Beta-carboline naphthoquinone derivatives, processes for their preparation and medical uses thereof

Abstract

The application belongs to the field of medicine, and discloses a kind of beta-quinoline naphthoquinone derivatives and its preparation method and medical use. Beta-quinoline aromatic heterocycle is coupled with 1,2-naphthoquinone-4-sodium sulfonate, so as to design and synthesize novel beta-quinoline derivatives with quinone structure, and the structural formula is shown as general formula 1. The beta-quinoline naphthoquinone derivative provided in the application selectively has a strong inhibitory effect on the proliferation of liver cancer, breast cancer, colon cancer, lung cancer and other various tumor cells, and has less damage to normal cells, and can be used as an active ingredient for the preparation of drugs for treating and / or preventing malignant tumors.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a class of β-carbolinenaphthoquinone derivatives, their preparation methods, and pharmaceutical uses. Background Technology

[0002] Cancer is the second leading cause of death in humans after cardiovascular disease. Although various anti-tumor drugs are available clinically, due to the complexity of cancer etiology, tumor drug resistance, and the toxic side effects of anti-tumor drugs, existing drugs still cannot meet the treatment needs. Therefore, the search for novel anti-tumor drugs with high efficacy, strong targeting, and minimal toxic side effects is of great significance.

[0003] β-Carboline compounds are a large class of naturally occurring indole alkaloids with a planar tricyclic pyridine [3,4-b]indole skeleton similar in structure to carbazole. Naturally occurring β-carboline compounds are widely distributed and diverse, mainly found in various terrestrial plants and marine invertebrates. These compounds generally possess multiple biological activities, including antitumor, antiviral, and antitrypanosome activity. Especially in antitumor activity, they act on multiple biological targets while exhibiting very low toxicity. These unique biological characteristics and mechanisms of action have attracted increasing attention from researchers both domestically and internationally. The natural product harmine is a major β-carboline alkaloid found in the seeds and roots of plants in the genus *Pyrrosia*. Studies have found that it inhibits cancer cell proliferation by blocking DNA replication at low concentrations. Recent studies have found that designing new drug molecules using β-carboline alkaloids often involves appropriate substitutions at the 1 and 3 positions of β-carboline, which can enhance its antitumor activity and reduce its toxicity. Introducing a basic group at the 3 position of β-carboline can greatly enhance its affinity for DNA and other structure-activity relationship information, which also provides a basis for the application of β-carboline compounds in other fields. Summary of the Invention

[0004] The purpose of this invention is to provide a novel β-carbolinenaphthoquinone derivative, its preparation method, and its pharmaceutical applications.

[0005] In a first aspect, the present invention provides a β-carbazonaphthoquinone derivative having the structure of the following general formula I:

[0006]

[0007] R is selected from one of H, C1-C6 alkyl, phenyl, monomethyl-substituted phenyl, monomethoxy-substituted phenyl, dimethoxy-substituted phenyl, trimethoxy-substituted phenyl, mononitro-substituted phenyl, and 4-dimethylaminophenyl.

[0008] Furthermore, R is selected from one of H, methyl, isopropyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-nitrophenyl, 3-nitrophenyl, and 4-dimethylaminophenyl.

[0009] The preferred compound designations and corresponding structures of the above general formula I are shown in Table 1:

[0010] Table 1. Compound codes and corresponding structures for some compounds of general formula I.

[0011]

[0012]

[0013] In a second aspect, the present invention provides a method for preparing the compound of general formula I, specifically comprising: coupling compound 1 with sodium 1,2-naphthoquinone-4-sulfonate 2 in an ethanol solution of potassium carbonate to obtain the target compound I.

[0014] Furthermore, compound 1 was coupled with sodium 1,2-naphthoquinone-4-sulfonate 2 in a molar ratio of 1:1 to 1:2 in an ethanol solution of potassium carbonate at 0 degrees or room temperature to obtain target compound I.

[0015] The synthetic route of the above preparation method is as follows:

[0016]

[0017] R is selected from one of H, C1-C6 alkyl, phenyl, monomethyl-substituted phenyl, monomethoxy-substituted phenyl, dimethoxy-substituted phenyl, trimethoxy-substituted phenyl, mononitro-substituted phenyl, and 4-dimethylaminophenyl.

[0018] A third aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula I or a medically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0019] In a fourth aspect, the present invention provides the use of a β-carbamonaphthoquinone derivative of general formula I or a pharmaceutically acceptable salt thereof as an active ingredient in the preparation of a medicament for the treatment and / or prevention of malignant tumors.

[0020] Furthermore, the drug treats and / or prevents malignant tumors by selectively inhibiting tumor cell proliferation. The β-carbamonaphthoquinone derivatives of general formula I, or pharmaceutically acceptable salts thereof, cause far less damage to normal cells than they inhibit tumor cell proliferation.

[0021] Furthermore, the malignant tumor can be either a sensitive malignant tumor or a drug-resistant malignant tumor.

[0022] Furthermore, the term "commonly sensitive malignant tumors" refers to liver cancer, breast cancer, colon cancer, lung cancer, nasopharyngeal carcinoma, etc., while "drug-resistant malignant tumors" refers to liver cancer, colon cancer, nasopharyngeal carcinoma, etc.

[0023] The compounds of this invention can be formulated into pharmaceutical preparations, alone or in combination with one or more pharmaceutically acceptable carriers, for drug delivery. For example, solvents, diluents, etc., can be administered in oral dosage forms such as tablets, capsules, dispersible powders, granules, etc. Various dosage forms of the pharmaceutical compositions of this invention can be prepared according to methods well known in the pharmaceutical field. These pharmaceutical preparations may contain, for example, 0.05% to 90% by weight of the active ingredient in combination with a carrier, more commonly about 15% to 60% by weight of the active ingredient. The dosage of the compounds of this invention can be from 0.005 to 5000 mg / kg / day, and may exceed this range depending on the severity of the disease or the dosage form.

[0024] The compounds of this invention can be used in combination with other antitumor drugs such as alkylating agents (e.g., cyclophosphamide or cisplatin), antimetabolites (e.g., 5-fluorouracil or hydroxyurea), topoisomerase inhibitors (e.g., camptothecin), mitotic inhibitors (e.g., paclitaxel or vincristine), and DNA inserters (e.g., doxorubicin), and can also be used in combination with radiotherapy. These other antitumor drugs or radiotherapy can be administered simultaneously with or at different times from the compounds of this invention. These combined treatments can produce a synergistic effect, thereby helping to improve treatment efficacy.

[0025] Beneficial effects of this invention:

[0026] This invention combines the structural characteristics of the β-carboline alkaloid skeleton and the molecular biological functional characteristics of naphthoquinone, and incorporates the structure-activity relationship and lipid-water distribution coefficient of β-carboline derivatives reported in the literature. This project couples the β-carboline aromatic heterocycle with sodium 1,2-naphthoquinone-4-sulfonate to design and synthesize novel β-carboline derivatives with a quinone structure, and studies their inhibitory effects on tumor cells. Currently, no reports have been found on this type of compound. The compound of this invention is prepared by the coupling reaction of 3-amino-β-carboline with sodium 1,2-naphthoquinone-4-sulfonate. Introducing a basic group at the 3-position of β-carboline significantly enhances its affinity for DNA and improves its lipid-water distribution coefficient; simultaneously, the introduction of naphthoquinone enables the generation of ROS through the NQO1 pathway, enhancing its antitumor activity. Activity tests on various types of cancer cells revealed that this type of compound selectively and strongly inhibits the proliferation of various tumor cells (including liver cancer, breast cancer, colon cancer, lung cancer, etc.) while causing minimal damage to normal cells. Furthermore, introducing an alkyl group or substituting an aryl group at the 1-position of carbline can enhance the antitumor activity of the compound and allow for further investigation of its structure-activity relationship. Therefore, the compounds of this invention have significant potential for pharmaceutical applications. Detailed Implementation

[0027] To further illustrate the present invention, a series of embodiments are given below. These embodiments are purely illustrative and are only used to specifically describe the present invention, and should not be construed as limiting the present invention. It should be understood that, within the scope of the present invention, the above-described technical features of the present invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to constitute preferred technical solutions.

[0028] Example 14: Preparation of ((9H-pyridin[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (I1)

[0029] Under nitrogen protection, sodium naphthoquinone sulfonate (195 mg, 0.75 mmol) and K₂CO₃ (69 mg, 0.5 mmol) were added to a reaction flask containing 10 mL of water and magnetically stirred until the solid was completely dissolved. Compound 9H-pyrido[3,4-b]indole-3-amine 1a (92 mg, 0.5 mmol) was accurately weighed, dissolved in 5 mL of 95% ethanol, and added dropwise to the reaction flask under ice bath conditions. The reaction was allowed to proceed at room temperature for 3 h, and TLC was used to confirm completion. The reaction solution was filtered, the filter cake was washed with water, and the residue was collected and dried. A purplish-black solid, I₁, was obtained, with a yield of 63.1%. 1H-N MR(400MHz,DMSO-d6)δ11.74(s,1H,NH),10.22(s,1H,NH),8.86(s,1H,ArH),8.46(d,J=7.8Hz,1H,ArH),8.27(d,J=7.8Hz,1H,ArH),8.18(s,1H,Ar H),8.07(d,J=7.6Hz,1H,ArH),7.90(m,1H,ArH),7.75(m,1H,ArH),7.67–7.56(m,2H,ArH),7.27(m,1H,ArH),6.66(s,1H,ArH).ESI-MS(m / z):calcd for C21H14N3O2+:340.1081,found340.1054.

[0030] Example 2 Preparation of 4-((1-methyl-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (Ⅰ2)

[0031] Under nitrogen protection, sodium 1,2-naphthoquinone-4-sulfonate (0.39 g, 1.5 mmol) was dissolved in 15 mL of water, followed by the addition of K₂CO₃ (0.138 g, 1.0 mmol). Then, 8 mL of an ethanolic solution of 1-methyl-9H-pyrido[3,4-b]indole-3-amine 1b (0.197 g, 1.0 mmol) was added. The mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction solution was filtered and dried to obtain a purplish-black solid I₂, with a yield of 84%. MS (ESI) m / z: 354 [M+H] +.1H NMR(d6-DMSO,400MHz)δ:11.80(s,1H,NH),10.29(s,1H,Ar-H),8.50(d,J=7.9Hz,1H,Ar-H),8.29(d,J=7.8Hz,1H,Ar-H),8.15–8.02(m ,2H,Ar-H),7.94(m,1H,Ar-H),7.79(m,1H,Ar-H),7.70–7.60(m,2H,Ar-H),7.34–7.26(m,1H,CH=C),6.66(s,1H,NH),2.87(s,3H,CH3).

[0032] Example 3 Preparation of 4-((1-isopropyl-9H-pyridin[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (I3)

[0033] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-isopropyl-9H-pyrido[3,4-b]indole-3-amine 1c to give black solid I3, with a yield of 60.3%. 1 H-NMR(400MHz,DMSO-d6)δ11.72(s,1H,NH),10.04(s,1H,NH),8.45(d,J=8.0Hz,1H, ArH),8.22(d,J=8.0Hz,1H,ArH),8.07(d,J=7.6Hz,2H,ArH),7.91(m,1H,ArH),7.74 (m,1H,ArH),7.63(d,J=8.2Hz,1H,ArH),7.58(m,1H,ArH),7.26(m,1H,ArH),6.94(s ,1H,ArH),3.72(p,J=6.8Hz,1H,CH),1.43(d,J=6.7Hz,6H,CH3).ESI-MS(m / z):calcd for C24H20N3O2+:382.1556, foun d 382.1545.

[0034] Example 4 Preparation of 4-((1-phenyl-9H-pyridin[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (I4)

[0035] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-phenyl-9H-pyrido[3,4-b]indole-3-amine 1d to give black solid I3, with a yield of 68.8%. 1H-NMR (400MHz, DMSO-d6) δ11.08(s,1H,NH),10.23(s,1H,NH),8.48(d,J=7.8Hz,1H,ArH ),8.24(d,J=7.8Hz,1H,ArH),8.05(d,J=6.9Hz,2H,ArH),7.87(m,1H,ArH),7.72(m,1H,A rH),7.61–7.53(m,2H,ArH),7.49(d,J=8.4Hz,1H,ArH),7.39(d,J=4.2Hz,1H,ArH),7.2 3(m,1H,ArH),7.05(s,1H,ArH),6.80(s,1H,ArH),6.74(m,2H,ArH).ESI-MS(m / z):calcd for C27H18N3O2+:416.1399, found 416.1387.

[0036] Example 5 Preparation of 4-((1-(4-methylphenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (Ⅰ5)

[0037] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-p-tolyl-9H-pyrido[3,4-b]indole-3-amine 1e to prepare compound 4-((1-(4-methylphenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I5), yield 85%. MS (ESI) m / z: 430 [M+H] + .1H-NMR (400MHz, DMSO-d6) δ11.62 (s, 1H, NH), 10.17 (s, 1H, NH), 8.47 (d, J = 8.0Hz, 1H, ArH), 8. 28(d,J=7.8Hz,1H,ArH),8.18(s,1H,ArH),8.07(m,1H,ArH),7.98(d,J=8.0Hz,2H,ArH),7.95– 7.85(m,1H,ArH),7.75(m,1H,ArH),7.67(d,J=8.2Hz,1H,ArH),7.63–7.55(m,1H,ArH),7.45(d ,J=7.9Hz,2H,ArH),7.29(m,1H,ArH),6.90(s,1H,ArH),2.45(s,3H,CH3).ESI-MS(m / z):calcd for C25H20N3O2 + :430.1556,found430.1546.

[0038] Example 3 Preparation of 4-((1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (Ⅰ6)

[0039] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine 1f to prepare compound 4-((1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I6), yield 83%. MS (ESI) m / z: 446 [M+H] + .1H-NMR(400MHz,DMSO-d6)δ11.82(s,1H,NH),10.17(s,1H,NH),8.79(s,1H,ArH),8.39( d,J=7.9Hz,1H,ArH),8.17–8.12(m,3H,ArH),8.04(d,J=8.7Hz,1H,ArH),7.97–7.85(m,1H ,ArH),7.70(d,J=8.2Hz,1H,ArH),7.60(m,1H,ArH),7.56–7.50(m,1H,ArH),7.32(m,1H, ArH),7.19(d,J=8.7Hz,2H,ArH),6.83(s,1H,ArH),3.89(s,3H,CH3).ESI-MS(m / z):calcd for C28H20N3O3 + :446.1505,found 446.1497.

[0040] Example 4 Preparation of 4-((1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (Ⅰ7)

[0041] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1 g of 1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine to prepare compound 4-((1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I7), yield 84%. MS (ESI) m / z: 446 [M+H] +.1H NMR(d6-DMSO,400MHz)δ:11.54(s,1H,NH),8.42(d,J=7.9Hz,1H,Ar-H),8.19(d,J=7.9Hz,1H,Ar-H),8.07(s,1H,Ar-H),7.99–7.95(m, 1H,Ar-H),7.79(m,1H,Ar-H),7.67–7.45(m,7H,Ar-H),7.19(m,1H,Ar-H),7.06–7.01(m,1H,CH=C),6.86(s,1H,NH),3.82(s,3H,OCH3).

[0042] Example 5 Preparation of 4-((1-(2-methoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (Ⅰ8)

[0043] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-(2-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine for 1 h to prepare compound 4-((1-(2-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I8), yield 81%. MS (ESI) m / z: 446 [M+H] + .1H-NMR(400MHz,DMSO-d6)δ11.66(s,1H,NH),10.16(s,1H,NH),8.46(d,J=7.8Hz,1H,Ar H),8.27(d,J=7.7Hz,1H,ArH),8.20(s,1H,ArH),8.07(d,J=7.7Hz,1H,ArH),7.90(m,1H), 7.74(d,J=14.9Hz,1H,ArH),7.69–7.64(m,2H,ArH),7.62–7.51(m,3H,ArH),7.29(m,1H, ArH),7.12(d,J=7.7Hz,1H,ArH),7.06(s,1H,ArH),3.90(s,3H,CH3).ESI-MS(m / z):calcd for C28H20N3O3 + :446.1505,found446.1495.

[0044] Example 6 Preparation of 4-((1-(2,3-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (Ⅰ9)

[0045] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-(2,3-dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine 1i to prepare compound 4-((1-(2,3-dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I9), yield 82%. MS (ESI) m / z: 476 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ11.19(s,1H,NH),10.17(s,1H,NH),8.46(m,1H,ArH) ,8.34–8.14(m,2H,ArH),8.06(d,J=7.6Hz,1H,ArH),7.90(m,1H,ArH),7.74(m, 1H,ArH),7.62–7.54(m,2H,ArH),7.29–7.24(m,3H,ArH),7.15(d,J=7.1Hz,1H, ArH),6.70(s,1H,ArH),3.92(s,3H,CH3),3.55(s,3H,CH3).ESI-MS(m / z):calcd for C29H22N3O4 + :476.1610,found476.1601.

[0046] Example 7 4-((1-(2,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (I) 10 Preparation of )

[0047] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-(2,4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine 1j to prepare compound 4-((1-(2,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I) 10 Yield 83%. MS (ESI) m / z: 476 [M+H] +.1H-NMR (400MHz, DMSO-d6) δ11.08(s,1H,NH),10.23(s,1H,NH),8.48(d,J=7.8Hz,1H,ArH),8.24(d,J= 7.8Hz,1H,ArH),8.05(d,J=7.0Hz,2H,ArH),7.87(m,1H,ArH),7.72(m,1H,ArH),7.59–7.53(m,2H,ArH) ,7.49(d,J=8.4Hz,1H,ArH),7.39(d,J=4.2Hz,1H,ArH),7.23(m,1H,ArH),7.14–6.98(m,1H,ArH),6.81 (d,J=1.8Hz,1H,ArH),6.77–6.68(m,2H,ArH),3.89(s,3H,CH3),3.83(s,3H,CH3).ESI-MS(m / z):calcd for C29H22N3O4 + :476.1610,found476.1604.

[0048] Example 8 4-((1-(3,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (I) 11 Preparation of )

[0049] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-(3,4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine 1k to prepare compound 4-((1-(3,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I) 11 Yield 84%. MS (ESI) m / z: 476 [M+H] +.1H-NMR (400MHz, DMSO-d6) δ11.61(s,1H,NH),10.21(s,1H,NH),8.50(d,J=7.9Hz,1H,ArH),8.26(d,J=7. 9Hz,1H),8.15(s,1H,ArH),8.10–8.05(m,1H,ArH),8.02(d,J=7.8Hz,1H,ArH),7.94–7.87(m,1H,ArH),7.7 4(m,1H,ArH),7.60(d,J=7.4Hz,1H,ArH),7.51–7.40(m,2H,ArH),7.28(m,1H,ArH),7.22(d,J=8.9Hz,1H,A rH),7.09(d,J=6.7Hz,1H,ArH),7.06(s,1H,ArH),3.92(s,3H,CH3),3.86(s,3H,CH3).ESI-MS(m / z):calcd for C29H22N3O4 + :476.1610,found476.1596.

[0050] Example 9 4-((1-(3,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (I) 12 Preparation of )

[0051] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-(3,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine 11 to prepare compound 4-((1-(3,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I) 12 Yield 82%. MS (ESI) m / z: 476 [M+H] +.1H-NMR(400MHz,DMSO-d6)δ11.62(s,1H,NH),10.09(s,1H,NH),8.46(d,J=7.8Hz,1H,ArH), 8.26(d,J=7.8Hz,1H,ArH),8.19(s,1H,ArH),8.06(d,J=7.6Hz,1H,ArH),7.88(m,1H,ArH),7 .73(m,1H,ArH),7.68(d,J=8.2Hz,1H,ArH),7.59(m,1H,ArH),7.28(m,1H,ArH),7.19(d,J=2 .1Hz,2H,ArH),7.14(s,1H,ArH),6.67(m,1H,ArH),3.88(s,6H,CH3).ESI-MS(m / z):calcdfor C29H22N3O4 + :476.1610, found 476.1599.

[0052] Example 13 4-((1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (I) 13 Preparation of )

[0053] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine 1m to prepare compound 4-((1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I) 13 Yield 85%. MS (ESI) m / z: 506 [M+H] + .1H-NMR(400MHz,DMSO-d6)δ11.67(s,1H,NH),10.12(s,1H,NH),8.49(d,J=7.8Hz ,1H,ArH),8.27(d,J=7.8Hz,1H,ArH),8.21(s,1H,ArH),8.07(d,J=7.9Hz,1H,ArH ),7.91(m,1H,ArH),7.74(m,1H,ArH),7.67(d,J=8.2Hz,1H,ArH),7.60(m,1H,ArH ),7.33–7.25(m,4H,ArH),3.96(s,6H,CH3),3.80(s,3H,CH3).ESI-MS(m / z):calcd for C30H23N3O5 + :506.1638,found506.1702.

[0054] Example 14 4-((1-(4-nitrophenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (I) 14 Preparation of )

[0055] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-(4-nitrophenyl)-9H-pyrido[3,4-b]indole-3-amine 1n to prepare compound 4-((1-(4-nitrophenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I) 14 Yield 80%. MS (ESI) m / z: 461 [M+H] + .1H-NMR (400MHz, DMSO-d6) δ11.83(s,1H,NH),10.26(s,1H,NH),8.41(d,J=8.9Hz,2H,ArH),8.28(d,J=9.0Hz,2H,ArH),8.08(d,J=7.8Hz,1H,ArH),7. 90(m,1H,ArH),7.75(m,1H,ArH),7.70–7.57(m,3H,ArH),7.50(s,1H,ArH),7.32(m,1H,ArH),7.23(s,1H,ArH),6.82(s,1H,ArH).ESI-MS(m / z):calcd forC27H17N4O4 + :461.1250,found 461.1245.

[0056] Example 15 4-((1-(3-nitrophenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (I) 15 Preparation of )

[0057] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-(3-nitrophenyl)-9H-pyrido[3,4-b]indole-3-amine 1o to prepare compound 4-((1-(3-nitrophenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthalene-1,2-dione (I) 15 Yield 81%. MS (ESI) m / z: 461 [M+H] +.1H-NMR(400MHz,DMSO-d6)δ11.77(s,1H,NH),10.17(s,1H,NH),8.81(s,1H,ArH),8.77(s,1H, ArH),8.46(d,J=6.3Hz,1H,ArH),8.36(d,J=8.1Hz,1H,ArH),8.29(d,J=7.9Hz,1H,ArH),8.10(s ,1H,ArH),8.04(d,J=7.6Hz,1H,ArH),7.92(d,J=8.4Hz,1H,ArH),7.85(m,1H,ArH),7.72(d,J=7 .3Hz,1H,ArH),7.66–7.60(m,2H,ArH),7.28(m,1H,ArH),6.52(s,1H,ArH).ESI-MS(m / z):calcd forC27H17N4O4 + :461.1250,found 461.1181.

[0058] Example 16 4-((1-(4-dimethylaminophenyl)-9H-pyrido[3,4-b]indol-3-yl)amino)naphthalene-1,2-dione (I) 16 Preparation of )

[0059] Following the preparation method of I1, sodium 1,2-naphthoquinone-4-sulfonate was reacted with 1-(4-dimethylaminophenyl)-9H-pyrido[3,4-b]indole-3-amine 1p to prepare compound 4-((1-(4-dimethylaminophenyl)-9H-pyrido[3,4-b]indole-3-yl)amino)naphthyl-1,2-dione (I) 16 Yield 77%. MS (ESI) m / z: 459 [M+H] + .

[0060] Example 17: In vitro antitumor activity study

[0061] Four cell lines were selected: A549 (human lung cancer cell line), HT-29 (human colon cancer cell line), MCF-7 (human breast cancer cell line), and HepG2 (human liver cancer cell line). The test target compound I was measured. 1-16 The inhibition rate of the positive control drug Harmine on the test cells was compared. The natural β-carboline alkaloid Harmine was used as a positive control; detailed test results are shown in Table 2.

[0062] The test results showed that most of the target compounds exhibited a half-maximal inhibitory inhibition (IC50) rate against the four tested tumor cell lines. 50The activity was higher than that of the positive control drug Harmine. Among them, compound I2, with a methyl group introduced at the 1-position of β-carboline, showed strong anti-proliferative activity against four human tumor cell lines: A549, HT29, MCF-7, and HepG2 (IC50 ≤ 5 μM). Overall, I... 1-16 The inhibitory activity against MCF-7 and HepG2 cell lines was stronger than that against A549 and HT29 cell lines. According to the data in Table 2, compound I... 1-3 Its antitumor activity is significantly stronger than that of I 4-16 This indicates that compounds with an alkyl group introduced at the 1-position of β-carboline exhibit stronger anti-proliferative activity than those with an aromatic group introduced. Secondly, based on compound I... 5-6 and I 14 The antiproliferative activity of the four cell lines tested was as follows: 4-OCH3Ph > 4-CH3Ph > 4-NO2Ph, indicating that the compound with the electron-donating group introduced onto the benzene ring at the 1-position of β-carbamoline exhibits stronger antitumor activity. Furthermore, based on compound I... 6-8 Antiproliferative activity against A549, HT-29, and MCF-7 cell lines showed the order: 4-OCH3Ph > 3-OCH3Ph > 2-OCH3Ph, indicating that compounds with para-substitution at the 1-position of the benzene ring in β-carboline generally exhibit stronger antitumor activity than those with ortho- and meta-substitution. Finally, based on compound I... 6-8 I 9-11 and I 13 Antiproliferative activity against A549 cell line showed the order: monosubstituted > trisubstituted > disubstituted. Antitumor activity against HT-29, MCF-7, and HepG2 cell lines showed the order: monosubstituted > disubstituted > trisubstituted.

[0063] Example 18: Evaluation of Cytotoxicity Experiments

[0064] To further evaluate target compound I 1-15 To determine the selectivity of the target compound for normal somatic cells and tumor cells, we used the MTT assay to determine the cytotoxicity of the target compound to CCD841 (human normal colonic epithelial cells) and LO2 (human normal hepatocytes) cell lines.

[0065] Test results show that the compounds of this invention are significantly less toxic to normal cells than to tumor cells (Table 3), especially compound I. 1-4 For LO2 cell line IC 50 The value is 10 to 20 times higher than that of the HepG2 cell line, and the IC50 value for the CCD841 cell line is also higher. 50 It is 4 to 10 times that of the HT29 cell line. These results indicate that compound I... 1-15It exhibits a certain degree of selectivity for tumor cells, with a higher selectivity for liver cancer cells.

[0066] Table 2. Inhibitory activity of the compounds of the present invention against four types of human tumor cells.

[0067]

[0068] ND: Not detected

[0069] Table 3. Evaluation of the toxicity of the compounds of this invention to two types of normal human cells.

[0070]

[0071]

[0072] ND: Not detected

[0073] While the embodiments disclosed in this application are as described above, the content is merely for the purpose of facilitating understanding of this application and is not intended to limit this application. Any person skilled in the art to which this application pertains may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application; however, the scope of protection of this application shall still be determined by the scope defined in the appended claims.

Claims

1. A β-carbazonaphthoquinone derivative, characterized in that, The β-carbolinenaphthoquinone derivative has the structure shown in general formula I: R is selected from one of H, C1-C6 alkyl, phenyl, monomethyl-substituted phenyl, monomethoxy-substituted phenyl, dimethoxy-substituted phenyl, trimethoxy-substituted phenyl, mononitro-substituted phenyl, and 4-dimethylaminophenyl.

2. A β-carbolinenaphthoquinone derivative according to claim 1, characterized in that, R is selected from one of H, methyl, isopropyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-nitrophenyl, 3-nitrophenyl, and 4-dimethylaminophenyl.

3. A method for preparing the β-carbamolinenaphthoquinone derivative according to claim 1, characterized in that, The preparation method is as follows: compound 1 and sodium 1,2-naphthoquinone-4-sulfonate 2 are coupled in an ethanol solution of potassium carbonate to obtain target compound I; The synthetic route of the preparation method is as follows: R is selected from one of H, C1-C6 alkyl, phenyl, monomethyl-substituted phenyl, monomethoxy-substituted phenyl, dimethoxy-substituted phenyl, trimethoxy-substituted phenyl, mononitro-substituted phenyl, and 4-dimethylaminophenyl.

4. The use of the β-carbolinenaphthoquinone derivative of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient in the preparation of a medicament for the treatment and / or prevention of malignant tumors, wherein the malignant tumor is one of liver cancer, breast cancer, colon cancer, and lung cancer.

5. The application according to claim 4, characterized in that, The drug treats and / or prevents malignant tumors by selectively inhibiting the proliferation of tumor cells.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the β-carbonathoquinone derivative of claim 1 or 2, or a medically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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