阅读说明：本技术 基于2-甲基-5,7-二氯-8-羟基喹啉构筑的稀土配合物及其制备方法和应用 (Rare earth complex constructed based on 2-methyl-5, 7-dichloro-8-hydroxyquinoline and preparation method and application thereof ) 是由 邹华红 梁福沛 于 2019-11-01 设计创作，主要内容包括：本发明公开了两例基于2-甲基-5,7-二氯-8-羟基喹啉构筑的稀土配合物及其制备方法和应用。这两例配合物分别为配合物1和配合物2,配合物1的分子式为[Er(ClQ)<Sub>3</Sub>(H<Sub>2</Sub>O)],配合物2的分子式为[Ho(ClQ)<Sub>3</Sub>(H<Sub>2</Sub>O)],其中ClQ为2-甲基-5,7-二氯-8-羟基喹啉脱去羟基氢原子,带一个单位负电荷。本发明所述稀土配合物的制备方法为：取2-甲基-5,7-二氯-8-羟基喹啉和硝酸铒六水合物或硝酸钬六水合物,用混合溶剂溶解,在pH＝7.7-8.2且加热条件下反应,即得。申请人的试验结果表明,这两例稀土配合物对多种肿瘤细胞具有显著抗增殖作用,且对人正常肝细胞毒性低,有望开发成抗肿瘤药物。(The invention discloses two rare earth complexes constructed based on 2-methyl-5, 7-dichloro-8-hydroxyquinoline, and a preparation method and application thereof. The two complexes are respectively complex 1 and complex 2, and the molecular formula of the complex 1 is [ Er (ClQ) 3 (H 2 O)]The molecular formula of the complex 2 is [ Ho (ClQ) 3 (H 2 O)]Wherein ClQ is 2-methyl-5, 7-dichloro-8-hydroxyquinoline without hydroxyl hydrogen atom, and has a unit negative charge. The preparation method of the rare earth complex comprises the following steps: dissolving 2-methyl-5, 7-dichloro-8-hydroxyquinoline and erbium nitrate hexahydrate or holmium nitrate hexahydrate in a mixed solvent, and reacting under the heating condition at the pH value of 7.7-8.2 to obtain the compound preparation. The test results of the applicant show that the two rare earth complexes are used for treating various tumorsThe cell has obvious antiproliferative effect and low toxicity to normal human liver cells, and is expected to be developed into antitumor drugs.)

1. The rare earth complex constructed based on 2-methyl-5, 7-dichloro-8-hydroxyquinoline is a complex 1 or a complex 2, wherein:

the molecular formula of the complex 1 is as follows: [ Er (ClQ)₃(H₂O)]Wherein ClQ is 2-methyl-5, 7-dichloro-8-hydroxyquinoline without hydroxyl hydrogen atom, and has a unit negative charge;

the complex belongs to a monoclinic system, C2/C space group, and the unit cell parameters are as follows:

the molecular formula of the complex 2 is as follows: [ Ho (ClQ)₃(H₂O)]Wherein ClQ is 2-methyl-5, 7-dichloro-8-hydroxyquinoline without hydroxyl hydrogen atom, and has a unit negative charge;

the complex belongs to a monoclinic system, C2/C space group, and the unit cell parameters are as follows:

2. a process for producing a rare earth complex as claimed in claim 1, characterized in that: dissolving 2-methyl-5, 7-dichloro-8-hydroxyquinoline and erbium nitrate hexahydrate or holmium nitrate hexahydrate in a mixed solvent, adjusting the pH of the obtained solution to be 7.7-8.2, and reacting the obtained mixed solution under the heating condition to obtain a corresponding target product; wherein the mixed solvent is a composition of ethyl acetate and water.

3. The method of claim 2, wherein: in the mixed solvent, the volume ratio of ethyl acetate to water is 3-5: 1.

4. the method of claim 2, wherein: the reaction is carried out at 60-100 ℃.

5. The method of claim 2, wherein: the pH of the solution was adjusted with triethylamine.

6. The use of the rare earth complex constructed based on 2-methyl-5, 7-dichloro-8-hydroxyquinoline and the pharmaceutically acceptable salts thereof as claimed in claim 1 in the preparation of anti-tumor drugs.

7. Use according to claim 6, characterized in that: is applied to the preparation of the medicine for treating human bladder cancer and/or human ovarian cancer and/or human cervical cancer.

8. A pharmaceutical composition comprising a therapeutically effective amount of a rare earth complex according to claim 1 or a pharmaceutically acceptable salt thereof.

Technical Field

The invention relates to a rare earth complex, in particular to a rare earth complex constructed based on 2-methyl-5, 7-dichloro-8-hydroxyquinoline, and a preparation method and application thereof.

Background

At present, tumors are the second most serious diseases of human death, and seriously endanger the physical and mental health of the nation. The malignant tumor is commonly of lung cancer, cervical cancer, breast cancer, liver cancer, lymph cancer, leukemia and other types. Clinically, platinum antineoplastic drugs are still one of the important chemotherapy drugs for treating tumors, and account for more than 50% of the application of clinical chemotherapy drugs. The main target of the medicine against cancer is double-stranded DNA, wherein the main action mechanism is to interfere double-stranded replication of DNA in tumor cells, thereby playing a role in restraining cell growth. Despite their important impact as anticancer drugs, these drugs have significant side effects, coupled with their inherent inadequate drug resistance, prompted researchers to develop new platinum and non-platinum compounds. Such a situation has led to the study of a series of complexes characterized by metal ions, of which ruthenium compounds have been the more successful example in clinical trials and thus are also the best representative of drug candidates. In constructing complexes, researchers in the field recognize that participation in the construction through the use of biologically active ligands is an effective way to achieve a synthetic multifunctional compound, such that the construction of the target product ideally results in a synergistic effect between the metal center and the ligand.

Quinoline and hydroxyquinoline are considered a special structure because these heterocycles are widely found in natural and synthetic bioactive molecules, interacting with different targets, inducing important functional changes in a variety of disease states. Chemical studies of quinoline derivatives have received particular attention in the last few years even up to now, and researchers have synthesized a variety of quinoline-carried antimalarial, antiallergic, antiviral, antiinflammatory, bactericidal, and the like. The existing experiments show that 2-methyl-5, 7-dichloro-8-hydroxyquinoline has no antiproliferative activity (IC) on various tumor cells₅₀>50uM), no report related to the construction of the complex by using 2-methyl-5, 7-dichloro-8-hydroxyquinoline as a ligand and lanthanide metals of erbium and holmium is found at present, so that the obtained complex has obvious tumor inhibition activity.

Disclosure of Invention

The invention aims to solve the technical problem of providing two rare earth complexes which have obvious inhibitory activity on various tumor cells and low toxicity on normal human liver cells and are constructed on the basis of 2-methyl-5, 7-dichloro-8-hydroxyquinoline, and a preparation method and application thereof.

The invention relates to a rare earth complex constructed based on 2-methyl-5, 7-dichloro-8-hydroxyquinoline, in particular to a complex 1 or a complex 2, wherein:

the molecular formula of the complex 1 is as follows: [ Er (ClQ)₃(H₂O)]Wherein ClQ is 2-methyl-5, 7-dichloro-8-hydroxyquinoline without hydroxyl hydrogen atom, and has a unit negative charge;

the complex belongs to a monoclinic system, C2/C space group, and the unit cell parameters are as follows:

α＝90.00°，β＝119.199(2)°，γ＝90.00°；

the molecular formula of the complex 2 is as follows: [ Ho (ClQ)₃(H₂O)]Wherein ClQ is 2-methyl-5, 7-dichloro-8-hydroxyquinoline without hydroxyl hydrogen atom, and has a unit negative charge;

the complex belongs to a monoclinic system, C2/C space group, and the unit cell parameters are as follows:

α＝90.00°，β＝119.095(2)°，γ＝90.00°。

the invention also provides a preparation method of the rare earth complex constructed based on 2-methyl-5, 7-dichloro-8-hydroxyquinoline, which comprises the following steps: dissolving 2-methyl-5, 7-dichloro-8-hydroxyquinoline and erbium nitrate hexahydrate or holmium nitrate hexahydrate in a mixed solvent, adjusting the pH of the obtained solution to be 7.7-8.2, and reacting the obtained mixed solution under the heating condition to obtain a corresponding target product; wherein the mixed solvent is a composition of ethyl acetate and water.

The 2-methyl-5, 7-dichloro-8-hydroxyquinoline involved in the above preparation method can be prepared by a method reported in the prior art (e.g., JiantongCui, Synthesis of chloroquinaldol, Zhongguo Yiyao Gongye Zazhi,39(2008), 733; or Oleg V.Larionov, Direct, catalytic, and geographic synthetic of 2-alkyl-, aryl-, and alkyl-substitated N-heterocyclic N-oxides, organic letters,16(2014),864-867), or can be synthesized by a self-designed scheme or purchased directly.

In the preparation method, the molar ratio of the 2-methyl-5, 7-dichloro-8-hydroxyquinoline to the erbium nitrate hexahydrate or the holmium nitrate hexahydrate is a stoichiometric ratio, and the erbium nitrate hexahydrate or the holmium nitrate hexahydrate can be in relative excess during actual operation.

In the above preparation method, the volume ratio of ethyl acetate to water in the mixed solvent is preferably 3-5: 1. the amount of the mixed solvent to be used may be determined as required, and it is usually preferable to dissolve the starting materials to be reacted, specifically, the total amount of the mixed solvent to be used for all the starting materials is usually 5 to 10mL based on 1mmol of 2-methyl-5, 7-dichloro-8-hydroxyquinoline. In the specific dissolving step, the rare earth nitrate (erbium nitrate hexahydrate or holmium nitrate hexahydrate) and 2-methyl-5, 7-dichloro-8-hydroxyquinoline are respectively dissolved by using mixed solvents and then mixed together for reaction, or the rare earth nitrate and the 2-methyl-5, 7-dichloro-8-hydroxyquinoline are mixed and then added with the mixed solvent for dissolving.

In the above preparation method, the pH value of the solution can be adjusted by using the conventional basic substances (such as sodium carbonate, pyridine or sodium tert-butoxide, etc.), and the pH value of the solution is preferably adjusted by using triethylamine. In the technical scheme of the invention, the pH value of the solution is preferably adjusted to 7.9-8.1.

In the above-mentioned production method, the mixed solution obtained by adjusting the pH value is usually placed in a container, sealed and then reacted under heating. The reaction is preferably carried out at 60-100 ℃, and the reaction time in the temperature range is usually controlled to be 30-80h, and can be more than 80 h; the reaction time is preferably controlled to be 60 to 80 hours. The reaction is more preferably carried out at 80 to 100 ℃. A thick-walled hard glass tube with one end closed is usually used to contain the mixed solution obtained after pH adjustment.

The invention also comprises the application of any rare earth complex constructed based on 2-methyl-5, 7-dichloro-8-hydroxyquinoline and the pharmaceutically acceptable salt thereof in preparing anti-tumor medicaments, in particular to the application in preparing medicaments for treating human bladder cancer and/or human ovarian cancer and/or human cervical cancer.

The invention further includes a pharmaceutical composition comprising a therapeutically effective amount of any of the rare earth complexes described above or a pharmaceutically acceptable salt thereof.

Compared with the prior art, the invention provides two rare earth complexes which have novel structures and are constructed based on 2-methyl-5, 7-dibromo-8-hydroxyquinoline and preparation methods thereof, and test results of the applicant show that the two rare earth complexes have obvious antiproliferative effects (the activity is obviously higher than that of cisplatin) on various tumor cells, and the two rare earth complexes have low toxicity on normal human liver cells and are expected to be developed into antitumor drugs.

Drawings

FIG. 1 is a crystal structure diagram of a final product obtained in example 1 of the present invention.

FIG. 2 is a crystal structure diagram of the final product obtained in example 4 of the present invention.

Detailed Description

The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.

The 2-methyl-5, 7-dichloro-8-hydroxyquinoline (also referred to below simply as ligand or ligand H-ClQ) referred to in the following examples was prepared according to the following synthetic route:

the preparation method comprises the following steps: 0.1mol of 2-methyl-8-hydroxyquinoline is added to 100mL of cold glacial acetic acid, and then 0.05mol (13.74g) of dichlorohydantoin is divided into two portions and added in portions (every 20min) to the glacial acetic acid solution of the substrate. After each portion was added, the reaction was continued in an ice-water bath. After 3h, the reaction was completed and the reaction solution was poured into ice water without interruptionStirring to obtain yellow precipitate. Suction filtration, washing the filter cake with ice water for three times, and drying at normal temperature to obtain yellow solid. And recrystallizing the crude product by using methanol to obtain the target product 2-methyl-5, 7-dichloro-8-hydroxyquinoline. Elemental analysis (%) (C)₁₀H₇NOCl₂) The experimental values are C, 52.83, H, 3.19 and N, 6.06; theoretical values of C,52.63, H, 3.07 and N, 6.14. IR (KBr, cm)^-1):2833(w)，2468(w)，1610(m)，1437(s)，1321(s)，1244(s)，1167(m)，946(s)，849(m)，762(m)，695(w)。