Naringenin ether compound containing isopropanolamine structure and preparation method thereof

Abstract

The invention discloses a naringenin ether compound containing an isopropanolamine structure as shown in a formula I as well as a preparation method and application of the naringenin ether compound. # imgabs0 # R1 and R2 are respectively and 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-C10 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.

Description

Technical field:

[0001] The invention relates to the field of organic synthesis, and in particular to a naringenin ether compound containing an isopropanolamine structure and a preparation method thereof. Background technology:

[0002] Natural products are important resources for the creation of new medicines and pesticides. Natural products have the characteristics of wide sources, wide variety, diverse physiological activities, less toxic and adverse reactions, easy degradation or good environmental compatibility, so they have been widely used by people for thousands of years. Naringenin is a natural dihydroflavonoid compound, which is mainly present in the form of glycosides in grapefruit, tomatoes, grapes and citrus fruits of the Rutaceae family. It has applications in chemistry, medicine, food science and pesticides, and has a wide range of biological activities such as antibacterial, anti-inflammatory, antioxidant, antitussive and expectorant, lipid-lowering, and anti-tumor.

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

[0004] In 2013, Yoon et al. [Yoon, H.; Kim, TW; Shin, SY; Park, MJ; Yong, Y.; Kim, DW; Islam, T.; Lee, YH; Jung, KY; 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 five naringenin derivatives substituted at position 7 and evaluated their inhibitory effects on human colon cancer cells HCT116. The results showed that the half maximum inhibitory concentration IC50 of the five naringenin derivatives was between 1.20 and 20.01 uM, which was significantly better than the control agent naringenin.

[0005] In 2019, Latif et al [Latif, AD; Gonda, T.; M.;Kúsz, N.;Kulmány, A.;Ocsovszki, I.;Zomborszki, Z.P;Zupkó, 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 that 8 oxime or oxime ether derivatives of naringenin were obtained by addition condensation between the 4-carbonyl group of naringenin and the amino group. The results of biological tests showed that tert-butyl oxime ether derivatives had a strong inhibitory 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 oximes. The results of antibacterial activity evaluation showed that naringenin oxime derivatives had higher antibacterial activity against Enterococcus faecalis, Staphylococcus aureus, Acinetobacter baumannii, Klebsiella pneumoniae and Helicobacter pylori than 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 antiviral activity of naringenin, enoyl naringenin and its derivatives against influenza. The results showed that the spatial effect of the compound is an important factor affecting its antiviral activity. In the structure of naringenin, the substituent pentenyl can enhance its antiviral activity, and its structure and position have a significant effect on its cellular permeability.

[0008] Based on the structure of naringenin, a nitrogen-containing isopropanolamine structure was introduced at the 7-position to synthesize a series of naringenin ether compounds containing isopropanolamine structure, which has not been reported so far. Summary of the invention:

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

[0010] The present invention is achieved through the following technical solutions:

[0011] The naringenin ether compound containing isopropanolamine structure shown in formula I:

[0012]

[0013] R 1 and R 2 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylhydroxy, C6-C10 aryl or substituted aryl or C6-10 heteroaryl or substituted heteroaryl; or R 1 and R 2 They are connected to form a 5-10 membered ring or a ring containing a heteroatom, wherein the heteroatom is N or O.

[0014] The term "alkyl" used in the present invention includes branched and straight chain saturated hydrocarbon groups having a specific number of carbon atoms. For example, "C1-C6 alkyl" means an alkyl group having 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 both straight and branched structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. For example, "C2-C6 alkenyl" refers to C2, C3, C4, C5 and C6 alkenyl. Examples of alkenyl include, but are not limited to, vinyl, 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 both straight or branched structures and has one or more carbon-carbon triple bonds that appear at any stable point in the chain. For example, "C2-C6 alkynyl" refers to C2, C3, C4, C5 and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

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

[0018] The term "heteroaryl" refers to substituted and unsubstituted 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, the heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of the heteroatom-containing heteroaryl group may 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 may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the nitrogen and other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom in any ring. If the other ring is a cycloalkyl or heterocycle, it is additionally optionally substituted with =0 (oxygen) when valence permits.

[0019] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

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

[0021] If not otherwise specified, the compounds of the present invention are understood to include free states and salts thereof. The term "salt" means acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "salt" may include zwitterions (inner salts), such as when the compound of formula I contains 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 acceptable metal and amine salts, in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps used in the preparation process, and are therefore also included in the scope of the present invention.

[0022] Preferably, R 1 and R 2 Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, vinyl, propynyl, hydroxyethyl, benzyl, 4-fluorobenzyl; when R 1 and R 2 When connected to form a ring, it is the following group:

[0023] Any of .

[0024] Most preferably, the naringenin ether compound containing an isopropanolamine structure is selected from the following compounds:

[0025]

[0026]

[0027] The preparation formula of naringenin ether compounds containing isopropanolamine structure is as follows:

[0028]

[0029] The following steps are involved:

[0030] 1) Using naringenin and epibromopropane as raw materials, in K2 CO 3 The intermediate 7-O-(oxyethylene-2-ylmethyl)-naringenin is prepared by reaction under catalysis;

[0031] 2) 7-O-(oxyethylene-2-ylmethyl)-naringenin and amines in K 2 CO 3 The reaction is carried out under catalysis to obtain naringenin ether compounds containing isopropanolamine structure.

[0032] The beneficial effects of the present invention are as follows: Based on naringenin, the present invention introduces a nitrogen-containing isopropanolamine structure at position 7 to synthesize a series of naringenin ether compounds containing an isopropanolamine structure, and it is found that the compound is used as a proliferation inhibitor of human liver cancer cells and human colon cancer cells. Specific implementation method:

[0033] The following is a further description of the present invention, rather than a limitation of the present invention.

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

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

[0036] Naringenin (1.84 mmol) and K 2 CO 3 (7.35mmol) was added to 5mL acetone solution containing epibromopropane (7.35mmol), and the reaction was stopped at 60℃ for 3h, and the solvent was removed. The product was extracted with 15mL dichloromethane, washed with water, dried, removed, and purified by column chromatography to obtain a light yellow solid with a yield of 26.5%. Its NMR data is: 1 H NMR (400MHz, DMSO) δ12.11(s,1H,5-OH),9.62(s,1H,4′-OH),7.32(d,J=8.6Hz,2H,2′-H+6′-H),6.80(d,J=8.6Hz,2H,3 ′-H+5′-H),6.12(dd,J=8.6,2.3Hz,2H,8-H+6-H),5.48(dd,J=12.9,2.8Hz,1H,2-H),4.41(dt,J=11.7,2.1Hz,1H,1″aO CH 2 CH),3.86(ddd,J=11.7,6.8,2.3Hz,1H,1″bO CH 2 CH),3.36–3.28(m,2H,3a-H+3″a-CH 2O),2.86–2.81(m,1H,2″-OCH),2.72(dd,J=17.2,3.0Hz,1H,3b-H),2.68(dd,J=5.0,2.6Hz,1H,3″b-CH 2 O); 13 C NMR (101MHz, DMSO) δ197.1,166.4,163.3,163.0,157.9,128.8,128.5,115.3,102.9,95.2,94.4,78.8,69.7,49.5,43.8,42.1.

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

[0038] 7-O-(oxyethylene-2-ylmethyl)-naringenin (1.52 mmol) was added to a solution of K 2 CO 3 (1.52 mmol) and dimethylamine (1.52 mmol) in 7 mL of isopropanol solution, react at 60°C for 12 h, then stop the reaction, extract with 30 mL of dichloromethane, wash with water, dry, desolventize, and purify by column chromatography to obtain an orange solid with a yield of 36.6%.

[0039] The structures, hydrogen nuclear magnetic resonance spectra and carbon nuclear magnetic resonance spectra of the synthesized naringenin ether compounds containing isopropanolamine structures are shown in Table 1, and the physicochemical properties are shown in Table 2.

[0040] Example 2-Example 19: Preparation of Compound 2-Compound 19

[0041] Refer to Example 1, except that the dimethylamine in step 2) is replaced by a corresponding substituted amine such as diethylamine.

[0042] The structures, hydrogen nuclear magnetic resonance spectra and carbon nuclear magnetic resonance spectra of the synthesized naringenin ether compounds containing isopropanolamine structures are shown in Table 1, and the physicochemical properties are shown in Table 2.

[0043] Table 1 H NMR and C 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 hepatocarcinoma (HepG2) cells, human colon cancer (HCT116) cells, and human non-small cell lung cancer (A549) cells were used as test subjects and inoculated in RPMI1640 medium containing 10% fetal bovine serum and placed at 37°C and 5% CO. 2 The cells were subcultured in an incubator with saturated humidity. The MTT method was used to detect the inhibitory effect of the compounds on the proliferation of three types of cells: tumor cells in the logarithmic growth phase were taken, digested, counted, and the cell concentration was adjusted to 3×10 4 / ml, inoculated in 96-well plates, 100μL per well. After 24h, the original culture medium was removed, and 200μL of culture medium with a compound concentration of 20.0μmol / L was added to each well. The blank control and each concentration group were set up with 6 replicate wells, and the plates were incubated at 37℃, 5% CO 2 After culturing in the incubator for 48 hours, 20 μL of freshly prepared 5% MTT solution was added to each well. After further culturing for 4 hours, the culture supernatant was discarded, 150 μL of dimethyl sulfoxide was added to each well, and the mixture was shaken for 10 minutes. 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 based on the logarithm of the compound concentration and the corresponding inhibition rate to calculate the half inhibitory concentration (IC) of each compound on tumor cells. 50 ).

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

[0056]

[0057] Table 4 IC values ​​of compounds and 5-FU against three types of human tumor cells 50 (μmol / L, n=3)

[0058]

[0059] Note: “5-FU” stands for the positive control 5-fluorouracil.

[0060] As can be seen from Tables 3 and 4, in the in vitro antitumor activity test, some target compounds showed good cytotoxicity against human liver cancer (HepG2) cells and human colon cancer (HCT116) cells. 50 The IC values ​​of compound 16 on human hepatocellular carcinoma (HepG2) cells were 35.62 μmol / L and 35.70 μmol / L, respectively. 50 It is 22.33μmol / L; it can be used as a potential drug to inhibit the proliferation of human liver cancer (HepG2) cells and human colon cancer (HCT116) cells, and has good application prospects.

[0061] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. Naringin ether compounds containing isopropanolamine structure shown in formula I: R1 and R2 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylhydroxyl, C6-C10 aryl or substituted aryl or C6-10 heteroaryl or substituted heteroaryl; or R1 and R2 are linked to form a 5-10 membered ring or a ring containing a heteroatom, wherein the heteroatom is N or O.

2. The compound according to claim 1, characterized in that R1 and R2 are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, vinyl, propynyl, hydroxyethyl, benzyl, 4-fluorobenzyl; when R1 and R2 are linked to form a ring, they are the following groups: Any of .

3. The compound according to claim 1, characterized in that The naringenin ether compound containing an isopropanolamine structure is selected from the following compounds:

4. The method for preparing the naringenin ether compound containing isopropanolamine structure according to claim 1, characterized in that: The following steps are involved: 1) Using naringenin and epibromopropane as raw materials, the intermediate 7-O-(oxyethylene-2-ylmethyl)-naringenin was prepared by reaction under the catalysis of K2CO3; 2) 7-O-(oxyethylene-2-ylmethyl)-naringenin and amine react under the catalysis of K2CO3 to obtain naringenin ether compounds containing isopropanolamine structure.

5. The use of the naringenin ether compound containing isopropanolamine structure according to claim 1, characterized in that: Used as a proliferation inhibitor of human liver cancer cells and human colon cancer cells.

Images