A naringenin ether compound containing an isopropanolamine structure and a preparation method thereof

Abstract

The application discloses a naringenin ether compound containing isopropyl alcohol amine structure shown in formula I and a preparation method and application thereof. R1 and R2 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl hydroxyl, C6-C10 aryl or substituted aryl or C6-10 heteroaryl or substituted heteroaryl; or R1 and R2 are connected to form a 5-10 membered ring or a ring containing a heteroatom, and the heteroatom is N or O.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to naringenin ether compounds containing isopropylamine structure and a preparation method thereof. BACKGROUND

[0002] Natural products are important resources for the creation of new medicines and new pesticides. Natural products have the characteristics of wide source, diverse types, diverse physiological activities, less toxic side effects, easy degradation or good environmental compatibility, and have been widely used by people for thousands of years. Naringenin is a natural dihydroflavonoid compound, which mainly exists in the form of glycoside in grapefruit, tomato, grape and citrus fruits of Rutaceae, and has applications in chemistry, medicine, food science and pesticides, etc. It has a wide range of biological activities such as antibacterial, anti-inflammatory, antioxidant, cough and phlegm, blood lipid-lowering, anti-tumor, etc.

[0003] The research progress of the biological activity of naringenin compounds is as follows:

[0004] In 2013, Yoon et al. [Yoon, H.; Kim, T. W.; Shin, S. Y.; Park, M. J.; Yong, Y.; Kim, D. W.; Islam, T.; Lee, Y. H.; Jung, K. Y.; Lim, Y. Design, synthesis and inhibitory activities of naringenin derivatives on human colon cancer cells [J]. Bioorg. Med. Chem. Lett., 2013, 23, 232-238.] reported 5 kinds of naringenin derivatives substituted at 7 position, and evaluated their inhibitory effect on human colon cancer cells HCT116. The results showed that the half maximal inhibitory concentration IC50 of 5 kinds of naringenin derivatives was between 1.20-20.01 uM, which was significantly better than the control drug naringenin.

[0005] In 2019, Latif et al. [Latif, A. D.; Gonda, T.; Kato, K.; Kato, M.; Kato, N. Synthesis and biological evaluation of naringenin derivatives as potential anti-cancer agents [J]. Bioorg. Med. Chem., 2019, 27, 115-123.] reported the synthesis of 5 kinds of naringenin derivatives, and evaluated their anti-cancer activity. The results showed that the IC50 of 5 kinds of naringenin derivatives was between 0.22-1.48 uM, which was significantly better than the control drug naringenin. M.; Kus, N.; Kulmany, A.; Ocsovszki, I.; Zomborszki, Z. P.; Zupko, I.; Hunyadi, A. Synthesis and In Vitro Antitumor Activity of Naringenin Oxime and Oxime Ether Derivatives [J]. Int. J. Mol. Sci., 2019, 20, 2184. reported 8 kinds of naringenin oxime or oxime ether derivatives obtained by addition condensation of naringenin 4-carbonyl group and amino group. The biological test results showed that the tert-butyl oxime ether derivatives had strong inhibition effect on the growth of leukemia (HL-60) and cervical cancer (HeLa, Siha) and breast cancer (MCF-7, MDA-MB-231) cells.

[0006] In 2020, Duda-Madej et al. [Duda-Madej, A.; Kozlowska, J.; Krzyzek, P.; Aniol, M.; Seniuk, A.; Jermakow, K.; Dworniczek, E. Antimicrobial O-Alkyl Derivatives of Naringenin and Their Oximes Against Multidrug-Resistant Bacteria [J]. Molecules., 2020, 25, 3642.] reported 18 new O-alkyl derivatives of naringenin and its oxime. The results of antibacterial activity evaluation showed that the antibacterial activity of naringenin oxime derivatives on Enterococcus faecalis, Staphylococcus aureus, Acinetobacter baumannii, Klebsiella pneumoniae and Helicobacter pylori was higher than that of naringenin derivatives.

[0007] In 2022, Morimoto et al. [Morimoto, R.; Matsubara, C.; Hanada, A.; Omoe, Y.; Ogata, T.; Isegawa, Y. Effect of Structural Differences in Naringenin, Prenylated Naringenin, and Their Derivatives on the Anti-Influenza Virus Activity and Cellular Uptake of Their Flavanones [J]. Pharmaceuticals., 2022, 15, 1480.] reported the anti-viral activity of naringenin, prenylated naringenin and their derivatives against influenza, and the research results showed that the spatial effect of the compound was an important factor affecting its anti-viral activity. In the structure of naringenin, the pentenyl substituent can enhance its anti-viral activity, and its structure and position have a significant influence on its cell permeability.

[0008] A series of naringenin ether compounds containing isopropanolamine structure are synthesized based on the structure of naringenin by introducing nitrogen-containing isopropanolamine structure at position 7, and there is no report at present. SUMMARY

[0009] The purpose of the present application is to provide a naringenin ether compound containing isopropanolamine structure and its preparation method and application.

[0010] The present application is realized by the following technical solutions:

[0011] The naringenin ether compound containing isopropanolamine structure represented by formula I:

[0012]

[0013] R1 and R2 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl hydroxyl, C6-C10 aryl or substituted aryl, or C6-10 heteroaryl or substituted heteroaryl; or R1 and R2 are connected to form a 5-10 membered ring or a heteroatom-containing ring, and the heteroatom is N or O.

[0014] The term "alkyl" used in the present application includes branched and straight chain saturated hydrocarbon groups with a specified number of carbon atoms. For example, "C1-C6 alkyl" means an alkyl group with 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl) and the like.

[0015] "Alkenyl" is a hydrocarbon that includes straight-chain or branched-chain structures and has one or more carbon-carbon double bonds occurring at any stable point along the chain. For example, "C2-C6 alkenyl" refers to alkenyl groups that include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl, 1- propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

[0016] "Alkynyl" is a hydrocarbon that includes straight-chain or branched-chain structures and has one or more carbon-carbon triple bonds occurring at any stable point along the chain. For example, "C2-C6 alkynyl" refers to alkynyl groups that include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0017] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having from 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which can be substituted.

[0018] The term "heteroaryl" refers to substituted and non-substituted aromatic 5- or 6- membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups, having at least one heteroatom (O, S or N) in at least one ring, with the heteroatom containing rings preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroatom containing heteroaryl group can contain one or two oxygen or sulfur atoms and / or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms can optionally be oxidized and the nitrogen atoms can optionally be quaternized. The bicyclic or tricyclic heteroaryl must include at least one fully aromatic ring, and the other fused rings can be aromatic or non-aromatic. The heteroaryl can be attached at any available nitrogen or carbon atom of any ring. When valence permits, the other ring is additionally optionally substituted with =0 (oxo) if the other ring is a cycloalkyl or heterocycloalkyl.

[0019] Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

[0020] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

[0021] If not otherwise stated, the compounds of the present application are understood to include the free form and salts thereof. The term "salt" denotes an acid and / or a base addition salt. In addition, the term "salt" can include zwitterions (inner salts), for example when a compound of Formula I contains both a basic fragment, such as an amine or a pyridine or imidazole ring, and an acidic fragment such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as salts of acceptable metals and amines, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts can be useful, for example, in the preparation of compounds of this application during a purification step, and are included within the scope of the application.

[0022] Preferably, R1and R2are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, ethenyl, propynyl, hydroxyethyl, benzyl, 4-fluorobenzyl; when R1and R2are joined to form a ring, the following:

[0023]

[0024] Most preferably, the naringenin ether compound having an isopropanolamine structure is selected from the group consisting of:

[0025]

[0026]

[0027] The preparation equation of the naringenin ether compound having an isopropanolamine structure is as follows:

[0028]

[0029] The preparation method comprises the following steps:

[0030] 1) using naringenin and epoxy bromopropane as raw materials, and reacting under the catalysis of K2CO3 to prepare an intermediate 7-O-(oxirane-2-ylmethyl)-naringenin;

[0031] 2) reacting 7-O-(oxirane-2-ylmethyl)-naringenin and amine under the catalysis of K2CO3 to obtain the naringenin ether compound having an isopropanolamine structure.

[0032] ​The beneficial effects of the present application are as follows: the present application is based on naringenin, introducing nitrogen-containing isopropanolamine structure at 7 position, synthesizing a series of naringenin ether compounds containing isopropanolamine structure, and finding that the compound is used as a human hepatoma cell and human colon cancer cell proliferation inhibitor. DETAILED DESCRIPTION

[0033] The following is a further description of the present application, but not a limitation of the present application.

[0034] Example 1: Preparation of 7-O-(1-dimethylamino-2-hydroxypropyl)-naringenin (Compound 1)

[0035] 1) Preparation of intermediate 7-O-(oxirane-2-ylmethyl)-naringenin

[0036] Naringenin (1.84 mmol) and K2CO3 (7.35 mmol) were added to a 5 mL acetone solution containing epibromohydrin (7.35 mmol), and the reaction was stopped after 3 h of reaction at 60°C, desolved, 15 mL dichloromethane was extracted, washed with water, dried, desolved, and purified by column chromatography to obtain a light yellow solid with a yield of 26.5%. Its nuclear magnetic resonance data is as follows: 1 H NMR (400 MHz, DMSO) δ 12.11 (s, 1H, 5-OH), 9.62 (s, 1H, 4'-OH), 7.32 (d, J = 8.6 Hz, 2H, 2'-H + 6'-H), 6.80 (d, J = 8.6 Hz, 2H, 3'-H + 5'-H), 6.12 (dd, J = 8.6, 2.3 Hz, 2H, 8-H + 6-H), 5.48 (dd, J = 12.9, 2.8 Hz, 1H, 2-H), 4.41 (dt, J = 11.7, 2.1 Hz, 1H, 1''a-O CH 2CH), 3.86 (ddd, J = 11.7, 6.8, 2.3 Hz, 1H, 1''b-O CH 2CH), 3.36-3.28 (m, 2H, 3a-H + 3''a-CH2O), 2.86-2.81 (m, 1H, 2''-OCH), 2.72 (dd, J = 17.2, 3.0 Hz, 1H, 3b-H), 2.68 (dd, J = 5.0, 2.6 Hz, 1H, 3''b-CH2O); 13 C NMR (101 MHz, DMSO) δ 197.1, 166.4, 163.3, 163.0, 157.9, 128.8, 128.5, 115.3, 102.9, 95.2, 94.4, 78.8, 69.7, 49.5, 43.8, 42.1.

[0037] 2) Preparation of 7-O-(1-dimethylamino-2-hydroxypropyl)-naringenin

[0038] 7-O-(oxirane-2-ylmethyl)-naringenin (1.52 mmol) was added to a solution of K2CO3 (1.52 mmol) and dimethylamine (1.52 mmol) in 7 mL of isopropanol, and the reaction was stopped after 12 h at 60 °C, extracted with 30 mL of dichloromethane, washed with water, dried, desolved, and purified by column chromatography to obtain an orange solid with a yield of 36.6%.

[0039] The structure and the 1H NMR and 13C NMR data of the synthesized naringenin ether compounds containing isopropanolamine structure are shown in Table 1, and the physicochemical properties are shown in Table 2.

[0040] Examples 2-19: Preparation of compounds 2-19

[0041] Reference Example 1, except that dimethylamine in step 2) was replaced with diethylamine or the corresponding substituted amine.

[0042] The structure and the 1H NMR and 13C NMR data of the synthesized naringenin ether compounds containing isopropanolamine structure are shown in Table 1, and the physicochemical properties are shown in Table 2.

[0043] Table 1: 1H NMR and 13C NMR data of compounds

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] Table 2: Physicochemical properties of target compounds

[0051]

[0052] Test Example 1: In vitro anti-tumor activity test:

[0053] Human hepatoma (HepG2) cells, human colon carcinoma (HCT116) cells, human non-small cell lung cancer (A549) cells were used as test objects, inoculated in RPMI1640 medium containing 10% fetal bovine serum, and placed in a 37℃, 5% CO2, saturated humidity incubator for subculture. MTT method was used to detect the inhibition of compound on the proliferation of three kinds of cells: logarithmic growth period of tumor cells was digested, counted and adjusted to a cell concentration of 3×10 4 Each well was inoculated with 100 μL. After 24 h, the original culture medium was removed, and 200 μL of culture medium containing 20.0 μmol / L of compound was added to each well. Six replicates were set for blank control and each concentration group. After 48 h of culture in a 37℃, 5% CO2 incubator, 20 μL of freshly prepared thiazolyl blue (MTT) solution with a concentration of 5% was added to each well. After 4 h of continuous culture, the supernatant was discarded, 150 μL of dimethyl sulfoxide was added to each well, and the mixture was shaken for 10 min. The absorbance (OD) was measured at 590 nm using a microplate reader.

[0054] Inhibition rate (%) = (OD 对照组 - OD 实验组 ) / OD 对照组 × 100%. Linear regression was performed according to the logarithm of the compound concentration and the corresponding inhibition rate to calculate the half-inhibitory concentration (IC 50 ) of each compound on tumor cells.

[0055] Table 3 Inhibition activity (%) of compounds on in vitro proliferation of three kinds of human tumor cells at 20.0 μmol / L, n = 3

[0056]

[0057] Table 4 IC 50 (μmol / L, n = 3

[0058]

[0059] Note: "5-FU" represents the positive control 5-fluorouracil.

[0060] As can be seen from Tables 3 and 4, in the in vitro anti-tumor activity test, some target compounds showed good cytotoxicity on human hepatoma (HepG2) cells and human colon carcinoma (HCT116) cells. The IC 50 of compounds 13 and 16 on human colon carcinoma (HCT116) cells were 35.62 μmol / L and 35.70 μmol / L, respectively, and the IC 50 of compound 16 on human hepatoma (HepG2) cells was 35.70 μmol / L.The concentration is 22.33 micromole per liter; the compound can be used for potential inhibition of human hepatoma (HepG2) cell and human colon cancer (HCT116) cell proliferation drugs, and has good application prospect.

[0061] The above-described embodiments are only used to describe the preferred modes of the present application, and are not used to limit the scope of the present application. Without departing from the design spirit of the present application, various modifications and improvements of the technical solutions of the present application made by those skilled in the art shall fall within the protection scope of the present application.

Claims

1. Naringenin ether compounds containing isopropylamine structure, characterized in that, selected from the group consisting of: 、 。 2. The method for preparing the naringenin ether compound containing the isopropanolamine structure according to claim 1, characterized in that, comprising the following steps: 1) preparing 7-O-(oxirane-2-ylmethyl)-naringenin as an intermediate by reacting naringenin and epibromohydrin in the presence of K2CO3; 2) reacting 7-O-(oxirane-2-ylmethyl)-naringenin and amine in the presence of K2CO3 to obtain naringenin ether compounds containing isopropanolamine structure.

3. The use of the naringenin ether compound having the isopropanolamine structure according to claim 1, characterized in that, for preparing a human hepatoma cell or human colon cancer cell proliferation inhibitor.

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