Indolone spiro norcarene diene compounds having anticancer activity and methods of making and using the same

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to an indole-2-spirocarene compound, its preparation method, and its application. The key technical points are as follows: the indole-2-spirocarene compound is used to inhibit the growth activity of human liver cancer cells or human breast cancer cells. The preparation method involves dissolving 3-diazo-2-indoleone in an aromatic hydrocarbon, reacting under visible light irradiation with stirring at room temperature to obtain the indole-2-spirocarene compound. The indole-2-spirocarene provided by this invention is a novel anticancer compound, exhibiting significant growth inhibitory activity against human liver cancer cells (HepG2) and human breast cancer cells (MCF-7). This invention may provide a solid foundation for the research and development of new anticancer drugs.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to an indole spirocarbazepine compound with anticancer activity, its preparation method, and its application. Background Technology

[0002] Cancer is one of the most serious health problems worldwide, killing tens of millions of people every year. Chemotherapy is one of the main treatments for cancer. In recent years, significant progress has been made in the research of anticancer drugs, and several drugs targeting different types of cancer are now on the market. However, problems such as low cure rates and significant side effects remain in the field of cancer chemotherapy. Developing anticancer drugs with better efficacy and fewer side effects has always been a hot topic in drug research.

[0003] The indolonespirocyclopropane skeleton is widely found in many natural products and active pharmaceutical molecules, making it one of the advantageous skeletons in drug research. However, the synthesis of the indolonespirocyclopropane skeleton is relatively difficult under current techniques, and research on its biological activity is limited. Summary of the Invention

[0004] The first objective of this invention is to provide an indole spirocarediene compound with anticancer activity, its preparation method, and its application. The desired indole spirocarediene compound is obtained by a cycloaddition reaction under visible light irradiation using various substituted 3-diazo-2-indole ketones and aromatic hydrocarbons as raw materials, which exhibits significant inhibitory effects on cancer cells.

[0005] The above-mentioned technical objective of the present invention is achieved through the following technical solution:

[0006] The present invention provides an indole-1, spirocarbazepine compound with anticancer activity, the structure of which is as follows:

[0007]

[0008] Among them, R 1 It is any one or more of hydrogen, alkyl, alkoxy, aryl, halogen, alkenyl, amino, hydroxyl, nitro, acyl, cyano or trifluoromethyl at any position on the benzene ring.

[0009] R 2 It is any one or more of hydrogen, alkyl, alkoxy, aryl, halogen, alkenyl, amino, hydroxyl, nitro, acyl, cyano, or trifluoromethyl in any position.

[0010] Furthermore, R 1 It is any one of hydrogen, alkyl, or halogen.

[0011] Furthermore, R 2 It is any one of hydrogen, alkyl, or halogen.

[0012] The second objective of this invention is to provide a method for preparing an indole spirocarbazepine compound with anticancer activity, which has the same technical effect.

[0013] The present invention provides a method for preparing an indole-1, spirocarbazeline compound with anticancer activity, and the synthetic route is as follows:

[0014] Where R 1 It is any one or more of hydrogen, alkyl, alkoxy, aryl, halogen, alkenyl, amino, hydroxyl, nitro, acyl, cyano or trifluoromethyl at any position on the benzene ring.

[0015] R 2 It is any one or more of hydrogen, alkyl, alkoxy, aryl, halogen, alkenyl, amino, hydroxyl, nitro, acyl, cyano, or trifluoromethyl in any position.

[0016] Furthermore, the preparation method of the indole spirocarediene compound is as follows: 3-diazo-2-indole ketone is dissolved in an aromatic hydrocarbon, and the reaction is carried out under visible light irradiation with stirring at room temperature to obtain the indole spirocarediene compound.

[0017] Furthermore, 3-diazo-2-indolone is any one of 5-chloroindoin diazo, 6-bromoindoin diazo, 5-fluoroindoin diazo, 5-methylindoin diazo, or 6-chloroindoin diazo.

[0018] Furthermore, the aromatic hydrocarbon is any one of benzene, fluorobenzene, chlorobenzene, p-xylene, or p-difluorobenzene.

[0019] Furthermore, the visible light is blue LED light.

[0020] Furthermore, the amount of 3-diazo-2-indolone used is 0.1–0.3 mmol, and the amount of aromatic hydrocarbon used is 1–5 ml.

[0021] The third objective of this invention is to provide an application of an indole spirocarbazepine compound with anticancer activity, which has the same technical effect.

[0022] In this invention, indole spirocarbazepine compounds are used to inhibit the growth activity of human liver cancer cells or human breast cancer cells.

[0023] In summary, the present invention has the following beneficial effects:

[0024] The indole spirocarbazepine provided by this invention is a novel anticancer compound that exhibits significant growth inhibitory activity against human liver cancer cells (HepG2) and human breast cancer cells (MCF-7). This invention may provide a solid foundation for the research and development of new anticancer drugs. Attached Figure Description

[0025] Figure 1 The general structural formula of the compound provided by this invention;

[0026] Figure 2 Synthetic routes for the compounds provided by this invention;

[0027] Figure 3 The structural formulas of the compounds provided in Examples 1-15 are shown. Detailed Implementation

[0028] To further illustrate the technical means and effects adopted by the present invention to achieve the intended purpose, the specific implementation methods, features and effects of an indole spirocarbazepine compound with anticancer activity proposed according to the present invention, its preparation method and application are described in detail below.

[0029] This specific embodiment provides an application of indole-spirocarene compound in anticancer activity, in which indole-spirocarene compound is used to inhibit the growth activity of human liver cancer cells or human breast cancer cells.

[0030] The structure of the indole spirocarboxadiene compound provided in this specific embodiment is as follows:

[0031]

[0032] Among them, R 1 It is any one or more of hydrogen, alkyl, alkoxy, aryl, halogen, alkenyl, amino, hydroxyl, nitro, acyl, cyano or trifluoromethyl at any position on the benzene ring.

[0033] R 2 It is any one or more of hydrogen, alkyl, alkoxy, aryl, halogen, alkenyl, amino, hydroxyl, nitro, acyl, cyano, or trifluoromethyl in any position.

[0034] The indole spirocarbidone compound and its synthetic route are as follows:

[0035] Where R 1 It is any one or more of hydrogen, alkyl, alkoxy, aryl, halogen, alkenyl, amino, hydroxyl, nitro, acyl, cyano or trifluoromethyl at any position on the benzene ring.

[0036] R 2 It is any one or more of hydrogen, alkyl, alkoxy, aryl, halogen, alkenyl, amino, hydroxyl, nitro, acyl, cyano, or trifluoromethyl in any position.

[0037] The preparation method of the indole spirocarediene compound is as follows: 3-diazo-2-indole ketone is dissolved in aromatic hydrocarbons, and the reaction is carried out under visible light irradiation and stirred at room temperature to obtain the indole spirocarediene compound.

[0038] Example 1: 5-Chlorospiro[dihydroindole-3,4'-piperidine]-2-one

[0039] The indole spirorocarbidide compound provided in this embodiment is specifically 5-chlorospiro[dihydroindole-3,4'-piperidin]-2-one; its English name is:

[0040] 5'-chlorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0041]

[0042] Its preparation method is as follows:

[0043] 38.7 mg (0.2 mmol, 1 eq) of 5-chloroindocin diazo was added to benzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give product 3a (26 mg), a white solid, in 53% yield.

[0044] 1 H NMR (400MHz, CDCl3): δ9.82 (s, 1H), 7.02 (d, J = 2.0Hz, 1H), 6.85 (dd, J = 8.2, 2.0Hz, 1H), 6.54-6.48 (m, 3H), 6.14-6.10 (m, 2H), 3.25 (t, J = 2.6Hz, 2H).

[0045] Example 2: 3,5'-Dichlorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0046] The indole spirorocarediene compound provided in this embodiment is specifically 3,5'-dichlorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0047] 3,5'-dichlorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0048]

[0049] Its preparation method is as follows:

[0050] 38.7 mg (0.2 mmol, 1 eq) of 5-chloroindigo diazonium was added to chlorobenzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give product 3b (6 mg), a white solid, with a yield of 11%.

[0051] 1 H NMR (400MHz, CDCl3): δ9.75(s,1H),7.18(dd,J=8.2,2.2Hz,1H),6.95(d,J=8.3Hz,1H),6.61-6.57(m,2H),6 .48(dd,J=9.3,6.5Hz,1H), 6.08(dd,J=9.3,5.2Hz,1H), 3.33(d,J=9.0Hz,1H), 3.26(dd,J=9.0,5.2Hz,1H).

[0052] Example 3: 5'-Chloro-3-fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0053] The indole spirorocarediene compound provided in this embodiment is specifically 5'-chloro-3-fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0054] 5'-chloro-3-fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0055]

[0056] Its preparation method is as follows:

[0057] 38.7 mg (0.2 mmol, 1 eq) of 5-chloroindocyanine diazo was added to fluorobenzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give product 3c (5 mg), a white solid, with a yield of 10%.

[0058] 1H NMR (400MHz, CDCl3): δ9.60 (s, 1H), 7.17 (dd, J = 8.3, 2.1Hz, 1H), 6.94 (d, J = 8.3Hz, 1H), 6.63 (d, J = 2.1Hz, 1H), 6.4 9(ddd,J=9.3,6.8,4.6Hz,1H),6.11(ddd,J=10.8,6.8,1.4Hz,1H),5.92(dd,J=9.3,5.1Hz,1H),3.40-3.29(m,2H).

[0059] Example 4: 6'-Bromospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0060] The indole spirorocarediene compound provided in this embodiment is specifically 6'-bromospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0061] 6'-bromospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0062]

[0063] Its preparation method is as follows:

[0064] 47 mg (0.2 mmol, 1 eq) of 6-bromoindigo diazonium was added to benzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give product 3d (4 mg), a white solid, with a yield of 7%.

[0065] 1 H NMR (400MHz, CDCl3): δ9.70 (s, 1H), 7.16 (d, J = 1.9 Hz, 1H), 7.00 (dd, J = 8.3, 1.8 Hz,1H),6.51-6.46(m,3H),6.12(dt,J=10.2,2.8Hz,2H),3.26(t,J=3.1Hz,2H).

[0066] Example 5: 5'-Fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0067] The indole spirorocarediene compound provided in this embodiment is specifically 5'-fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0068] 5'-fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0069]

[0070] Its preparation method is as follows:

[0071] 35.4 mg (0.2 mmol, 1 eq) of 5-fluoroindigo diazonium was added to benzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product 3e (8 mg) was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give a white solid, yield 17%.

[0072] 1 H NMR (400MHz, CDCl3): δ9.97 (s, 1H), 6.93 (dd, J=8.5, 4.7Hz, 1H), 6.85 (td, J=8.8, 2.6Hz, 1H), 6. 53-6.51(m,2H),6.39(dd,J=9.6,2.6Hz,1H),6.11(dt,J=6.2,3.0Hz,2H),3.27(t,J=3.1Hz,2H).

[0073] Example 6: 5'-Methylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0074] The indole spirorocarediene compound provided in this embodiment is specifically 5'-methylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0075] 5'-methylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0076]

[0077] Its preparation method is as follows:

[0078] 35 mg (0.2 mmol, 1 eq) of 5-methylindoin diazo was added to benzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give product 3f (7 mg), a white solid, with a yield of 16%.

[0079] 1 H NMR (400MHz, CDCl3): δ9.92 (s, 1H), 7.26-7.18 (m, 2H), 6.80-6.77 (m, 3H), 6.40 (dt, J = 10.0, 3.0Hz, 2H), 3.53 (t, J = 3.1Hz, 2H), 2.53 (s, 3H).

[0080] Example 7: 6'-Chlorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0081] The indole spirorocarediene compound provided in this embodiment is specifically 6'-chlorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0082] 6'-chlorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0083]

[0084] Its preparation method is as follows:

[0085] 38.7 mg (0.2 mmol, 1 eq) of 6-chloroindigo diazonium was added to benzene (2 mL), and the reaction was carried out under 470 nm blue light for 72 h. After purification by column chromatography (eluent: V(PE):V(EA) = 3:1), 3 g (13 mg) of product was given as a white solid, with a yield of 27%.

[0086] 1 H NMR (400MHz, CDCl3): δ9.82 (s, 1H), 7.02 (d, J = 2.0Hz, 1H), 6.85 (dd, J = 8.2, 2.0 Hz,1H),6.54-6.48(m,3H),6.12(dt,J=10.2,2.8Hz,2H),3.26(t,J=2.6Hz,2H).

[0087] Example 8: 5'-chloro-2,5-dimethylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0088] The indole spirorocarediene compound provided in this embodiment is specifically 5'-chloro-2,5-dimethylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one; its English name is:

[0089] The structural formula of 5'-chloro-2,5-dimethylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one is as follows:

[0090]

[0091] Its preparation method is as follows:

[0092] 38.7 mg (0.2 mmol, 1 eq) of 5-chloroindocin diazo was added to p-xylene (2 mL), and the reaction was carried out under 470 nm blue light for 72 h. After purification by column chromatography (eluent: V(PE):V(EA) = 3:1), the product was obtained as a white solid (3 h, 8 mg), with a yield of 15%.

[0093] 1 H NMR (300MHz, CDCl3): δ9.23 (s, 1H), 7.22 (d, J = 8.3Hz, 1H), 6.77-6.72 (m, 1H), 6.53 (d, J = 2.1Hz, 1H), 6.22 (s, 2H), 3.08 (s, 2H), 1.87 (s, 6H).

[0094] Example 9: 2,5,5'-Trimethylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0095] The indole spirorocarediene compound provided in this embodiment is specifically 2,5,5'-trimethylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0096] 2,5,5'-trimethylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0097]

[0098] Its preparation method is as follows:

[0099] 35 mg (0.2 mmol, 1 eq) of 5-chloroindochrome diazo was added to p-xylene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give product 3i (10 mg), a white solid, with a yield of 20%.

[0100] 1H NMR (300MHz, CDCl3): δ9.22(s,1H),6.96(d,J=8.0Hz,1H),6.89(d,J=7.8Hz,1H),6.42(s,1H),6.18(s,2H),3.03(s,2H),2.24(s,3H),1.87(s,6H).

[0101] Example 10: 5'-chloro-2,5-difluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0102] The indole spirorocarediene compound provided in this embodiment is specifically 5'-chloro-2,5-difluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one; its English name is:

[0103] 5'-chloro-2,5-difluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0104]

[0105] Its preparation method is as follows:

[0106] 38.7 mg (0.2 mmol, 1 eq) of 5-chloroindocin diazo was added to p-difluorobenzene (2 mL), and the reaction was carried out under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give product 3j (10 mg), a white solid, with a yield of 17%.

[0107] 1 H NMR (300MHz, CDCl3): δ9.23 (s, 1H), 7.22 (d, J = 8.2Hz, 1H), 6.94 (d, J = 8.3Hz, 1H), 6.75 (s, 1H), 6.02 (t, J = 6.3Hz, 2H), 3.42 (s, 2H).

[0108] Example 11: 3-Fluoro-5'-methylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0109] The indole spirorocarediene compound provided in this embodiment is specifically 3-fluoro-5'-methylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0110] 3-fluoro-5'-methylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0111]

[0112] Its preparation method is as follows:

[0113] 35 mg (0.2 mmol, 1 eq) of 5-methylindoin diazo was added to fluorobenzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give product 3k (4 mg), a white solid, with a yield of 8%.

[0114] 1 H NMR (400MHz, CDCl3): δ9.19 (s, 1H), 7.01 (d, J = 7.7Hz, 1H), 6.90 (d, J = 7.9Hz, 1H), 6.52 (s, 1H), 6.45 (ddd, J = 9.3, 6.8, 4. 6Hz,1H),6.07(dd,J=10.9,6.9Hz,1H),5.91(dd,J=9.3,5.1Hz,1H),3.37-3.33(m,1H),3.30-3.26(m,1H),2.26(s,3H).

[0115] Example 12: 2,5-Difluoro-5'-methylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0116] The indole spirorocarediene compound provided in this embodiment is specifically 2,5-difluoro-5'-methylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0117] 2,5-difluoro-5'-methylspiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0118]

[0119] Its preparation method is as follows:

[0120] 35 mg (0.2 mmol, 1 eq) of 5-methyl red diazo was added to p-difluorobenzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give 3 l (9 mg) of product as a white solid, yield 16%.

[0121] 1 H NMR (400MHz, CDCl3): δ8.95(s,1H),7.05(dd,J=8.0,1.7Hz,1H),6.90(d,J=7.9Hz,1H),6.62(s,1H),5.98(t,J=6.4Hz,2H),3.36(s,2H),2.28(s,3H).

[0122] Example 13: 6'-chloro-3-fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0123] The indole spirorocarediene compound provided in this embodiment is specifically 6'-chloro-3-fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0124] 6'-chloro-3-fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0125]

[0126] Its preparation method is as follows:

[0127] 38.7 mg (0.2 mmol, 1 eq) of 6-chlorored diazo was added to fluorobenzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give 3 mL (6 mg) of product, a white solid, with a yield of 11%.

[0128] 1 H NMR (400MHz, CDCl3): δ8.92(s,1H),7.01(d,J=1.9Hz,1H),6.89(dd,J=8.2,1.9Hz,1H),6.59(d,J=8.2Hz,1H),6.47 -6.42(m,1H),6.06(dd,J=10.8,6.8Hz,1H),5.91(dd,J=9.3,5.1Hz,1H),3.38-3.34(m,1H),3.28(t,J=8.6Hz,1H).

[0129] Example 14: 3,6'-Dichlorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0130] The indole spirorocarediene compound provided in this embodiment is specifically 3,6'-dichlorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0131] 3,6'-dichlorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0132]

[0133] Its preparation method is as follows:

[0134] 38.7 mg (0.2 mmol, 1 eq) of 6-chlorored diazo was added to chlorobenzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product 3n (6 mg) was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give a white solid, yield 11%.

[0135] 1 H NMR (400MHz, CDCl3): δ9.13 (s, 1H), 7.02 (d, J = 2.0Hz, 1H), 6.88 (dd, J = 8.3, 1.8Hz, 1H), 6.54 (dd, J = 13.2, 7.4Hz, 2H), 6.43 (dd, J=9.3, 6.5Hz, 1H), 6.08 (dd, J=9.3, 5.1Hz, 1H), 3.30 (d, J=9.0Hz, 1H), 3.23 (dd, J=9.0, 5.1Hz, 1H).

[0136] Example 15: 3-Chloro-5'-Fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one

[0137] The indole spirorocarediene compound provided in this embodiment is specifically 3-chloro-5'-fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-diene-2'-one; its English name is:

[0138] 3-chloro-5'-fluorospiro[bicyclo[4.1.0]heptane-7,3'-indoline]-2,4-dien-2'-one, with the following structural formula:

[0139]

[0140] Its preparation method is as follows:

[0141] 35.4 mg (0.2 mmol, 1 eq) of 5-fluorored diazo was added to chlorobenzene (2 mL), and the mixture was irradiated under 470 nm blue light for 72 h. The product was purified by column chromatography (eluent: V(PE):V(EA) = 3:1) to give product 30 (4 mg), a white solid, with a yield of 8%.

[0142] 1 H NMR (400MHz, CDCl3): δ9.22(s,1H),7.25(d,J=6.5Hz,2H),6.93(d,J=6.5Hz,1H),6.80(dd,J=9.3,6.5Hz,1 H), 6.73 (d, J = 9.4Hz, 1H), 6.42 (dd, J = 9.3, 5.1Hz, 1H), 3.66 (d, J = 9.0Hz, 1H), 3.60 (dd, J = 9.0, 5.2Hz, 1H).

[0143] Performance testing:

[0144] Two cancer cell lines, HepG2 (human liver cancer cells) and MCF-7 (human breast cancer cells), were used as test cell lines, with pentafluorouracil as a positive control. 100 μL / well of cancer cells in the logarithmic growth phase were seeded into 96-well plates. When the cells reached 70%–80% cell growth per well, they were treated with 50 μM of the compounds prepared in Examples 1–15 for 48 h. Each group was tested in triplicate. The results are shown in Table 1. The results are as follows:

[0145] Table 1. Results of anticancer activity tests on compounds in Examples 1-15

[0146]

[0147]

[0148] The above test results show that the compounds provided by the present invention have certain inhibitory activities against both HepG2 and MCF-7; among them, the compound provided in Example 2 has the highest inhibitory effect on HepG2, and Examples 1 to 3 have high inhibitory activity against MCF-7.

[0149] HepG2 and MCF-7 cancer cell lines were selected as test cell lines. The MTT assay was used to test the in vitro anticancer activity of the compounds provided in Examples 1-3, with pentafluorouracil as a positive control. Cancer cells in the logarithmic growth phase were centrifuged and diluted with RPMI 1640 or DMEM medium, 100 μL / well, and seeded into 96-well plates. The plates were incubated overnight at 37°C, then different concentrations of the sample were added, and the plates were incubated for another 72 h. Finally, 10.0 μL of MTT solution (5 mg / mL) was added. -1 After incubating at 37°C for 4 hours, 100 μL of DMSO (to dissolve purple formazan crystals) was added to each well. After 10 minutes, the plate was shaken, and then placed on an automated microplate spectrophotometer. The absorbance was measured at 570 nm, and the half-maximal inhibitory concentration (IC50) was calculated using the Bliss method. 50 The test results are shown in Table 2. Each group of samples underwent three parallel tests.

[0150] Table 2. IC50 values ​​of compounds

[0151]

[0152]

[0153] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been shown above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. An indole ketone spirocarbazepine compound with anticancer activity, characterized in that, The molecular structure of the indolone spirocycloalkadiene compound is as follows: .

2. The method for preparing an indole-1-spirocarbazeline compound with anticancer activity according to claim 1, characterized in that, The synthetic route for the indole-1, spirocarbidopa compound is as follows: ； in, It is one of the molecular structural formulas of the indole spirocarbamate compound in claim 1; 3-diazo-2-indolone was dissolved in an aromatic hydrocarbon and reacted under visible light with stirring at room temperature to obtain the indolone spirocarbazeline compound.

3. The method for preparing an indole-1, spirocarbazeline compound with anticancer activity according to claim 2, characterized in that, The 3-diazo-2-indolone is any one of 5-chloroindigo diazo, 6-bromoindigo diazo, 5-fluoroindigo diazo, 5-methylindigo diazo, or 6-chloroindigo diazo.

4. The method for preparing an indole-1, spirocarbazeline compound with anticancer activity according to claim 2, characterized in that, The aromatic hydrocarbon is any one of benzene, fluorobenzene, chlorobenzene, p-xylene, or p-difluorobenzene.

5. The method for preparing an indole-1, spirocarbazeline compound with anticancer activity according to claim 2, characterized in that, The visible light is blue LED light.

6. The method for preparing an indole-1, spirocarbazeline compound with anticancer activity according to claim 2, characterized in that, The amount of 3-diazo-2-indolone used is 0.1~0.3 mmol, and the amount of aromatic hydrocarbon used is 1~5 ml.

7. The application of the indole-1-spirocarboxadiene compound with anticancer activity according to claim 1, characterized in that, The application of the indole-1, spirocarbazepine compound in the preparation of antitumor drugs that inhibit the proliferation of human hepatocellular carcinoma cells HepG2 and / or human breast cancer cells MCF-7.

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