the advantages of broad anticancer spectrum, effective hypoxic cells, strong action and the like, has been widely used for treating testicular cancer, ovarian cancer, uterine cancer, bladder cancer, neck cancer, prostate cancer, brain cancer and the like, and has remarkable curative effect. However, cisplatin has a certain toxicity for treating cancer, and drug resistance generated by long-term administration is also a problem which is difficult to solve. Therefore, there is a continuous need to find new antitumor drugs with clinical effects similar to cisplatin.
Disclosure of Invention
Aiming at the defects, the invention solves the technical problem of providing a novel compound with an inhibition effect on tumor cells.
The structural formula of the compound is shown in the formula I:
wherein X is a carbon atom or a nitrogen atom, and R is selected from a C1-C4 alkyl group, a C1-C4 alkoxy group or a halogen atom.
In one embodiment of the invention, X is a carbon atom or a nitrogen atom and R is selected from methyl, ethyl, methoxy, ethoxy, isopropyl, fluorine or chlorine atoms.
The preferred structural formula of the compound is any one of the following structural formulas:
as a preferred embodiment, the compounds have the formula
The invention also provides pharmaceutically acceptable salts of the compounds of the invention.
The compounds of the present invention may be prepared as pharmaceutically acceptable salts, such as nitrates, hydrochlorides and the like.
The invention also provides application of the compound in preparing a medicament for inhibiting tumor cell growth.
The compounds of the present invention have an inhibitory effect on a variety of tumor cells, which in a preferred embodiment of the present invention are liver cancer cells or breast cancer cells.
The invention also provides an anti-tumor pharmaceutical composition.
The active ingredient of the antitumor pharmaceutical composition comprises an effective dose of the compound or pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention has the following beneficial effects:
the invention synthesizes a series of novel compounds, discovers that the compounds have inhibition effect on the growth of tumor cells, in particular to liver cancer cells and breast cancer cells, has good inhibition effect, can be applied to anti-tumor drugs, and lays a foundation for the research and development of novel anti-tumor drugs.
Detailed Description
The compound is a1, 2, 4-oxadiazole heterocyclic compound, and the structural formula of the compound is shown in formula I:
wherein X is a carbon atom or a nitrogen atom, and R is selected from a C1-C4 alkyl group, a C1-C4 alkoxy group or a halogen atom.
The invention synthesizes a series of novel compounds, discovers that the compounds have inhibition effect on the growth of tumor cells, in particular to liver cancer cells and breast cancer cells, has good inhibition effect, and can be applied to antitumor drugs.
In one embodiment of the invention, X is a carbon atom or a nitrogen atom and R is selected from methyl, ethyl, methoxy, ethoxy, isopropyl, fluorine or chlorine atoms.
The preferred structural formula of the compound is any one of the following structural formulas:
as a preferred embodiment, the compounds have the formula
The compounds of the present invention may be prepared as pharmaceutically acceptable salts, such as nitrates, hydrochlorides and the like.
The compound has inhibiting effect on various tumor cells, such as human colon cancer cells including HCT116, sw480, sw620 and the like; human breast cancer cells including MCF-7, MDA-MB-231, A2870S, and the like; human liver cancer cells including HepG2, HCC-LM3, and the like; human cervical cancer cell HeLa, etc.; human ovarian cancer cells SKOV-3, etc.; human melanoma cells a875 and a375, etc.; human prostate cancer cells PC-3, etc.; human glioma cells U87, and the like.
In a preferred embodiment of the present invention, the tumor cell is a liver cancer cell or a breast cancer cell.
The active ingredient of the antitumor pharmaceutical composition comprises an effective dose of the compound or pharmaceutically acceptable salt thereof.
The compounds of the present invention may be used alone or in combination with pharmaceutically acceptable carriers or excipients in the form of pharmaceutical compositions, and when used in the form of pharmaceutical compositions, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, is typically combined with at least one pharmaceutically acceptable carrier or diluent to form a suitable dosage form for use.
The antitumor pharmaceutical composition of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intracardiac, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, with oral, intramuscular, intraperitoneal or intravenous modes of administration being preferred.
The "C1-C4 alkyl" in the present invention means an alkyl group having any integer of 1 to 4 carbon atoms, and includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.
"C1-C4 alkoxy" refers to an alkoxy group having any integer between 1 and 4 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
The following describes the invention in more detail with reference to examples, which are not intended to limit the invention thereto.
Example 1 Synthesis of Compounds
The synthetic route of the compound is as follows:
the specific synthesis method comprises the following steps:
at normal temperature, 4-hydroxypiperidine (a) and di-tert-butyl dicarbonate (b) are dissolved in Tetrahydrofuran (THF) at a ratio of 1:1, and 3 times the amount of triethylamine (Et) is added 3 N), stirring at normal temperature (rt) for 8h; after completion of the reaction, the mixture was separated by column chromatography to give a colorless oil c.
Under ice bath, naH is slowly added into THF solution of c and bromoacetic acid, after the reaction is completed, the pH is adjusted to be acidic by dilute hydrochloric acid, the reaction is treated, and column chromatography is used for separation, thus obtaining yellow solid d.
And e, adding the mixture into the mixed solution of water and ethanol in equal proportion, adding hydroxylamine hydrochloride, mixing, and stirring at the temperature of 80 ℃. After the reaction is completed, separating by column chromatography to obtain white powder f.
F, g, isobutyl chloroformate and the like are added into toluene in equal proportion, stirred, and triethylamine with three times of the amount is added; and after the reaction is finished, separating by column chromatography to obtain white powder of target molecules.
Wherein, according to the difference of R and X, the compounds shown in the table 1 are respectively synthesized:
TABLE 1
The nuclear magnetic characterization results were as follows:
compound A1:
1 H NMR(400MHz,Chloroform)δ＝7.98(dt,J＝7.4,1.4,1H),7.72(t,J＝1.4,1H),7.45(t,J＝7.5,1H),7.17(dt,J＝7.5,1.4,1H),4.57(s,2H),3.85(dt,J＝12.4,5.5,2H),3.59(p,J＝7.5,1H),3.37(dt,J＝12.4,5.5,2H),2.50(s,3H),2.20(ddt,J＝12.9,7.5,5.5,2H),1.78(ddt,J＝12.8,7.5,5.5,2H),1.49(s,9H).
compound A2:
1 H NMR(400MHz,Chloroform)δ＝7.76(dt,J＝7.5,1.5,1H),7.39(t,J＝7.5,1H),7.28(t,J＝1.4,1H),7.02(dt,J＝7.4,1.4,1H),4.58(s,2H),3.91–3.80(m,5H),3.63(p,J＝7.5,1H),3.37(dt,J＝12.3,5.4,2H),2.21(ddt,J＝12.9,7.5,5.4,2H),1.76(ddt,J＝12.8,7.5,5.4,2H),1.49(s,9H).
compound A3:
1 H NMR(400MHz,Chloroform)δ＝7.99(dt,J＝7.5,1.5,1H),7.85(t,J＝1.4,1H),7.49(t,J＝7.5,1H),7.35(dt,J＝7.5,1.4,1H),4.58(s,2H),3.85(dt,J＝12.3,5.4,2H),3.63(p,J＝7.5,1H),3.37(dt,J＝12.3,5.4,2H),2.98(dt,J＝12.8,6.4,1H),2.21(ddt,J＝12.9,7.5,5.4,2H),1.76(ddt,J＝12.8,7.5,5.5,2H),1.49(s,9H),1.26(d,J＝6.4,6H).
compound A4:
1 H NMR(400MHz,Chloroform)δ＝7.86(dt,J＝7.4,1.4,1H),7.56–7.43(m,2H),7.20(ddd,J＝9.1,2.8,1.4,1H),4.57(s,2H),3.85(dt,J＝12.4,5.4,2H),3.60(p,J＝7.5,1H),3.37(dt,J＝12.4,5.5,2H),2.20(ddt,J＝12.9,7.5,5.5,2H),1.78(ddt,J＝12.9,7.5,5.5,2H),1.49(s,9H).
compound B1:
1 H NMR(400MHz,Chloroform)δ＝8.67(d,J＝7.5,1H),7.96(dd,J＝7.5,1.5,1H),7.68(d,J＝1.4,1H),4.57(s,2H),3.85(dt,J＝12.3,5.4,2H),3.62(p,J＝7.5,1H),3.37(dt,J＝12.4,5.5,2H),2.71(s,3H),2.21(ddt,J＝12.9,7.6,5.5,2H),1.76(ddt,J＝12.9,7.6,5.5,2H),1.49(s,9H).
compound B2:
1 H NMR(400MHz,Chloroform)δ＝7.70(d,J＝7.5,1H),7.22(dd,J＝7.5,1.4,1H),6.35(d,J＝1.4,1H),4.60(s,2H),3.96(s,3H),3.94–3.78(m,3H),3.38(dt,J＝12.4,5.5,2H),2.08(ddt,J＝12.7,7.3,5.4,2H),1.84(ddt,J＝12.7,7.4,5.5,2H),1.42(s,9H).
compound B3:
1 H NMR(400MHz,Chloroform)δ＝8.63(d,J＝7.5,1H),7.99(dd,J＝7.5,1.4,1H),7.71(d,J＝1.4,1H),4.57(s,2H),3.85(dt,J＝12.3,5.5,2H),3.62(p,J＝7.5,1H),3.43–3.23(m,3H),2.20(ddt,J＝12.9,7.5,5.4,2H),1.76(ddt,J＝12.8,7.5,5.4,2H),1.49(s,9H),1.34(d,J＝6.4,6H).
compound B4:
1 H NMR(400MHz,Chloroform)δ＝8.30(d,J＝7.5,1H),8.17(dd,J＝7.5,1.4,1H),7.50(dd,J＝7.9,1.4,1H),4.57(s,2H),3.85(dt,J＝12.3,5.4,2H),3.62(p,J＝7.5,1H),3.37(dt,J＝12.4,5.5,2H),2.21(ddt,J＝12.9,7.5,5.4,2H),1.76(ddt,J＝12.9,7.5,5.5,2H),1.49(s,9H).
example 2 anti-tumor Activity test
Tumor cells selected for the experiment were: human colon cancer cells, including HCT116, sw480 and Sw620; human breast cancer cells, including MCF-7 and MDA-MB-231; human hepatoma cells, including HepG2 and HCC-LM3; human cervical cancer cell HeLa; human ovarian cancer cells SKOV-3; human melanoma cells a875 and a375; human prostate cancer cells PC-3; human glioma cells U87. The above cells were all purchased from ATCC.
The experimental method comprises the following steps:
taking tumor cells in logarithmic growth phase, digesting with pancreatin, and isolatingThe heart was resuspended in fresh medium and the cells were seeded at the appropriate density in 96-well plates at 100 μl per well. After inoculation, the 96-well plate is placed into an incubator for continuous culture for 24 hours, so that tumor cells are attached to the wall. Culture environment: temperature 37 ℃,5% CO 2 . When the cells adhere to the wall and reach the proper cell density, the experiment is stopped after 72 hours, 20 mu L of CCK8 solution is added, and the mixture is placed in a cell culture box for 2 to 4 hours. The absorbance (OD) at 450nm of each well was measured using a microplate reader, and the in vitro proliferation inhibition rate and cell survival rate of tumor cells in each experimental group were calculated. According to the formula: relative cell proliferation inhibition (%) = (blank control group-experimental group)/blank control group×100%. Each set was provided with 3 parallel duplicate wells and each experiment was repeated three times. Finally, IC is adopted 50 Calculation software determination IC 50 (half inhibition concentration in. Mu. Mol/L).
The experimental results are shown in Table 2.
TABLE 2
Therefore, the compound has an inhibiting effect on various tumor cells, particularly the compound A3 has a good inhibiting effect on liver cancer cells HepG2 and breast cancer cells MCF-7, and half inhibition concentration is even lower than that of cisplatin, so that the compound A3 has a good cell inhibiting effect, can be used for preparing medicines for treating liver cancer or breast cancer, and lays a foundation for new antitumor medicines.
Claims (8)
1. The structural formula is a compound shown in a formula I:
wherein X is a carbon atom or a nitrogen atom, and R is selected from a C1-C4 alkyl group, a C1-C4 alkoxy group or a halogen atom.
2. A compound according to claim 1, characterized in that: x is a carbon atom or a nitrogen atom, and R is selected from methyl, ethyl, methoxy, ethoxy, isopropyl, fluorine atom or chlorine atom.
3. A compound according to claim 1, characterized in that: the structural formula is any one of the following structural formulas:
4. a compound according to claim 3, characterized in that: the structure is as follows
5. A pharmaceutically acceptable salt of a compound of any one of claims 1 to 4.
6. Use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for inhibiting the growth of tumour cells.
7. The use according to claim 6, characterized in that: the tumor cells are liver cancer cells or breast cancer cells.
8. A pharmaceutical composition for treating cancer, characterized in that: an active ingredient comprising an effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
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| KR20160119100A (en) * | 2014-02-18 | 2016-10-12 | 다이이찌 산쿄 가부시키가이샤 | Aminopyrazolone derivative |
| CN113149980A (en) * | 2020-01-07 | 2021-07-23 | 上海市奉贤区中心医院 | Tert-butyloxycarbonyl micromolecule organic compound targeting PUF60, derivative thereof and application thereof |
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