CN109846876B

CN109846876B - Application of lignan compound in resisting tumor and preparation of medicine thereof

Info

Publication number: CN109846876B
Application number: CN201910313578.5A
Authority: CN
Inventors: 李扬; 王琳; 夏重升
Original assignee: AFFILIATED HOSPITAL OF JINING MEDICAL UNIVERSITY
Current assignee: AFFILIATED HOSPITAL OF JINING MEDICAL UNIVERSITY
Priority date: 2019-04-18
Filing date: 2019-04-18
Publication date: 2021-05-25
Anticipated expiration: 2039-04-18
Also published as: CN109846876A

Abstract

The invention relates to application of lignan compounds in tumor resistance and preparation of medicaments thereof, and particularly provides a new pharmaceutical application of combination of dihydrosinapyl alcohol and hemlock dineolignin A. The dihydrosinapyl alcohol promotes the dissolution of the hemlock dineolignin A in water on one hand, inhibits the nausea and vomiting toxic and side effects of the hemlock dineolignin A on the other hand, has the synergistic and attenuated synergistic effect when being combined, and lays a foundation for the application of the hemlock dineolignin A in clinic.

Description

Application of lignan compound in resisting tumor and preparation of medicine thereof

Technical Field

The invention relates to an anti-tumor drug, in particular to an application of diniconazole A in combination with dihydrosinapyl alcohol in tumor resistance and a drug preparation thereof.

Background

After the middle of the 20 th century, the incidence and mortality of lung cancer has risen rapidly in developed and developing countries. Three years of review of the total causes of death in 1973-1975 and the sampling of death in malignant tumors in China in 1990-1992 show that: the death rate of lung cancer in China is improved from 7.09/10 ten thousand in the 70 th of the 20 th century to 17.54/10 ten thousand in the 90 th of the 20 th century, and is increased by 147.39% (wherein the male is increased by 158.94%, and the female is increased by 122.55%).

At present, although the existing treatment means have advanced sufficiently, the rising momentum of the treatment means cannot be suppressed. With the change of medical mode, the key point of tumor curative effect evaluation is also changed from the situation of simply pursuing local remission rate to the situation of obtaining the highest tumor remission rate on the basis of higher quality of life and longer survival time. In recent years, the traditional Chinese medicine for treating lung cancer plays a remarkable curative effect in the aspects of stabilizing focus, prolonging survival time, improving life quality and the like, is effective when used alone, can be used together with surgery, radiotherapy and chemotherapy to improve clinical curative effect and reduce toxic and side effects, and has advantages in clinical practice by applying cheap traditional Chinese medicine for treating cancer. Through the research on the action mechanism of the traditional Chinese medicine, the effective action parts and the effective components of the medicinal materials are found, so that reference is provided for the standardized application of the traditional Chinese medicine, and an idea is provided for the clinical development of new medicines.

Chinese patent CN109053641A discloses a dineolignan compound, a separation preparation method and application thereof, wherein, the dineolignan A of hemlock fir has good tumor inhibition activity in an in vitro anti-tumor activity experiment and can be used for preparing anti-tumor drugs. However, when the compound is used in vitro experiments, rats show obvious heterophily behaviors, and further experimental studies find that the hemlock dinicone A has toxic and side effects of nausea and vomiting.

Disclosure of Invention

In order to reduce the toxic and side effects of hemlock bar dineolignan A, the invention aims to provide the application of the hemlock bar dineolignan A combined with dihydrosinapyl alcohol in resisting tumors and a pharmaceutical composition thereof.

In order to achieve the purpose of the invention, the inventor combines the dihydrosinapyl alcohol with solubilization and the hemlock bar dineolignan A discovered in earlier researches, on one hand, the dissolution of the hemlock bar dineolignan A is promoted, on the other hand, the nausea and vomiting toxic and side effects of the hemlock bar dineolignan A are inhibited, thereby achieving the purposes of synergy and attenuation and tumor resistance. Specifically, the technical scheme of the invention is summarized as follows: application of diniconazole A in combination with dihydrosinapyl alcohol in preparing antitumor drugs is provided.

The tumors comprise breast cancer, esophagus cancer, stomach cancer, lung cancer, intestinal cancer, liver cancer, cervical cancer and the like, the hemlock dineolignin A (TNA) related by the invention has a chemical structural formula shown in a formula (I), and the chemical structural formula of Dihydrosinapyl alcohol (DSA) is shown in a formula (II).

Further preferably, the anti-tumor drug of the present invention is an injection. The injection comprises, by mass, 5-60% of hemlock pine dineolignan A and dihydrosinapyl alcohol: 1. still further preferably, the injection comprises the following components in a mass ratio of hemlock pine dineolignan A to dihydrosinapyl alcohol of 20-40: 1. in a most preferred embodiment of the present invention, the injection comprises 30% by mass of hemlock pine and dihydrosinapyl alcohol: 1.

in the present invention, the term "injection" refers to a general term for a dosage form for injection. The injection is further preferably injection or freeze-dried powder injection for injection.

The second purpose of the invention is to provide an anti-tumor pharmaceutical composition, which contains hemlock bar dineolignin A and dihydrosinapyl alcohol, can be an injection and can also be an oral preparation, and the oral preparation comprises tablets, capsules, granules, dropping pills and the like. The oral preparation can be prepared by adding pharmaceutically acceptable adjuvants such as filler, disintegrant, lubricant, binder, solubilizer, sustained-release matrix material, etc. into the above active ingredients by conventional preparation process in the field.

Further preferably, the active ingredients in the pharmaceutical composition consist only of hemlock dineolignan a and dihydrosinapyl alcohol. Still further preferably, the active ingredients in the pharmaceutical composition are hemlock bar dineolignin A and dihydrosinapyl alcohol according to the mass ratio of 5-60: 1. Still further preferably, the active ingredients in the pharmaceutical composition are prepared from hemlock bar dineolignin A and dihydrosinapyl alcohol according to the mass ratio of 20-40: 1. In a most preferred embodiment of the present invention, the active ingredients in the pharmaceutical composition are extracted from hemlock bar and dihydrosinapyl alcohol in a mass ratio of 30: 1.

Compared with the prior art, the invention has the following beneficial effects: the combination of the dihydrosinapyl alcohol and the hemlock pine dineolignan A promotes the dissolution of the hemlock pine dineolignan A in water on one hand, and inhibits the nausea, vomiting and toxic and side effects of the hemlock pine dineolignan A on the other hand, and the combination of the dihydrosinapyl alcohol and the hemlock pine dineolignan A has the synergistic effect of synergism and attenuation, thereby laying a foundation for the application of the hemlock pine dineolignan A in clinic.

Detailed Description

The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. It should be understood that the illustrated embodiments are exemplary only, and are not intended to limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit of the invention, and it is intended to cover all such changes and modifications as fall within the scope of the invention. In addition, the specific technical operation steps or conditions not indicated in the examples are performed according to the common techniques or conditions described in the literature in the field or according to the product specification. The reagents or instruments used are not indicated by the manufacturer, and are all conventional reagents or instrument products that are commercially available.

Test example 1

24 Wistar rats are male, are naturally illuminated for 12 hours, freely drink water and are adaptively raised, namely, the rats are simultaneously given with the normal feed and the kaolin feed after quantification, the two feeds are taken out every day at regular time, the surface of the feed is observed to have no bite mark until the rats no longer gnaw the kaolin, and then the Wistar rats are randomly divided into the following three groups: NS group, TNA-DSA group, each group of 8 rats. Fasting is carried out one day before the test, the test is started on the morning next day, the NS group is injected with 10ml/kg of physiological saline by taking the mass of the rat body as a reference, and the physiological saline is injected with 10ml/kg of physiological saline respectively after 1 hour interval; in the TNA group, 300mg/kg of hemlock pine dineolignan A is injected, and 10ml/kg of normal saline is injected after 1 hour interval; the TNA-DSA group was injected with 300mg/kg of Sequoia dinieri A, and the interval was 1 hour later with 10mg/kg of dihydrosinapyl alcohol. The injection mode is intraperitoneal injection. The iso-kaolin behavior of the rats in each group was observed within 24 hours after the administration, and the consumption of normal feed and kaolin per rat was calculated, see table 1.

The test statistics result shows that compared with a blank control, the intake of kaolin in rats in the TNA group injected with the dinicoxin A is greatly increased (P is less than 0.01), which indicates that the dinicoxin A can cause the rats to have heterophilic kaolin behavior. Compared with the TNA group, the TNA-DSA group rats injected with the hemlock dineolignin A and the dihydrosinapyl alcohol have obviously reduced intake of the kaolin (P <0.01), which indicates that the dihydrosinapyl alcohol can reduce the vomiting side effect of the hemlock dineolignin A.

Table 1: kaolin intake and food intake comparison of rats in each group

Compared with the TNA group, the method has the advantages that,^*P<0.01

test example 2

Inoculating human hepatoma cell HepG-2, human breast cancer cell MCF-7 and human lung cancer cell strain LTEP in logarithmic growth phase to a 96-well plate at a rate of 100 mu L/well, carrying out adherent growth for 24 hours, then sucking supernatant, and adding 100 mu L of liquid medicine with different concentrations into each well. Each concentration is provided with 5 multiple holes, and fetal calf serum culture medium without liquid medicine is arranged for comparison. Cancer cells were continued at 37 ℃ with 5% CO₂Culturing for 24 hr in incubator, adding 10 μ L MTT into each well, culturing for 4 hr in carbon dioxide incubator, taking out, removing supernatant, adding DMSO into 150 μ L/well, measuring absorbance at 490nm with microplate reader, and calculating IC₅₀See table 2.

Table 2: half-maximal effective inhibitory concentrations (μ M) of different test substances against tumor cells

The test statistical result shows that the hemlock dinicones A have obvious inhibition effect on human liver cancer cells HepG-2, human breast cancer cells MCF-7 and human lung cancer cell strains LTEP, and the dihydrosinapyl alcohol has no inhibition effect on three kinds of cancer cells.

Claims

1. Application of diniconazole A and dihydrosinapyl alcohol in preparing antitumor drugs is provided.

2. The use according to claim 1, wherein the anti-neoplastic agent is an injection.

3. The use of claim 2, wherein the injection comprises a mass ratio of hemlock pine and dihydrosinapyl alcohol of 5-60: 1.

4. the use of claim 2, wherein the injection comprises the following components in a mass ratio of hemlock pine and dihydrosinapyl alcohol of 20-40: 1.

5. the use of claim 2, wherein the injection comprises 30% by weight of hemlock pine and dihydrosinapyl alcohol: 1.

6. the use of claim 2, wherein the injection is an injection or a lyophilized powder for injection.

7. An anti-tumor pharmaceutical composition, comprising diniconazole A and dihydrosinapyl alcohol.

8. The anti-tumor pharmaceutical composition according to claim 7, wherein the active ingredients of the pharmaceutical composition comprise hemlock-bushy A and dihydrosinapyl alcohol.

9. The anti-tumor pharmaceutical composition according to claim 8, wherein the active ingredients in the pharmaceutical composition comprise hemlock bar-pine-dineolignan A and dihydrosinapyl alcohol in a mass ratio of 5-60: 1.

10. The anti-tumor pharmaceutical composition according to claim 9, wherein the active ingredients in the pharmaceutical composition comprise hemlock bar-pine-dineolignan a and dihydrosinapyl alcohol in a mass ratio of 20-40: 1.