阅读说明：本技术 萘醌二聚体在制备抗肿瘤转移药物中的应用 (Application of naphthoquinone dimer in preparation of anti-tumor metastasis drugs ) 是由 汪哲 谭宁华 李玲 王佳 于 2020-07-27 设计创作，主要内容包括：本发明公开了茜草属Rubia植物来源的萘醌二聚体及以其为活性成分的药物组合物在制备抗肿瘤转移药物中的应用。由于本发明所述的萘醌二聚体为天然化合物,其剂型和用药方式多样化,具有广泛的临床应用前景。(The invention discloses a naphthaquinone dimer derived from Rubia plants and application of a pharmaceutical composition taking the naphthaquinone dimer as an active ingredient in preparation of anti-tumor metastasis medicaments. The naphthoquinone dimer is a natural compound, so that the preparation form and the administration mode of the naphthoquinone dimer are diversified, and the naphthoquinone dimer has a wide clinical application prospect.)

1. The application of naphthoquinone dimer Rubioncolin C shown in the following structural formula or pharmacologically acceptable salt thereof in preparing anti-tumor metastasis medicaments,

2. the use according to claim 1, wherein the pharmacologically acceptable salt comprises a salt with the mineral acid hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, or the organic acid maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, tannic acid, or the alkali metals lithium, sodium, potassium, or the alkaline earth metals calcium, magnesium, or the basic amino acid lysine.

3. The medicine composition for resisting tumor metastasis contains effective amount of naphthoquinone dimer Rubioncolin C or its pharmacologically acceptable salt and pharmaceutically acceptable carrier,

4. the pharmaceutical composition according to claim 3, comprising 0.1 to 99.5% by weight of naphthoquinone dimer Rubioncolin C or a pharmacologically acceptable salt thereof.

5. The pharmaceutical composition according to claim 3, comprising 0.5 to 95% by weight of naphthoquinone dimer Rubioncolin C or a pharmacologically acceptable salt thereof.

6. The pharmaceutical composition of claim 3, wherein the pharmaceutical dosage form is tablet, capsule, oral liquid, injection, lyophilized injection or powder injection.

7. The pharmaceutical composition of claim 3, wherein the pharmacologically acceptable salt comprises a salt with an inorganic acid selected from the group consisting of hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, tannic acid, and lithium, sodium, potassium alkali metals, calcium, magnesium alkali earth metals, and lysine.

8. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable carrier is a pharmaceutical carrier, diluent, excipient water, filler starch or sucrose; a binder cellulose derivative, alginate, gelatin or polyvinylpyrrolidone; a humectant glycerin; disintegrating agent agar, calcium carbonate or sodium bicarbonate; an absorption enhancer quaternary ammonium compound; surfactant cetyl alcohol; adsorption carrier kaolin or soap clay; lubricants talc, calcium stearate, magnesium stearate or polyethylene glycol; further adding other adjuvant flavoring agent or sweetener.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an application of naphthoquinone dimer in preparation of an anti-tumor metastasis medicine.

Background

Tumors are new organisms formed by hyperproliferation and abnormal differentiation of body cells under the long-term action of different carcinogenic factors, and can be generally divided into benign and malignant types. The growth of either benign or malignant tumors is not under the normal physiological control of the body and continues to grow spontaneously after stimulation ceases. Malignant tumor has strong invasive ability, is easy to relapse and transfer to remote organs, and the final death of most tumor patients is caused by the metastasis of the malignant tumor. Therefore, the research of anti-tumor metastasis drugs has become an important direction for the development of new drugs in this century.

Tumor metastasis is a complex process involving multiple organs, steps, and stages. "tumor metastasis" was originally proposed in 1829 and is a hallmark of malignancy. The primary tumor cells acquire the potential of metastasis to become invasive cancer cells, invade surrounding normal tissues or tumor newly-built vasculature singly or in clusters, and the circulating tumor cells enter capillaries of remote organs along with blood circulation, extravasate through blood vessel walls to enter matrixes, and finally generate metastatic colonies to form obvious colonization. Tumor metastasis is mainly carried out in four ways, 1) the tumor metastasis directly diffuses from a primary part, invades and destroys surrounding tissues and forms a new tumor focus; 2) invade lymph vessels, metastasize and spread among lymph nodes at all levels, forming metastases; 3) enter into blood vessels of human body, flow with blood, and are transported to various parts of the body to form secondary tumor in other organs; 4) invasion into body cavity or hollow organs results in the formation of transplanted metastatic cancer. Most cancer patients die from metastatic cancer rather than primary cancer. Statistically, the metastasis rate of malignant tumor patients reaches 60% in the initial diagnosis, and 90% of clinical tumor patients die due to tumor metastasis. At present, although some anti-tumor metastasis medicaments such as avastin, onddegree and the like are clinically applied, the treatment efficiency is low due to the problems of high toxic and side effects, easy generation of drug resistance and the like. Therefore, the development of the anti-tumor metastasis medicament with less toxic and side effects and better curative effect has extremely important practical significance.

The naphthoquinone dimer Rubioncolin C is obtained by separating root and rhizome of plants of Rubia such as Rubia petiolata (Rubia podathha) and Rubia harorum (Rubia ocotricha). Researches show that the Rubioncolin C has an inhibiting effect on the growth of various tumor cells, IC₅₀The value is between 1.14 and 9.93 mu M, and can induce the apoptosis and autophagic death of a colon cancer cell HCT116 and a liver cancer cell HepG2, and simultaneously play an in-vitro and in-vivo anti-tumor role by inhibiting Akt/mTOR/P70S6K and NF-kappa B signal pathways.

Disclosure of Invention

The purpose of the invention is as follows: aiming at the prior art, the invention provides a new application of naphthoquinone dimer in preparing anti-tumor metastasis medicaments.

The technical scheme is as follows: the structural formula of the naphthoquinone dimer Rubioncolin C is shown as follows:

the invention discloses application of naphthoquinone dimer Rubioncolin C or pharmacologically acceptable salt thereof in preparing anti-tumor metastasis medicaments.

The invention also discloses a pharmaceutical composition for resisting tumor metastasis, which contains therapeutically effective amount of naphthoquinone dimer Rubioncolin C shown in the structural formula or pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier.

Further, the pharmaceutical composition preferably contains the naphthoquinone dimer or a pharmacologically acceptable salt thereof in an amount of 0.1 to 99.5% by weight, and most preferably contains the naphthoquinone dimer or a pharmacologically acceptable salt thereof as an active ingredient in an amount of 0.5 to 95% by weight.

The pharmacologically acceptable salts described herein include salts with the inorganic acids hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, or the organic acids maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, tannic acid, or the alkali metals lithium, sodium, potassium, or the alkaline earth metals calcium, magnesium, or the basic amino acids lysine.

The pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the pharmaceutical field, diluent, excipient water, filler starch or sucrose; a binder cellulose derivative, alginate, gelatin or polyvinylpyrrolidone; a humectant glycerin; disintegrating agent agar, calcium carbonate or sodium bicarbonate; an absorption enhancer quaternary ammonium compound; surfactant cetyl alcohol; adsorption carrier kaolin or soap clay; lubricants talc, calcium stearate, magnesium stearate or polyethylene glycol; further adding other adjuvant flavoring agent or sweetener.

The administration amount of the drug of the present invention may vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated, etc., and the daily dose thereof may be 0.01 to 40mg/kg body weight, preferably 0.1 to 20mg/kg body weight, and may be administered once or more. The pharmaceutical composition can be tablets, capsules, oral liquid, injection, freeze-dried injection or powder injection and the like. The naphthoquinone dimer can be extracted and separated from madder such as madder, madder and the like, and the preparation of pharmaceutical dosage forms such as tablets, capsules, oral liquid, injection, freeze-dried injection or powder injection and the like is conventional knowledge in the field. Therefore, various pharmaceutical dosage forms prepared from the above naphthoquinone dimer and a corresponding carrier can also be realized by those skilled in the art.

The compounds of the present invention may be administered in the form of compositions by oral, nasal, rectal or parenteral administration to a patient in need of such treatment. For oral administration, it can be made into conventional solid preparations such as tablet, powder, granule, capsule, etc., liquid preparations such as aqueous or oil suspension, or other liquid preparations such as syrup, elixir, etc.; for parenteral administration, it can be formulated into solution for injection, aqueous or oily suspension, etc. Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional production methods in the pharmaceutical field. For example, the active ingredient may be combined with one or more carriers and then formulated into the desired dosage form.

Has the advantages that: the invention utilizes human breast cancer cells MDA-MB-231 to evaluate the in vitro anti-tumor metastasis activity of the Rubioncolin C, and utilizes mouse breast cancer cell strain 4T1-Luc to evaluate the in vivo anti-tumor metastasis activity of the Rubioncolin C. The result shows that the Rubioncolin C can obviously inhibit the tumor metastasis in vivo and in vitro, and can be used for preparing the anti-tumor metastasis medicament. The invention firstly shows that the naphthoquinone dimer Rubioncolin C is a tumor metastasis inhibitor and can effectively exert the in-vivo and in-vitro anti-tumor metastasis activity, so that the Rubioncolin C can be used for preparing anti-tumor metastasis medicaments. The naphthoquinone dimer is a natural compound, so that the preparation form and the administration mode of the naphthoquinone dimer are diversified, and the naphthoquinone dimer has a wide clinical application prospect.

Drawings

FIG. 1 is a test of the in vitro anti-tumor metastasis activity of naphthoquinone dimer of the present invention;

FIG. 2 is a test of the in vivo anti-tumor metastasis activity of naphthoquinone dimer of the present invention.

Detailed Description

The present invention will be described in detail with reference to specific examples.

The equipment, materials and reagents used in the present embodiment can be purchased and obtained from the market, except for special instructions.

The preparation method of naphthoquinone dimer Rubioncolin C described in the present invention can be referred to Wang, Z., et al, rubipodanones A-D, naphthoquinone dimers from the roots and rhizomorph Rubia podantha phytochemistry,2018,145, 153-.