Tetrahydrophenanthrene-2 (1H)-ketone compound as well as preparation method and application thereof

Abstract

The invention discloses a tetrahydrophenanthrene-2 (1H)-ketone compound as well as a preparation method and application thereof. The tetrahydrophenanthrene-2 (1H)-ketone structure compound containing four continuous quaternary carbon chiral centers is constructed by using a cyclohexanediamine aromatic amide derivative with excellent asymmetric catalytic performance through a one-pot method. Activity evaluation shows that the compound shows good inhibitory activity on human lung adenocarcinoma cells A549, and provides a new thought for development of novel anti-cancer drugs as a lead compound.

Description

Technical Field

[0001] The present invention belongs to the technical field of fine organic chemistry and biomedicine, and particularly relates to a tetrahydrophenanthrene-2(1H)-ketone compound constructed by Michael addition reaction, a preparation method and application thereof. Background Art

[0002] Phenanthrene and its derivatives have an important position in the field of organic chemistry due to their unique structure and properties, and their synthesis methods have always been a hot topic of research. As an important derivative of phenanthrene, the study of the synthesis of tetrahydrophenanthrene-2(1H)-one compounds helps to deeply understand the mechanism of organic chemical reactions, enrich the theory of organic synthetic chemistry, and provide a theoretical basis for the development of new synthetic methods and strategies. Tetrahydrophenanthrene-2(1H)-one compounds are a class of natural products with biological activity (J.Nat.Prod.2011,74,181–184) and key skeletons for the synthesis of biologically active compounds and their precursors. In the field of medicinal chemistry, the keto carbonyl and other functional groups in its structure can undergo a variety of chemical reactions and introduce different substituents, thereby improving the hydrophilicity, lipophilicity, metabolic stability, etc. of drug molecules, providing possibilities for the development of new drugs. For example, abietane-type diterpenoids with cyanoenone functional groups are novel and highly effective inhibitors of nitric oxide (NO) production in mouse macrophages, and have also been shown to be orally active in preliminary in vivo inflammation models (J. Org. Chem. 2006, 71, 8, 3314–3316). Octahydrophenanthrene-2,7-diol derivatives act as pathway-selective or "dissociative" agonists of the glucocorticoid receptor (GR) (J. Med. Chem. 2009, 52, 6, 1731–1743). Chirality is one of the essential properties of nature. In the past three decades, the huge demand for single enantiomer chiral compounds in the pharmaceutical industry and fine chemicals has promoted the rapid development of asymmetric synthesis methodologies. Although tetrahydrophenanthrene-2(1H)-one is an important structural unit, the direct asymmetric synthesis of this hydrogenated phenanthrene skeleton is still not perfect. Therefore, it is highly desirable to construct this scaffold in a stereocontrolled manner. In terms of the asymmetric synthesis of hydrophenanthranone, the You group explored several examples of asymmetric synthesis of tetrahydrophenanthran-2(1H)-one with two stereocenters via intramolecular Michael addition desymmetrization of 2,5-cyclohexadienone (Org. Lett. 2011,13 , 19, 5192–5195). Chauhan's group asymmetrically synthesized hydrophenanthranone with multiple stereocenters via aromatic amide-catalyzed domino 1,4- / 1,4-addition desymmetrization (Org. Lett. 2023, 25, 43, 7911–7916).

[0003] The one-pot method of constructing tetrahydrophenanthrene-2(1H)-one compounds containing multiple stereocenters through Michael addition desymmetrization of 2,5-cyclohexenone is of great significance for the discovery of lead compounds and drug development. Summary of the invention

[0004] In view of the problems existing in the prior art, the purpose of the present invention is to provide a tetrahydrophenanthrene-2 ​​(1H) -one compound and a preparation method and application thereof. Through reasonable reaction design, 1,3-cyclohexanedione compounds are reacted with chloronitroolefins under the action of cyclohexanediamine aromatic amide catalysts, and the asymmetric construction of tetrahydrophenanthrene-2 ​​(1H) -one compounds containing 4 consecutive quaternary carbon chiral centers is successfully achieved in one pot. The compound has a good inhibitory effect on human lung adenocarcinoma cell A549, can be used as a lead compound, and provides a new option for the development of new drugs.

[0005] The first aspect of the present invention provides a tetrahydrophenanthrene-2(1H)-one compound represented by formula (I):

[0006]

[0007] In formula (I), R 1 is methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, ethynyl; and X, Y, Ar, and Het are each independently any one of the following structures:

[0008]

[0009] X=O, CH2

[0010] Y=O, CH2, RCH, R2C, PhCH, BnCH, any one of the following.

[0011] Preferably, the tetrahydrophenanthrene-2(1H)-one compound represented by formula (I) is one of the following:

[0012]

[0013] The second aspect of the present invention provides a method for preparing a tetrahydrophenanthrene-2(1H)-ketone compound represented by formula (Ⅰ), which comprises: dissolving a base, a catalyst and a compound represented by formula (Ⅱ) in a solvent under air atmosphere, stirring for 3 minutes, adding a compound represented by formula (Ⅲ), stirring at room temperature for 10 hours, monitoring the completion of the reaction by TLC, and evaporating the reaction solution under reduced pressure until no liquid flows out to obtain a yellow oily liquid; the yellow oily liquid is subjected to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 8:1 to 3:1 as eluent, collecting an effluent having an Rf value of 0.2-0.4, and evaporating under reduced pressure to dryness to obtain a tetrahydrophenanthrene-2(1H)-ketone compound represented by formula (Ⅰ);

[0014] The catalyst is cyclohexanediamine thiourea or cyclohexanediamine aromatic amide;

[0015] The base is selected from any one of N-ethyldiisopropylamine, triethylenediamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate trihydrate, potassium bicarbonate, and sodium bicarbonate, preferably potassium bicarbonate; the solvent is an organic solvent, and the organic solvent is any one of dichloromethane, 1,2-dichloroethane, ethyl acetate, chloroform, diethyl ether, methyl tert-butyl ether, acetonitrile, n-hexane, toluene, mesitylene, trifluorotoluene, chlorobenzene, and nitrobenzene, preferably nitrobenzene;

[0016] The reaction formula is as follows:

[0017]

[0018] In formula (I), R 1 , Ar and Het are the same as R in formula (III) 1 , Ar, Het; X and Y in formula (Ⅰ) are the same as X and Y in formula (Ⅱ).

[0019] Preferably, the catalyst is selected from cyclohexanediamine thiourea C1 or differently substituted cyclohexanediamine aromatic amides C2, C3, C4, wherein the structural formulas of C1, C2, C3, C4 are as follows:

[0020]

[0021] Preferably, the ratio of the amount of the compound represented by formula (III) to the amount of the compound represented by formula (II) is 1:1-5, preferably 1:1.5; the ratio of the amount of the compound represented by formula (III) to the amount of the catalyst is 1:0.01-0.1, preferably 1:0.1; the ratio of the amount of the compound represented by formula (III) to the amount of the base is 1:1-5, preferably 1:1; the volume of the solvent used is 10-60mL / mmol, preferably 20mL / mmol, based on the amount of the compound represented by formula (III).

[0022] The third aspect of the present invention provides a use of a tetrahydrophenanthrene-2(1H)-one compound in the preparation of a drug for treating anti-tumor, wherein the tumor is caused by human lung adenocarcinoma cell A549.

[0023] The present invention uses a reasonable reaction design to react 1,3-cyclohexanedione compounds with chloronitroolefins under the action of a cyclohexanediamine aromatic amide derivative catalyst, and successfully achieves the asymmetric construction of tetrahydrophenanthrene-2(1H)-one compounds containing four consecutive quaternary carbon chiral centers in a one-pot method. A simple and efficient synthesis strategy has been developed, which provides a more direct and simple idea for the asymmetric construction of compounds with tetrahydrophenanthrene-2(1H)-one structures containing multiple stereo centers. Activity evaluation shows that the compound of the present invention has a good inhibitory effect on human lung adenocarcinoma cell A549, and can be used as a lead compound to provide a new idea for the development of anticancer drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Compound Ⅰ-1 1 H NMR spectrum;

[0025] Figure 2 Compound Ⅰ-1 13 C NMR spectrum;

[0026] Figure 3 Compound Ⅰ-20 1 H NMR spectrum;

[0027] Figure 4 Compound Ⅰ-20 13 C NMR spectrum. DETAILED DESCRIPTION

[0028] The present invention is further described below in conjunction with specific embodiments to facilitate a better understanding of the present technical solution.

[0029] Example 1

[0030] Preparation of (4bS,8aS,8bR,13bS)-4b-methoxy-8b-nitro-8a,8b,10,11,12,13b-hexahydrophenanthrene[9,10-b]benzofuran-7,13(4bH,8H)-dione Ⅰ-1:

[0031]

[0032] At room temperature, 1,3-cyclohexanedione Ⅱ (0.3mmol, 1.5eq.), nitrobenzene (4mL) and cyclohexanediamine aromatic amide catalyst C2 (0.02mmol, 0.1eq.) were added to the reaction tube. Potassium bicarbonate (0.4mmol, 2.0eq.) was stirred at room temperature for 3min, and then chloronitroolefin Ⅱ (0.075mmol, 1.5eq.) was added. Stir at room temperature and the reaction was completed by TLC detection. The reaction solution was directly subjected to silica gel column chromatography with petroleum ether and ethyl acetate in a volume ratio of 8:1 to 3:1 as eluents, and the effluent with an Rf value of 0.2-0.4 was collected and evaporated to dryness under reduced pressure to obtain a white solid product Ⅰ-1 (72% yield; 98% ee; >20:1dr), and the nuclear magnetic resonance hydrogen spectrum was shown Figure 1 As shown, 13 C NMR spectrum Figure 2 shown.

[0033] The product Ⅰ-1 was detected by HPLC and NMR spectrometry to obtain (4bS,8aS,8bR,13bS)-4b-methoxy-8b-nitro-8a,8b,10,11,12,13b-hexahydrophenanthrene.

[0034] [9,10-b]Benzofuran-7,13(4bH,8H)-dione, calculate the diastereomeric excess.

[0035] High performance liquid chromatography was performed using Shimadzu HPLC (AD-H, OD-H, IA, Amylose-2 chiral columns), mobile phase: V n-hexane / V isopropanol = 60:40-75:25, flow rate: 0.5-1.0 mL / min, detection wavelength: 254 nm.

[0036] Example 2-20

[0037] According to the similar method of Example 1, only R in the compound represented by formula I is replaced as shown in Table 1, and the effluent with Rf value of 0.2-0.4 is collected to obtain the corresponding compounds represented by formula I, wherein I1-20 1 H NMR spectrum Figure 3 As shown, 13 C NMR spectrum Figure 4 The H NMR spectrum results and high-resolution mass spectrum data of the above compounds are listed in Table 1. As can be seen from the above, the structures of the above compounds are correct and they are all compounds shown in Formula I.

[0038] Table 1 Nuclear magnetic resonance hydrogen spectrum data and high resolution mass spectrum data of the compound represented by formula I

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] Application example: Application of tetrahydrophenanthrene-2(1H)-one compounds in the evaluation of anticancer activity

[0048] 1. Preparation before the experiment

[0049] Experimental equipment: 100mm culture dish, 96-well plate, EP tube, pipette tip, etc.

[0050] Culture medium: DMEM culture medium, containing 10% fetal bovine serum, 1% double antibody.

[0051] Drug stock solution: Use DMSO and culture medium to prepare drug stock solutions with concentrations of 1, 10, 25, 50, 75, and 100 μM (first dissolve in DMSO, then dilute with fresh culture medium). The culture medium with the same volume of DMSO added was the blank control group, and the DMSO solution of DOX was the positive control group.

[0052] 2. Determination of tumor growth inhibition ability

[0053] Human lung adenocarcinoma cell line A549 (2.5×10 3 ) were inoculated in 96-well plates and three parallel groups were set up. After culturing at 37°C for 24 hours, the suspension was replaced with fresh medium containing different doses of drugs (1, 10, 25, 50, 75 and 100 μM). Negative control wells with drug-free medium and solvent control wells were set up with the same volume of DMSO. The cells were incubated at 37°C for 48 hours. Then, 100 μL of 0.5 mg / mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (first dissolved in PBS and then diluted with fresh medium) was added to each well and cultured for another 4 hours. The medium was then removed, and the MTT formazan precipitate was dissolved in 100 μL DMSO, mechanically shaken for 10 minutes, and then immediately read at 570 nm using a microplate reader (FlexStation 3, Molecular Devices).

[0054] Cell inhibition rate = [OD 570(Negative control well) – OD 570 (Dosing hole)] / OD 570 (Negative control well) x 100%.

[0055] The growth inhibition rates of the compounds shown in Formula I on human lung adenocarcinoma cell A549 were measured by the above method and the results are shown in Table 2.

[0056] Table 2 Growth inhibition rate of the compounds shown in formula I on human lung adenocarcinoma cell A549

[0057]

[0058]

[0059] The above results show that this series of compounds has good inhibitory activity against human lung adenocarcinoma cell A549, which further proves that the asymmetric synthesis method of this type of compounds developed by us can be used as a lead compound, providing new ideas for the development of anticancer drugs.

Claims

1. A tetrahydrophenanthrene-2(1H)-one compound represented by formula (I): In formula (I), R 1 is methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, ethynyl; and X, Y, Ar, and Het are each independently any one of the following structures: X=O, CH2, any one; Y=O, CH2, RCH, R2C, PhCH, BnCH, any one of the following.

2. The tetrahydrophenanthrene-2(1H)-one compound according to claim 1, characterized in that: The compound represented by formula (I) is one of the following:

3. The method for preparing the tetrahydrophenanthrene-2(1H)-ketone compound according to claim 1, characterized in that: The method comprises: dissolving a base, a catalyst and a compound represented by formula (II) in a solvent under air atmosphere, stirring for 3 minutes, then adding a compound represented by formula (III), stirring at room temperature for 10 hours, monitoring the reaction completion by TLC, and performing rotary evaporation under reduced pressure until no liquid flows out to obtain a yellow oily liquid; performing silica gel column chromatography on the yellow oily liquid using petroleum ether and ethyl acetate in a volume ratio of 8:1-3:1 as eluent, collecting an effluent with an Rf value of 0.2-0.4, and performing rotary evaporation under reduced pressure to dryness to obtain a tetrahydrophenanthrene-2(1H)-ketone compound represented by formula (I); The catalyst is cyclohexanediamine thiourea or cyclohexanediamine aromatic amide; The base is any one of N-ethyldiisopropylamine, triethylenediamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate trihydrate, potassium bicarbonate, and sodium bicarbonate; The solvent is an organic solvent, and the organic solvent is selected from any one of dichloromethane, 1,2-dichloroethane, ethyl acetate, chloroform, ether, methyl tert-butyl ether, acetonitrile, n-hexane, toluene, mesitylene, trifluorotoluene, chlorobenzene, and nitrobenzene; In formula (II), X and Y are the structures shown below; in formula (III), R 1 is methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, ethynyl; Ar and Het are each independently the following structures: X=O, CH2; Y=O, CH2, RCH, R2C, PhCH, BnCH; In formula (I), R 1 , Ar and Het are the same as R in formula (III) 1 , Ar, Het; X and Y in formula (Ⅰ) are the same as X and Y in formula (Ⅱ).

4. The method for preparing tetrahydrophenanthrene-2(1H)-ketone compounds according to claim 3, characterized in that: The catalyst is selected from any one of cyclohexanediamine thiourea C1 and cyclohexanediamine aromatic amides C2, C3, and C4 with different substitutions, wherein the structural formulas of C1, C2, C3, and C4 are respectively:

5. The method for preparing tetrahydrophenanthrene-2(1H)-ketone compounds according to claim 3, characterized in that: The ratio of the amount of the compound represented by formula (III) to the amount of the compound represented by formula (II) is 1:1-5; the ratio of the amount of the compound represented by formula (III) to the amount of the catalyst is 1:0.01-0.1; the ratio of the amount of the compound represented by formula (III) to the amount of the base is 1:1-5; the volume of the solvent used is 10-60mL / mmol based on the amount of the compound represented by formula (III).

6. Use of the tetrahydrophenanthrene-2(1H)-one compound according to claim 1 in the preparation of anti-tumor drugs.

7. The use according to claim 6, characterized in that The tumor was caused by human lung adenocarcinoma cell A549.

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