CN116410132A

CN116410132A - 8-hydroxyquinoline compound, preparation method thereof and application thereof in preparation of antitumor drugs

Info

Publication number: CN116410132A
Application number: CN202310166854.6A
Authority: CN
Inventors: 刘艳; 关颖祯; 伯纳德·莫涅
Original assignee: Guangdong University of Technology
Current assignee: Guangdong University of Technology
Priority date: 2023-02-23
Filing date: 2023-02-23
Publication date: 2023-07-11

Abstract

The invention belongs to the technical field of medicines, and particularly discloses an 8-hydroxyquinoline compound, which is prepared from 2-methyl-8-hydroxyquinoline serving as a raw material by a series of reactions such as C-2-site aldol addition, elimination reaction, michael addition and the like to synthesize an 8-hydroxyquinoline derivative with a four-coordination chelation effect. The inhibition of the compound to tumor cells is measured by thiazole blue (MTT) method, and the result shows that the safety of the synthesized compound is higher than that of the positive control drug 5-fluorouracil (5-FU). Wherein, the TDMQ51 has good in vitro inhibition activity on A375, colo829 and A549, and IC ₅₀ The values are respectively 12.4+/-2.1, 30.5+/-1.7 and 16.3+/-3.0 mu M, and the activity is better than that of a positive controlMedicine. The invention researches the structure-activity relationship of the in-vitro anti-tumor activity of the compound by adjusting the coordination atoms on the side chains and the substituent groups on the side chain end group coordination atoms, and the prepared compound has strong tumor inhibition activity, good safety and good prospect in preparing anti-tumor drugs.

Description

8-hydroxyquinoline compound, preparation method thereof and application thereof in preparation of antitumor drugs

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an 8-hydroxyquinoline compound, a preparation method thereof and application thereof in preparing antitumor drugs.

Background

Cancer is currently one of the leading causes of morbidity and mortality worldwide, severely threatening human health. An important method for clinical cancer treatment is chemotherapy, however, most antitumor drugs are prone to drug resistance and have large toxic and side effects. Therefore, the research and development of high-activity and low-toxicity therapeutic drugs have important clinical significance and are always hot spots of research.

Quinoline compounds have good biological activity and wide medicinal value, and drugs developed based on quinoline skeleton include anticancer drugs (ambtothecin, irinotecan, topotecan, etc.), antimalarial drugs (Quinine, quinidine, chloroquinone, mefloquinone, amodiaquine, primaquine, etc.), antibacterial drugs (Ciprofloxacin, sparfoxacin, gamifloxacin, etc.), antifungal drugs (Clioquinol), antiviral drugs (Saquinavir), anthelmintic drugs (oxamnine), local anesthetics (Dibucaine), antiasthmatic drugs (Montelukast), antipsychotic drugs (Aripiprazole, brexpiprazole, etc.), antiglaucomatous drugs (carlol), cardiotonic drugs (Vesnarinone), etc. In 1966, quinoline derivative camptothecine is taken as an anticancer drug, and from the moment, a quinoline skeleton plays an important role in the development of the anticancer drug, and the derivative has good anticancer effect through various different mechanisms such as blocking cell cycle, inducing apoptosis, inhibiting blood vessel growth, preventing cell migration, activating immune response and the like. For these reasons, quinoline anticancer drugs play an important role in modern pharmaceutical chemistry. However, due to the serious toxic side effects, poor drug resistance or poor selectivity of the quinoline chemotherapeutics used clinically, certain modification of the compounds is urgently needed to develop novel and efficient drug molecules with different action modes and toxicity characteristics.

In recent years, research shows that tumor development is closely related to copper metabolic disturbance in human body, copper level in tumor tissue and serum in tumor patients is obviously increased, and copper promotes angiogenesis, cell proliferation, tumor growth and metastasis. In addition, the influence of copper metabolic disturbance on the tumor is not limited to the tumor cells, and the influence of copper metabolic disturbance on the tumor is also related to the mutual crosstalk between the copper metabolic disturbance and the tumor microenvironment, and the tumor development is promoted through the regulation and the remodelling of the tumor microenvironment. Copper ions have become an emerging anticancer target in view of the increased copper levels in malignant tumors. At present, the antitumor action mechanisms based on the target mainly comprise two types: (1) Copper ion chelating agents, complexing and reducing the content of copper ions, inhibiting angiogenesis and tumor growth of tumors, and the strategy developed copper chelating agents have achieved certain effects in clinical trials; (2) The small molecular compound is complexed with redox copper ions in tumor tissues to generate Fenton reaction, generate active oxygen and induce death of tumor cells. However, the use of copper ion chelating agents in clinic tends to result in too low a concentration of copper ions in the patient, disrupting the normal physiological processes in which other copper ions participate, and thus creating serious toxic side effects. On the other hand, the chelating agent medicines have general chelation to in-vivo transition metals, have poor selective chelation to copper ions, cause the disorder of other metal ions in the body, and further generate toxic and side effects. Therefore, the chelating agent with specific recognition of copper ions (namely, complexing copper ions only without disturbing the physiological actions of other metal ions in the body), (1) chelating copper ions with high concentration in tumor tissues to transfer the copper ions to the copper-carrying proteins in the body to enable copper to return to steady state balance, (2) or, generating Fenton reaction in tumor cells to induce apoptosis of the tumor cells, and is hopeful to be developed into a low-toxicity and high-efficiency tumor therapeutic drug.

The inventor develops a series of quinoline micromolecular chelating agents in advance, and shows good patent medicine potential: (1) The method has the effects of specifically identifying and regulating copper ions, and has weaker complexing ability on other metal ions in the body; (2) The chelating agent does not affect the function of copper-carrying proteins and other important metallic proteins in the body and releases copper under reducing conditions for delivery to the copper-carrying proteins. Based on the strategy and the early research basis, the copper ion regulator anti-tumor small molecule compound is hopeful to be developed.

Disclosure of Invention

The invention aims at providing 8-hydroxyquinoline compounds.

The invention also aims to provide a preparation method of the compound and application of the compound in preparation of antitumor drugs.

Based on the coordination characteristic of copper ions, the invention takes 8-hydroxyquinoline as a mother nucleus, and designs and synthesizes 5 novel quinoline derivatives with four-coordination chelation by introducing a flexible side chain and a coordination atom at a C2 position, and carries out structural identification. Meanwhile, the structure-activity relationship of the compound in vitro anti-tumor activity is studied by adjusting the coordination atoms on the side chains and the substituent groups on the side chain terminal group coordination atoms. The MTT method is specifically adopted to measure the cytotoxic activity of the compound on human melanoma cell lines (A375 and Colo 829), human lung cancer cell lines (A549), human liver cancer cell lines (HepG 2), human cervical cancer cell lines (Hela) and human normal epidermis cell lines (Hacat), and the structure-activity relationship of the compound in vitro antitumor activity is studied by adjusting the coordination atoms on the side chains and the substituent groups on the terminal coordination atoms.

In order to achieve the above purpose, the invention adopts the following technical scheme:

an 8-hydroxyquinoline compound, wherein the structural formula of the 8-hydroxyquinoline compound is shown as follows:

wherein R is ¹ Selected from nitrogen, sulfur or oxygen atoms; r is R ² Selected from mercapto or amino; wherein the hydrogen atom in the mercapto or amino group may be replaced by one or more R ³ Substitution; r is R ³ Is hydrogen or C1-C3 saturated alkyl.

As a preferred embodiment, the hydrogen atom in the mercapto or amino group may be replaced by one or two R ³ And (3) substitution.

As a preferable technical scheme, R ³ Is hydrogen or C1-C2 saturated alkyl.

As a specific technical scheme, the structural formula of the 8-hydroxyquinoline compound is shown as follows:

the above series of 5 compounds was designated as TDMQ51 ultra-highThe cytotoxicity of the TDMQ55 to the normal human epidermal cell strain (Hacat) is lower than that of the positive control drug, and the compound has better safety. Wherein, the TDMQ51 has good in vitro inhibition activity on A375, colo829 and A549, and IC ₅₀ The values are respectively 12.4+/-2.1, 30.5+/-1.7 and 16.3+/-3.0 mu M, and the activity is superior to that of the positive control drug 5-fluorouracil (5-FU). The inhibition activity of TDMQ53 to A375 and the inhibition activity of TDMQ55 to Colo829 and A549 are higher than those of positive control drugs, and the compounds have better safety to normal cells, so that the series of compounds have reconstruction potential in improving anti-tumor activity and safety. Among the series of compounds, TDMQ51 has the strongest inhibitory activity on the human melanoma cell line A375, and can be used as a lead compound for intensive research.

The invention also discloses a preparation method of the 8-hydroxyquinoline compound, which takes 2-methyl-8-hydroxyquinoline as a raw material, and obtains the 8-hydroxyquinoline compound through C-2 site aldol addition, elimination reaction and Michael addition.

Based on the inhibition activity of the compounds, the invention simultaneously protects the application of the 8-hydroxyquinoline compounds in preparing antitumor drugs.

As a preferred embodiment, the tumor comprises lung cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, intestinal cancer, head and neck cancer, anal cancer, extrahepatic cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, bronchial adenoma, burkitt's lymphoma, carcinoid tumor, unknown primary cancer, central nervous system lymphoma, cervical cancer, childhood cancer, germ cell tumor, eye cancer, stomach cancer, kidney cancer, laryngeal cancer, blood cancer, liver cancer, non-small cell lung cancer, melanoma, prostate tumor, rectal cancer, salivary gland cancer, sarcoma, small intestine cancer, soft tissue sarcoma, uterine sarcoma, testicular cancer or breast cancer.

As a more preferable technical scheme, the tumor is one or more of melanoma, lung cancer, liver cancer or cervical cancer.

Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.

"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The minimum and maximum values of carbon atom content in the hydrocarbon groups are indicated by a prefix, e.g., the prefix (Ca-Cb) alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C1-C4) alkyl means alkyl containing 1 to 4 carbon atoms.

The C1-C6 alkyl group means a C1, C2, C3, C4, C5, C6 alkyl group, i.e., a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, etc. Alkoxy of C1-C6 also has the meaning corresponding to its radical.

The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.

The terms "salts", "acceptable salts" and "pharmaceutically acceptable salts" refer to the acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base as appropriate (for example, equivalent). These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium.

The term "solvate" refers to a solvent compound produced by dissolving an active substance, for example, the above-mentioned compound in a solvent, and binding a solvent molecule with a solute molecule or ion to change the state of the solute, but not affecting the activity thereof.

Compared with the prior art, the invention has the beneficial effects that:

the invention provides a series of 8-hydroxyquinoline compounds, the safety of which is higher than that of a positive control drug 5-fluorouracil (5-FU). Meanwhile, the compound has better inhibition activity, the activity is superior to that of a positive control medicine, and the compound has good prospect in preparing antitumor medicines.

Drawings

FIG. 1 is a diagram of Compound 2 ¹ H NMR spectrum;

FIG. 2 is a diagram of Compound 3 ¹ H NMR spectrum;

FIG. 3 is a schematic representation of the compound TDMQ51 ¹ H NMR spectrum;

FIG. 4 is a schematic diagram of the compound TDMQ51 ¹³ C NMR spectrum;

FIG. 5 is a schematic representation of compound TDMQ52 ¹ H NMR spectrum;

FIG. 6 is a diagram of compound TDMQ52 ¹³ C NMR spectrum;

FIG. 7 is a schematic representation of compound TDMQ53 ¹ H NMR spectrum;

FIG. 8 is a schematic representation of compound TDMQ53 ¹³ C NMR spectrum;

FIG. 9 is a schematic representation of compound TDMQ54 ¹ H NMR spectrum;

FIG. 10 is a schematic diagram of compound TDMQ54 ¹³ C NMR spectrum;

FIG. 11 is a schematic representation of compound TDMQ55 ¹ H NMR spectrum;

FIG. 12 is a diagram of compound TDMQ55 ¹³ C NMR a spectrogram;

FIG. 13 is a diagram of the compound TDMQ55.2HCl ¹ H NMR spectrum;

FIG. 14 is a diagram of the compound TDMQ55.2HCl ¹³ C NMR spectrum.

Detailed Description

The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

The test methods used in the embodiment of the invention are all conventional methods unless specified otherwise; the materials, reagents and the like used, unless otherwise specified, are those commercially available.

The general synthesis method is as follows:

the synthetic route of the compound TDMQ 51-55 is shown below, 2-methyl-8-hydroxyquinoline (1) is used as a raw material, and is subjected to C-2-bit Aldol addition reaction with paraformaldehyde under the catalysis of n-butyllithium to obtain 2- (2-hydroxyethyl) quinoline-8-alcohol (2), and the yield is 63%. Intramolecular elimination of the water molecules was carried out on compound 2 to give 2-vinylquinolin-8-ol (3) in a yield of 47%. The compound 3 and 1, 2-ethanedithiol are subjected to Michael addition reaction, and a flexible side chain with S atoms as coordination atoms is introduced at the near end and the far end at the C-2 position, so that the compound TDMQ51 is obtained, and the yield is 78%. In order to study the influence and structure-activity relationship of the coordination atom type on the side chain and the substituent on the far-end coordination atom on the in-vitro anti-tumor activity of the compound, the TDMQ 52-55 is designed and synthesized. The compound 3 is subjected to Michael addition reaction with 2-aminoethanethiol, and amino is introduced at the far end of a side chain, so that the S coordination atom at the far end of the side chain of the compound TDMQ51 is successfully converted into N atom, and the compound TDMQ52 is obtained with the yield of 67%. The compound 3 and 2- (thiomethyl) ethylamine are subjected to Michael addition reaction, the near-end S coordination atom of the flexible side chain of the TDMQ51 is changed into N atom, and the far-end mercapto group is converted into methylthio group, so that the compound TDMQ53 is obtained, and the yield is 70%. The compound 3 and 2- (methylthio) ethane-1-mercaptan are subjected to Michael addition reaction, S atoms are introduced at the proximal end of a C-2 side chain, methylthio is introduced at the distal end, and the distal mercapto group of TDMQ51 is changed into methylthio, so that a compound TDMQ54 is obtained, and the yield is 72%. The compound 3 and 2-dimethylamino ethanethiol are subjected to Michael addition reaction, S coordination atoms are introduced at the near end of the C-2 site, N coordination atoms are introduced at the far end of the C-2 site, and the far-end amino group of the side chain of the compound TDMQ52 is transformed into dimethylamino, so that the compound TDMQ55 is obtained with the yield of 87%. The compounds TDMQ 51-55 are all prepared by 1HNMR, ¹³ Structural identification was performed by the test methods such as C NMR, IR and HRMS.

The specific synthesis is as follows:

1. synthesis of Compound 2- (2-hydroxyethyl) -8-hydroxyquinoline (2)

Referring to literature methods, n-butyllithium (1.6M, 23.5mL,37.5 mmol) was added dropwise to a tetrahydrofuran solution (30 mL) containing 2-methyl-8-hydroxyquinoline (2 g,12.5 mmol) under argon atmosphere at-78deg.C, and after vigorous stirring for 2 hours, paraformaldehyde (1.5 g,50.0 mmol) was added, stirring was continued for 3 hours, and the reaction was allowed to warm to room temperature using NH ₄ The reaction was quenched with aqueous Cl. The resulting mixture was extracted with dichloromethane (3X 50 mL), anhydrous Na ₂ SO ₄ The crude product was purified by silica gel column chromatography (dichloromethane/methanol, 60/1 to 10/1, v/v) to give 1.5g of compound 2 as a white solid in 63% yield. ¹ H NMR(400MHz，CDCl ₃ )δ：8.04(d，J＝8.4Hz，1H)，7.38(t，J＝7.8Hz，1H)，7.31-7.26(m，2H)，7.16(d，J＝7.6Hz，1H)，4.13(t，J＝6.0Hz，2H)，3.20(t，J＝6.0Hz，2H).

2. Synthesis of Compound 2-vinyl-8-hydroxyquinoline (3)

Referring to literature methods, triethylamine (10.2 mL,75.0 mmol) and methanesulfonyl chloride (3.5 mL,45.0 mmol) were sequentially added to a dichloromethane solution (30 mL) in which 2- (2-hydroxyethyl) -8-hydroxy-quinoline (2) (2.8 g,15.0 mmol) was dissolved, followed by stirring for 3 hours, the reaction system was warmed to room temperature, TLC was followed by completion of the reaction, the solvent was distilled off under reduced pressure, the crude product was dissolved in ethanol (15 mL), aqueous sodium hydroxide solution (4M, 3.75 mL) was added, the reaction was stopped after stirring at reflux temperature for 5 hours, and cooled to room temperature, and the resulting mixture was neutralized to neutrality with hydrochloric acid, extracted with dichloromethane (3X 50 mL) and dried Na ₂ SO ₄ Drying, filtration and concentration under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/n-hexane, 1/80 to 3/1, v/v) to give 1.2g of compound 3 as a white solid in 47% yield. ¹ H NMR(400MHz，CDCl ₃ )δ：8.10(d，J＝8.4Hz，1H)，7.58(d，J＝8.4Hz，1H)，7.41(t，J＝7.6Hz，1H)，7.30(dd，J＝8.0，1.2Hz，1H)，7.16(dd，J＝7.6，1.2Hz，1H)，7.00(dd，J＝17.6，10.8Hz，1H)，6.32(dd，J＝17.6，0.8Hz，1H)，5.65(dd，J＝10.8，0.8Hz，1H).

3. Synthesis of Compound TDMQ51

To a methanol solution (2 mL) containing 2-vinyl-8-hydroxyquinoline (3) (100 mg,0.58 mmol) was added 1, 2-ethanedithiol (105. Mu.L, 1.17 mmol) at room temperature, and the mixture was stirred for 30 minutes, and the resulting mixture was extracted with methylene chloride (3X 50 mL) to give anhydrous Na ₂ SO ₄ Drying, filtering, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography (ethyl acetate/n-hexane, 1/25-2/5, v/v) to obtain 113mg of yellow oily compound TDMQ51 in 78% yield. ¹ H NMR(CDCl ₃ ，400MHz)δ：8.09(d，J＝8.4Hz，1H)，7.41(dd，J＝8.4，7.6Hz，1H)，7.33(d，J＝8.4Hz，1H)，7.30(dd，J＝8.4，1.2Hz，1H)，7.16(dd，J＝7.6，1.2Hz，1H)，3.28-3.24(m，2H)，3.10-3.06(m，2H)，2.83-2.79(m，2H)，2.79-2.74(m，2H)，1.72(t，J＝7.8Hz，1H)； ¹³ C NMR(CDCl ₃ ，100MHz)δ：158.1，151.8，137.7，136.5，127.1，127.0，122.3，117.7，110.1，38.5，36.5，31.1，24.8；IR(KBr)v：3349，3046，2914，2553，1599，1572，1504，1469，1429，1420，1397，1370，1311，1242，1227，1183，1154，1133，1086，1045，879，833，802，748，724，690，598，576，544，495，471，413cm ^-1 ；HRMS(ESI)calcd for C ₁₃ H ₁₆ NOS ₂ ：266.0668([M+H] ⁺ )，found：266.0665；Elemental analysis calcd(％)for C ₁₃ H ₁₅ NOS ₂ (apparent MW＝265.90)：C 58.84，H 5.70，N 5.28，found：C 59.01，H 5.68，N 5.07.

4. Synthesis of Compound TDMQ52

To a solution of 2-vinyl-8-hydroxyquinoline (100 mg,0.58 mmol) in methanol (2 mL) at room temperature was added a solution of 2-aminoethanethiol (44.8 mg,1.17 mmol) in methanol (1 mL), and the mixture was stirred for 1h, followed by reaction with dichloromethane (3X 50 mL)Extracting, anhydrous Na ₂ SO ₄ The crude product was purified by column chromatography on silica gel (dichloromethane/methanol, 50/1 to 5/1, v/v) to give 97mg of the brown solid compound TDMQ52 in 67% yield at m.p.110 to 112 ℃. ¹ H NMR(DMSO-d ₆ ，400MHz)δ：8.22(d，J＝8.4Hz，1H)，7.47(d，J＝8.4Hz，1H)，7.40-7.33(m，2H)，7.06(dd，J＝6.8，2.0Hz，1H)，3.20(t，J＝7.4Hz，2H)，3.06(t，J＝7.4Hz，2H)，2.72(t，J＝6.8Hz，2H)，2.60(t，J＝6.8Hz，2H)； ¹³ C NMR(DMSO-d ₆ ，100MHz)δ：158.7，152.5，137.8，136.4，127.4，126.8，122.4，117.7，111.1，41.3，38.3，34.9，30.1；IR(KBr)v：3376，3303，3046，2960，2923，2851，1597，1567，1504，1464，1437，1378，1338，1318，1263，1245，1197，1089，1072，1040，849，835，802，749，722cm ^-1 ；HRMS(ESI)calcd for C ₁₃ H ₁₇ N ₂ OS：249.1056([M+H] ⁺ )，found：249.1053；Elemental analysis calcd(％)for C ₁₃ H ₁₆ N ₂ OS·0.02CH ₂ Cl ₂ ·0.05C ₆ H ₁₄ ·0.3H ₂ O(apparent MW＝259.76)：C 61.59，H 6.73，N 10.78，found：C 61.91，H 6.35，N 10.39.

5. Synthesis of Compound TDMQ53

To a methanol solution (2 mL) in which 2- (methylthio) ethylamine hydrochloride (447 mg,3.51 mmol) was dissolved, a methanol solution (3 mL) of triethylamine (0.5 mL,4.21 mmol) was added dropwise thereto at room temperature, and the reaction was stirred for 2 hours ₂ SO ₄ The crude product was purified by column chromatography on silica gel (dichloromethane/methanol, 30/1 to 10/1, v/v) to give 210mg of the yellow solid compound TDMQ53 in 70%. M.p.188 to 190 ℃. ¹ H NMR(DMSO-d ₆ ，400MHz)δ：8.26(d，J＝8.4Hz，1H)，7.47(d，J＝8.4Hz，1H)，7.42-7.36(m，2H)，7.11(dd，J＝6.8，1.6Hz，1H)，3.52(t，J＝6.8Hz，2H)，3.35(t，J＝6.8Hz，2H)，3.15(t，J＝7.6Hz，2H)，2.82(t，J＝7.7Hz，2H)，2.10(s，3H)； ¹³ C NMR(DMSO-d ₆ ，100MHz)δ：156.5，152.6，137.5，136.6，127.5，126.9，122.3，117.7，111.6，46.1，45.2，33.7，29.2，14.5；IR(KBr)v：3383，2996，2947，2918，2786，2661，2451，1573，1509，1470，1450，1436，1333，1302，1267，1235，1197，1176，1144，994，831，756，748，638cm ^-1 ；HRMS(ESI)calcd for C ₁₄ H ₁₉ N ₂ OS：263.1213([M+H] ⁺ )，found：263.1209；Elemental analysis calcd(％)for C ₁₄ H ₁₈ N ₂ OS·0.35CH ₂ Cl ₂ ·0.4H ₂ O(apparent MW＝299.30)：C 57.59，H 6.57，N 9.26，found：C 57.61，H 6.58，N 9.26.

6. Synthesis of Compound TDMQ54

Referring to the procedure, to a methanol mixture (0.5 mL) of cesium carbonate (88 mg,1.50 mmol) and 2- (methylthio) ethanethiol (162 mg,1.50 mmol) at room temperature was added dropwise a methanol solution (2 mL) containing 2-vinyl-8-hydroxyquinoline (50 mg,0.3 mmol), and the reaction was reacted for 2 hours, and the reaction mixture was extracted with methylene chloride (3X 50 mL) and anhydrous Na ₂ SO ₄ The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 30/1 to 10/1, v/v) to give 60mg of the yellow oily compound TDMQ54 in 72% yield. ¹ H NMR(CDCl ₃ ，400MHz)δ：8.07(d，J＝8.4Hz，1H)，7.41(d，J＝7.6Hz，1H)，7.33-7.28(m，2H)，7.15(dd，J＝7.6，1.2Hz，1H)，3.26(t，J＝7.4Hz，2H)，3.08(t，J＝7.6Hz，2H)，2.81-2.66(m，4H)，2.12(s，3H)； ¹³ C NMR(CDCl ₃ ，100MHz)δ：158.2，151.9，137.8，136.6，127.2，127.1，122.4，117.8，110.1，38.6，34.3，32.1，31.4，15.8；IR(KBr)v：3394，2915，1599，1572，1561，1505，1470，1437，1366，1317，1246，1201，834，754，723，600，577，463，419cm ^-1 ；HRMS(ESI)calcd for C ₁₄ H ₁₈ NOS ₂ ：280.0824([M+H] ⁺ )，found：280.0818；Elemental analysis calcd(％)for C ₁₄ H ₁₇ NOS ₂ (apparent MW＝279.08)：C 60.10，H 6.00，N 4.79，found：C 60.18，H 6.13，N 5.01.

7. Synthesis of Compound TDMQ55

Referring to the literature method, to a mixture of 2-dimethylaminoethanol hydrochloride (410 mg,2.90 mmol) and triethylamine (400. Mu.L, 2.90 mmol) in methanol (1 mL) at room temperature was added dropwise a methanol solution (3 mL) in which 2-vinyl-8-hydroxyquinoline (100 mg,0.58 mmol) was dissolved, and the mixture was reacted for 2 hours, and the reaction mixture was extracted with methylene chloride (3X 50 mL) and anhydrous Na ₂ SO ₄ The crude product was purified by column chromatography on silica gel (dichloromethane/methanol, 50/1 to 10/1, v/v) to give 140mg of the white solid compound TDMQ55 in 87% yield. ¹ H NMR(DMSO-d ₆ ，400MHz)δ：8.21(d，J＝8.4Hz，1H)，7.46(d，J＝8.4Hz，1H)，7.39-7.33(m，2H)，7.07(dd，J＝6.8，2.0Hz，1H)，3.19(t，J＝7.2Hz，2H)，3.08(t，J＝7.2Hz，2H)，2.62(dd，J＝8.6，6.8Hz，2H)，2.42(dd，J＝8.4，6.4Hz，2H)，2.12(s，6H)； ¹³ C NMR(DMSO-d ₆ ，100MHz)δ：158.5，152.6，137.7，136.2，127.3，126.7，122.3，117.5，111.0，59.0，44.8，38.2，30.5，29.0；IR(KBr)v：3376，3030，2882，2779，1639，1608，1598，1464，1405，1388，1309，1153，1021，851，758cm ^-1 ；HRMS(ESI)calcd for C ₁₅ H ₂₁ N ₂ OS：277.1369([M+H]+)，found：277.1364.

8. Synthesis of compound TDMQ 55.2HCl

10M ethanol hydrochloride solution (2.5 mL,2.5 mmol) was added to TDMQ55 (140 mg,0.5 mmol) at 0deg.C, the reaction system was warmed to room temperature after stirring for 4 hours, and concentrated under reduced pressure and dried to give 120mg of pale yellow solid compound TDMQ 55.2 HCl, yield 76%. M.p.138-140deg.C. ¹ H NMR(DMSO-d ₆ ，400MHz)δ：11.06(s，1H)，8.93(d，J＝8.8Hz，1H)，8.05(d，J＝8.8Hz，1H)，7.70-7.64(m，2H)，7.54(d，J＝6.0Hz，1H)，3.58(t，J＝7.2Hz，2H)，3.30-3.25(m，2H)，3.11(t，J＝7.4Hz，2H)，3.02-2.98(m，2H)，2.76(s，3H)，2.75(s，3H)； ¹³ C NMR(DMSO-d ₆ ，100MHz)δ：158.3，148.7，144.8，129.5，128.2，123.4，118.2，116.0，55.5，41.8，33.8，29.7，24.4；IR(KBr)v：3376，3030，2882，2779，1639，1608，1598，1464，1405，1388，1309，1153，1021，851，758cm ^-1 ；HRMS(ESI)calcd for C ₁₅ H ₂₁ N ₂ OS：277.1369([M+H] ⁺ )，found：277.1364；Elemental analysis calcd(％)for C ₁₅ H ₂₀ N ₂ OS·2HCl·0.8H ₂ O(apparent MW＝363.73)：C 49.54，H 6.52，N 7.63，found：C 49.53，H 6.54，N 7.70.

Anti-tumor Activity study of target Compounds

1. Method for testing antitumor activity of compound

The in vitro antiproliferative activity of the compounds TDMQ 51-55 on A375 (melanoma), A549 (lung cancer), hela (cervical cancer), hepG2 (liver cancer), hacat (human immortalized keratinocyte) and Colo829 (melanoma) cells is tested by MTT method ₂ ) Incubating for 24 hr, adding diluted culture medium with TDMQ 51-55, adding the sample to be tested into 96-well plate at 100, 50, 25, 12.5, 6.25, 3.125 μmol/L, arranging 3 compound wells for each concentration, arranging blank control group and positive drug control group, adding 100 μL MTT (0.5 mg/mL) into each well after drug action for 48 hr, incubating for 4 hr, sucking liquid, adding 150 μL DMSO into each well, shaking, measuring absorbance values of 570nm drug adding well, blank well and control well by using SpectraMax@Paradigm@enzyme label instrument, and calculating IC by GraphPad Prism 8 ₅₀ Experiments were repeated at least three times and the results were shown as absorbance mean.+ -. SD.5-FU used as positive control.

2. Results

The in vitro antitumor activity of the compounds TDMQ 51-55 was tested by MTT method, 5-fluorouracil (5-FU) was used as a positive control, and the experimental results are shown in Table 1:

table 1 in vitro antiproliferative Activity of Compounds TDMQ 51-55 against five tumor cell lines and Normal cells

^a Data represent the mean±SD from at least three independent experiments. ^b Used as a positive control.

The results in Table 1 show that, compared with 5-fluorouracil (5-FU), the cytotoxicity of the compounds TDMQ 51-55 to human normal epidermal cell line (Hacat) is lower than that of the positive control drug, indicating that the safety of the compounds synthesized in this way is better than that of the positive control drug.

TDMQ51 shows good in vitro inhibition activity on A375, colo829 and A549, and IC ₅₀ The values are respectively 12.4+/-2.1, 30.5+/-1.7 and 16.3+/-3.0 mu M, the activity is superior to that of a positive control drug 5-fluorouracil (5-FU), and the activity is superior to that of HepG2 (IC) ₅₀ Values of 48.9±2.8 μm) was comparable to the positive control.

The structural relation research on the series of compounds shows that: (1) Methylation or conversion of the distal thiol group of TDMQ51 to a dimethylamino group (N (CH) ₃ ) ₂ ) The inhibition activities of the recombinant strain on A375, colo829, A549 and HepG2 cell strains are obviously reduced; (2) While the compound TDMQ52 obtained by converting the distal mercapto group of the C-2 flexible side chain of the TDMQ51 into amino (NH 2) has a certain inhibition effect on Hela cells (the IC50 value is 87.6+/-8.8 mu M), but loses the inhibition activity on the four tumor cells. The results show that: the side chain distal SH group is important for the inhibitory activity of the series of chelating agent small molecules. (3) The S atom at the near end of the TDMQ54 side chain is converted into N atom, and the obtained compound TDMQ53 has improved inhibition activity on series cell lines, which shows that the near end coordination atom has a certain modification space. (4) Inhibitory Activity of TDMQ53 on A375 (IC ₅₀ Values of 49.8.+ -. 5.3. Mu.M), TDMQ55 vs Colo829 (IC ₅₀ Values of 30.6.+ -. 1.6. Mu.M) and A549 (IC ₅₀ Values of 52.1.+ -. 2.9. Mu.M) are higher than the positive control. Notably, among the series of compounds, TDMQ53 and TDMQ55 both exhibited better safety against human normal cells, significantly superior to the positive control. Indicating that the series of compounds can improve the anti-swelling effectThe tumor activity and the improvement of safety have reconstruction potential.

It should be understood that the foregoing description of the specific embodiments is merely illustrative of the invention, and is not intended to limit the invention, and that any modifications, equivalents, improvements, etc. that fall within the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims

1. The 8-hydroxyquinoline compound is characterized by having the following structural formula:

2. The 8-hydroxyquinoline compound according to claim 1, wherein the hydrogen atom in the mercapto group or amino group is represented by one or two R ³ And (3) substitution.

3. The 8-hydroxyquinoline compound according to claim 2, wherein R ³ Is hydrogen or C1-C2 saturated alkyl.

4. The 8-hydroxyquinoline compound according to claim 1, wherein the 8-hydroxyquinoline compound has a structural formula as shown below:

5. a preparation method of the 8-hydroxyquinoline compound according to claim 1, wherein 2-methyl-8-hydroxyquinoline is used as a raw material, and the 8-hydroxyquinoline compound is obtained through C-2 site aldol addition, elimination reaction and Michael addition.

6. Use of the 8-hydroxyquinoline compounds according to any one of claims 1 to 4 for the preparation of a medicament for inhibiting tumors.

7. The use according to claim 6, wherein the tumor comprises lung cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, intestinal cancer, head and neck cancer, anal cancer, extrahepatic cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, bronchial adenoma, burkitt's lymphoma, carcinoid tumor, unknown primary cancer, central nervous system lymphoma, cervical cancer, childhood cancer, germ cell tumor, eye cancer, gastric cancer, renal cancer, laryngeal cancer, blood cancer, liver cancer, non-small cell lung cancer, melanoma, prostate cancer, rectal cancer, salivary gland cancer, sarcoma, small intestine cancer, soft tissue sarcoma, uterine sarcoma, testicular cancer or breast cancer.

8. The use according to claim 6 or 7, wherein the tumour is one or more of melanoma, lung cancer, liver cancer or cervical cancer.

9. The use according to claim 6, wherein the medicament is in the form of an injection, a tablet, a pill, a capsule, a suspension or an emulsion.

10. The use according to claim 6, wherein the medicament comprises a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate.