CN113164503B

CN113164503B - Use of 3β -O-Glc-DM and 20S-O-Glc-DM for treating lung or colorectal cancer

Info

Publication number: CN113164503B
Application number: CN201980075637.8A
Authority: CN
Inventors: 杨金玲; 朱平; 李燕; 陈天娇; 顾安頔; 杜倩倩
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2018-09-29
Filing date: 2019-09-29
Publication date: 2023-09-22
Anticipated expiration: 2039-09-29
Also published as: CN113164503A; CN110960540A; CN110960540B; WO2020063960A1

Abstract

The invention relates to application of non-natural ginsenoside in preparing medicines for resisting lung cancer or colorectal cancer. The 3 beta-O-D-glucopyranosyl-dammar-24-ene-3 beta, 20S-diol or 20S-O-D-glucopyranosyl-dammar-24-ene-3 beta, 20S-diol provided by the invention can effectively treat lung cancer or colorectal cancer.

Description

Use of 3β -O-Glc-DM and 20S-O-Glc-DM for treating lung or colorectal cancer

Technical Field

The invention relates to an application of non-natural ginsenoside 3 beta-O-Glc-DM or 20S-O-Glc-DM in preparing an anti-lung cancer or colorectal cancer medicament, belonging to the technical field of medicaments.

Background

The number of lung cancer patients worldwide in 2012 is up to 180 ten thousand, 160 ten thousand of which die. This makes lung cancer the most common cause of cancer-related death in men and the second most common cause of death in women after breast cancer. The etiology of lung cancer is not completely clear so far, and a large amount of data indicate that a great deal of smoking for a long time has a very close relationship with the occurrence of lung cancer.

Lung cancer can be classified into two types, small cell lung cancer and/or non-small cell lung cancer (approximately 80%). At present, chemotherapy is still one of the main means for treating lung cancer, but the effective rate of the lung cancer is low whether the lung cancer is advanced lung cancer or metastatic lung cancer.

Colorectal cancer is the leading cause of mortality in the second most prevalent cancer, and the third most common cancer worldwide. At present, the pathogenesis of colorectal cancer is not completely defined, and is mainly related to environmental factors and genetic factors. It resulted in 10% of all tumor deaths. In recent years, the incidence of colorectal cancer has been remarkably increased with changes in lifestyle and eating habits of people.

Metastasis refers to the continued growth of colorectal cancer tumor cells from the primary site into lymphatic vessels, blood vessels, or other pathways carried to other sites, forming a tumor of the same type as the primary site tumor, the tumor formed being referred to as a metastasis or metastatic carcinoma. Metastasis is a characteristic of exacerbation of colorectal cancer.

Distant metastasis from colorectal cancer is mainly liver, with preoperative or postoperative liver metastasis occurring in about 50% of patients. About 30% of patients have a pre-operatively undetectable B-ultrasonic or CT-based yin-latent liver metastasis. But only a small fraction (10% -20%) is suitable for surgical resection, and 70% of them recur after surgery. Therefore, many patients have to receive adjuvant chemotherapy. In the past three decades, 5-fluorouracil (5-FU) and 5-fluorouracil-based chemotherapy have been the primary methods of adjuvant therapy for colorectal cancer, effectively improving the therapeutic efficacy of colorectal cancer and reducing tumor recurrence. However, in recent years, the resistance of 5-fluorouracil has become more and more common during the course of treatment, which is an important factor in the failure of colorectal cancer treatment. At the same time, only 26% of patients respond to 5-fluorouracil and 5-fluorouracil/folinic acid (LV) treatment. Many patients do not respond or respond only a little to this approach. Some new drugs such as irinotecan (irinotecan) or oxaliplatin (oxaliplatin) increase the response rate of colorectal cancer treatment compared to 5-fluorouracil, but the desired therapeutic effect is not yet achieved.

On the other hand, modern medical research proves that the ginseng has remarkable effects in resisting tumor, aging, oxidization, regulating immunity, enhancing memory function and the like besides nourishing and strengthening body. Pharmacological studies have shown that the main active ingredient of ginseng is ginsenoside (ginsenoside). Ginsenoside belongs to triterpene compounds, and is an important secondary metabolite of Panax plant (such as Ginseng radix, notoginseng radix or radix Panacis Quinquefolii). According to the basic skeleton of aglycone, ginsenoside can be divided into two types: one is dammarane type tetracyclic triterpene saponins; the other is oleanane type pentacyclic triterpene saponin. Dammarane type saponins account for the majority of ginsenoside and are the main active components. Dammarane-type saponins include panaxadiol-type saponins and panaxatriol-type saponins. Heretofore, dammarane-type saponins isolated from plants of genus Panax have been up to 110.

A limited number of aglycone skeletons are used as parent nucleus structures to produce various ginsenosides, and glycosylation plays an extremely important role. The natural ginsenoside obtained by separation of ginseng contains 1-5 unequal glycosyl groups. Among dammarane-type saponins, protopanaxadiol-type saponins are mainly glycosylated at the hydroxyl groups at the C3 position and the C20 position, and the types of glycosyl are glucose, arabinose and xylose; the protopanaxatriol saponin is mainly glycosylated at the hydroxyl groups at the C6 position and the C20 position, and the types of the glycosyl are glucose, rhamnose and xylose.

The glycosyl modification not only ensures that the ginsenoside has rich species, but also has important influence on the biological activity of the ginsenoside in the aspects of glycosyl species, connection number, connection position and the like. Many ginsenosides produce very different pharmacological effects with only small differences in glycosyl modification. Taking ginsenoside Rh2 and Rb1 as examples, rh2 mainly shows anti-tumor effect, including various pharmacological activities such as anti-liver cancer, breast cancer, colon cancer, esophagus cancer and lung cancer, rb1 mainly plays a role in promoting growth of nerve cells, and from the structural aspect, rh2 is only connected with a glucose group on a hydroxyl group at a C3 position, and Rb1 is connected with a disaccharide chain consisting of two glucose groups on hydroxyl groups at the C3 position and the C20 position. Also acting on the central nervous system, rb1 and Rg1 have slightly different pharmacological activities and mechanisms of action due to different glycosyl modifications. Rb1 stimulates neurotransmitter release by activating the cAMP-dependent protein kinase pathway, while Rg1 produces the same effect through the protein kinase-II dependent signaling pathway. Furthermore, rb1 has a much weaker effect than Rg1, and even in some cases can have an inhibitory effect on the central nervous system.

The ginsenoside Rg3 is connected with a disaccharide chain consisting of two glucoses at the C3 position, has the activities of inhibiting tumor growth, resisting tumor metastasis, enhancing immunity and the like, and is used as a clinical combined medicament for treating various tumor diseases including non-small cell lung cancer, liver cancer, cervical cancer and the like. The Compound K is connected with a glucosyl group at the C20 position, has excellent anti-tumor, anti-allergic, anti-inflammatory, anti-diabetes, neuroprotection and other effects, and has the characteristics of multiple targets, high activity and low toxicity of biological activity, so that the Compound K has higher production value and wide application prospect.

In addition, chinese patent application CN103849672a also discloses ginsenoside 3β -O-D-glucopyranosyl-dama-24-ene-3β,20S-diol (3β -O-D-glucopyranosyl-dammar-24-ene-3β,20S-diol, abbreviated as 3β -O-Glc-DM). However, no pharmacological activity of 3β -O-Glc-DM has been reported.

Disclosure of Invention

The invention solves the technical problem of providing application of compounds I and II and pharmaceutically acceptable salts thereof in preparing medicines for resisting lung cancer or colorectal cancer.

In order to solve the technical problems of the invention, the invention provides the following technical scheme:

the first aspect of the technical scheme of the invention provides the application of the compound I and pharmaceutically acceptable salts thereof in preparing medicaments for preventing or treating lung cancer,

the chemical name of the compound I is 3β -O-D-glucopyranosyl-dammar-24-ene-3β,20S-diol (3β -O-D-glucopyranosyl-dammar-24-ene-3β,20S-diol, which is abbreviated as 3β -O-Glc-DM).

The lung cancer includes small cell lung cancer and/or non-small cell lung cancer.

The lung cancer includes advanced lung cancer and/or metastatic lung cancer.

The first aspect of the technical proposal of the invention also provides the application of the compound II and the pharmaceutically acceptable salt thereof in preparing medicaments for preventing or treating lung cancer,

the chemical name of the compound II is 20S-O-D-glucopyranosyl-dammar-24-ene-3β,20S-diol (20S-O-D-glucopyranosyl-dammar-24-ene-3β,20S-diol, abbreviated as 20S-O-Glc-DM).

The lung cancer includes advanced lung cancer and/or metastatic lung cancer.

The first aspect of the technical scheme of the invention also provides application of the pharmaceutical composition in preparing a medicine for preventing or treating lung cancer, and the pharmaceutical composition is characterized by comprising a compound I and pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier.

The lung cancer includes advanced lung cancer and/or metastatic lung cancer.

The dosage forms of the pharmaceutical composition comprise tablets, capsules, powder, granules, dripping pills, paste and powder.

The first aspect of the technical scheme of the invention also provides application of the pharmaceutical composition in preparing a medicine for preventing or treating lung cancer, and the pharmaceutical composition is characterized by comprising a compound II and pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier.

The lung cancer includes advanced lung cancer and/or metastatic lung cancer.

In a second aspect, the invention provides application of the compound I or II and pharmaceutically acceptable salts thereof in preparing medicines for preventing or treating colorectal cancer.

The colorectal cancer comprises advanced colorectal cancer and/or metastatic colorectal cancer.

The second aspect of the technical scheme of the invention also provides application of a pharmaceutical composition in preparing a medicament for preventing or treating colorectal cancer, which is characterized in that the pharmaceutical composition comprises a compound I or II, pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier.

The compounds, compositions, and methods described herein can be administered to a subject suffering from or diagnosed with lung cancer. A variety of means for administering compound I or II described herein to a subject are known to those of skill in the art. Such methods may include, but are not limited to: oral administration, parenteral administration, intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, airway administration (aerosol), pulmonary administration, dermal administration, topical administration, injection administration, or intratumoral administration. Administration may be local or systemic. In some embodiments, the preferred mode is oral administration.

The compounds, compositions, and methods described herein can be administered to a subject suffering from or diagnosed with colorectal cancer. A variety of means for administering compound I or II described herein to a subject are known to those of skill in the art. Such methods may include, but are not limited to: oral administration, parenteral administration, intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, airway administration (aerosol), pulmonary administration, dermal administration, topical administration, injection administration, or intratumoral administration. Administration may be local or systemic. In some embodiments, the preferred mode is oral administration.

In some embodiments, compound I or II, or a pharmaceutically acceptable salt thereof, is administered alone to a patient as the sole active ingredient.

In some embodiments, the second agent and/or treatment may be further administered to the subject prior to, after, or concurrently with the administration of compound I or II, or a pharmaceutically acceptable salt thereof, e.g., as part of a combination treatment. The second agent and/or treatment may include a chemotherapeutic agent and/or radiation therapy, and/or surgery.

As used herein, "chemotherapeutic agent" refers to a substance that reduces or decreases the growth, survival and/or metastasis of cancer cells. Chemotherapeutic agents may include toxins, small molecules, and/or polypeptides. Non-limiting examples of the second agent and/or treatment may include: radiation therapy; a surgical operation; taxane antitumor agents, vinblastine antitumor agents, platinum complexes and/or pyrimidine antagonists.

In some embodiments of the invention, taxane antineoplastic agents include, but are not limited to, paclitaxel and docetaxel; vinblastine antineoplastic agents include, but are not limited to, vinblastine, vincristine, vindesine, and vinorelbine; platinum complexes include, but are not limited to, miplatin, cisplatin, carboplatin, nedaplatin, and oxaliplatin; pyrimidine antagonists include, but are not limited to, cytarabine, ancitabine, capecitabine, gemcitabine, fluorouracil, bififluracine, doxifluridine, tegafur, and carmofur.

In addition, the method of treatment may further comprise the use of radiation or radiotherapy. In addition, the method of treatment may further comprise using a surgical treatment.

In certain embodiments, an effective dose of compound I or II, or a pharmaceutically acceptable salt thereof, described herein may be administered to a patient at one time. In certain embodiments, an effective dose of compound I or II, or a pharmaceutically acceptable salt thereof, may be repeatedly administered to a patient. For systemic administration, a therapeutically effective amount of compound I or II, or a pharmaceutically acceptable salt thereof, may be administered to a patient, including from 0.1mg/kg to 50mg/kg, such as 0.1mg/kg, 0.5mg/kg, 1.0mg/kg, 2.0mg/kg, 2.5mg/kg, 5mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 40mg/kg, 50mg/kg or more.

In some embodiments, treatment may be administered on a less frequent basis after the initial treatment regimen. For example, after three months of treatment every two weeks, the treatment may be repeated once a month to six months or one year or more. Treatment according to the methods described herein may reduce the level of a marker or symptom of a disorder, e.g., by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more.

The amount of compound I or II, or a pharmaceutically acceptable salt thereof, administered may be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.

The dosage of compound I or II, or a pharmaceutically acceptable salt thereof, described herein can be determined by a clinician and adjusted as necessary to accommodate the observed therapeutic effect. With respect to treatment duration and frequency of treatment, the subject is typically monitored by a skilled clinician to determine when treatment provides a therapeutic effect, and to determine whether to increase or decrease the dosage, increase or decrease the frequency of administration, discontinue treatment, resume treatment, or make other changes to the treatment regimen. Dosing schedules can vary from weekly to daily, depending on a number of clinical factors, such as the sensitivity of the subject to the component. The desired dose or amount of active may be administered at a time or divided into sub-doses, e.g., 2-4 sub-doses, and administered over a period of time (e.g., at appropriate time intervals throughout the day or other appropriate schedule). In some embodiments, administration may be chronic, such as one or more administrations and/or treatments per day over a period of weeks or months. Examples of dosing and/or treatment schedules are given once a day, twice a day, three times a day, four times a day or more over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months or 6 months or more. The composition may be administered over a period of time, for example, within 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 25 minutes.

In some embodiments of the present invention, there is provided a pharmaceutical composition for treating advanced lung cancer and/or metastatic lung cancer comprising compound I or II, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the invention, there is provided a pharmaceutical composition for the treatment of advanced colorectal cancer and/or metastatic colorectal cancer comprising compound I or II, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the invention, the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, drops, pastes, powders, and the like, preferably tablets and capsules. Wherein the tablet can be common tablet, dispersible tablet, effervescent tablet, sustained release tablet, controlled release tablet or enteric-coated tablet, and the capsule can be common capsule, sustained release capsule, controlled release capsule or enteric-coated capsule. The oral formulations may be prepared by conventional methods using pharmaceutically acceptable carriers well known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like. Fillers include starch, lactose, mannitol, microcrystalline cellulose, and the like; the absorbent comprises calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, and the like; the binder comprises hypromellose, povidone, microcrystalline cellulose, etc.; the disintegrating agent comprises croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose and the like; the lubricant comprises magnesium stearate, talcum powder, polyethylene glycol, sodium dodecyl sulfate, micro silica gel, talcum powder and the like. The pharmaceutical excipients also comprise coloring agents, sweeteners, etc.

In some embodiments, the pharmaceutical composition is a solid formulation suitable for oral administration. The composition may be in the form of a tablet or capsule. In a particular embodiment, the pharmaceutical composition is a capsule. In a particular embodiment of the invention, the pharmaceutically acceptable carrier of the oral solid formulation comprises mannitol, microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate.

In some embodiments, a pharmaceutical composition formulated in unit dosage form for treating lung cancer is provided. In some embodiments, the pharmaceutical composition in unit dosage form contains 2 mg to 20mg of compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains 5mg to 20mg of compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains 8 mg to 20mg of compound I or a pharmaceutically acceptable salt thereof, preferably 10mg to 16 mg of compound I or a pharmaceutically acceptable salt thereof, more preferably 10mg to 14 mg of compound I or II, or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition in unit dosage form contains 10mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition in unit dosage form contains 12 mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition in unit dosage form contains 14 mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition in unit dosage form contains 16 mg of compound I or a pharmaceutically acceptable salt thereof. For example, for a tablet or capsule, "pharmaceutical composition in unit dosage form" means each tablet or each capsule.

In some embodiments, a pharmaceutical composition formulated in unit dosage form for treating colorectal cancer is provided. In some embodiments, the pharmaceutical composition in unit dosage form contains 2 mg to 20mg of compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains 5mg to 20mg of compound I or II, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains 8 mg to 20mg of compound I or a pharmaceutically acceptable salt thereof, preferably 10mg to 16 mg of compound I or a pharmaceutically acceptable salt thereof, more preferably 10mg to 14 mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition in unit dosage form contains 10mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition in unit dosage form contains 12 mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition in unit dosage form contains 14 mg of compound I or a pharmaceutically acceptable salt thereof. In a particular embodiment, the pharmaceutical composition in unit dosage form contains 16 mg of compound I or a pharmaceutically acceptable salt thereof. For example, for a tablet or capsule, "pharmaceutical composition in unit dosage form" means each tablet or each capsule.

"pharmaceutically acceptable carrier" meansIt is used to prepare pharmaceutical compositions that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and that include it as acceptable for human pharmaceutical use. Pharmaceutically acceptable carriers and diluents include saline, aqueous buffer solutions, solvents, and/or dispersion vehicles. The use of such carriers and diluents is well known in the art. Some non-limiting examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) Lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc; (8) excipients, such as cocoa butter and thrombus waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol (PEG); (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) a pH buffer solution; (21) polyesters, polycarbonates and/or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids; (23) Serum components such as serum albumin, high density lipoprotein and low density lipoprotein; (24) C (C) ₂ -C ₁₂ Alcohols, such as ethanol; and (25) other non-toxic compatible substances for use in pharmaceutical formulations. Wetting agents, colorants, mold release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives and antioxidants may also be present in the formulation. Terms such as "excipient," "carrier," "pharmaceutically acceptable carrier," and the like are used interchangeably herein.

"pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and the like.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a human being for treating a disease, is sufficient to effect treatment of the disease.

"treatment" means any administration of a therapeutically effective amount of a compound and includes:

(1) Inhibiting the disease in a human experiencing or exhibiting the pathology or symptomology of the disease (i.e., arresting further development of the pathology and/or symptomology), or

(2) Improving the disease in a human experiencing or exhibiting the pathology or symptomology of the disease (i.e., reversing the pathology and/or symptomology).

"late" includes "locally advanced".

Beneficial technical effects

The invention relates to application of non-natural ginsenoside in preparing an anti-lung cancer medicament. The 3 beta-O-D-glucopyranosyl-dammar-24-ene-3 beta, 20S-diol or 20S-O-D-glucopyranosyl-dammar-24-ene-3 beta, 20S-diol provided by the invention can effectively treat lung cancer.

The invention relates to application of non-natural ginsenoside in preparing anti-colorectal cancer drugs. The 3 beta-O-D-glucopyranosyl-dammar-24-ene-3 beta, 20S-diol or 20S-O-D-glucopyranosyl-dammar-24-ene-3 beta, 20S-diol provided by the invention can effectively treat colorectal cancer.

Detailed Description

Example 13 preparation of beta-O-D-glucopyranosyl-dama-24-en-3 beta, 20S-diol (Compound I)

Reference is made to the process in CN103849672a to prepare 3β -O-D-glucopyranosyl-dammar-24-en-3β, 20S-diol.

EXAMPLE 2 preparation of 20S-O-D-glucopyranosyl-dammar-24-en-3 beta, 20S-diol (Compound II)

Reference is made to the process in CN103849672a to prepare 20S-O-D-glucopyranosyl-dammar-24-en-3 beta, 20S-diol.

Example 3 3 beta-O-Glc-DM in vitro anti-lung cancer Activity assay

Determination of lung cancer cell viability by MTT method: compoundK and Rg3 (purity > 98%, purchased from Nanjing spring and autumn bioengineering Co.) were used as positive controls. Cancer cell lines include human non-small cell lung cancer cell lines NCI-H1650, NCI-H1975, A549. Cells in logarithmic growth phase are digested with pancreatin to prepare single cell suspension with certain concentration, and the single cell suspension is inoculated into 96 well plates at 1500-3000 times per well according to the difference of cell growth speed, and 100 μl of cell suspension is added into each well. The next day fresh medium containing different concentrations of drug and corresponding solvent controls was added, 100 μl (DMSO final concentration < 0.1%) per well, 3-7 dose groups of test compound I were set, and three parallel wells were set per group. At 37 ℃,5% CO ₂ The culture was continued for 120 hours, and the supernatant was discarded, and 50. Mu.L of freshly prepared serum-free medium containing 2.0mg/mL MTT (Sigma Chemical) was added to each well. Continuously culturing for 4h, discarding supernatant, adding 150 μl DMSO into each well to dissolve MTT first hairpin precipitate, mixing uniformly by micro-oscillator oscillation, measuring Optical Density (OD) with enzyme-labeled instrument (Bio-Rad, USA) at detection wavelength of 570nm, using tumor cells treated by solvent contrast as contrast group, calculating inhibition rate of drug on tumor cells according to the following formula, and calculating IC according to the intermediate equation ₅₀ ：

The results are shown in Table 1.

TABLE 13 inhibition of growth of lung cancer cell lines by beta-O-Glc-DM

Example 43 evaluation of anti-lung cancer Activity in beta-O-Glc-DM in vivo

The mouse Lewis lung cancer model is prepared from C57BL/C mice (male, 6-8 weeks old) purchased from experimental animal center of Chinese medicine biological product verification in Beijing city, which are fed in SPF-class animal houses, 5-6 mice per cage, and fed and managed by professional personnel. The animal room has enough illumination, good ventilation and air conditioning equipment, the room temperature is 18-25 ℃, and the relative humidity is 50-70%. In the experiment, well-grown tumor tissue was taken, sheared and ground, and diluted into tumor cell suspension (5×10) with sterile physiological saline ⁷ Per ml), each mouse was inoculated with 0.2ml of tumor fluid on the axilla back. Animals were randomly grouped the next day after inoculation, weighed, and dosing was started.

Using Rg3 and Compound K as controls, the experimental animals were divided into 12 groups of 6 mice each using a mouse Lewis lung cancer model. Solvent control group (20% peg400, gastric lavage); paclitaxel 15.0mg/kg single dose group (once every 3 days, intraperitoneal injection); three dose groups (20% PEG400 in, once daily for 11 days) of Rg3, 10.0mg/kg, compound K, 10.0mg/kg, 3. Beta. -O-Glc-DM, 5.0mg/kg, 10.0mg/kg, 20.0 mg/kg; paclitaxel 15.0mg/kg was administered in combination with Rg3 (10.0 mg/kg), compound K (10.0 mg/kg), or 3β -O-Glc-DM (5.0 mg/kg, 10.0mg/kg, and 20.0 mg/kg), respectively. The administration time interval of the paclitaxel and ginsenoside combination group is 6h. At the end of the experiment, animals were sacrificed, weighed, tumor tissues were peeled off and weighed. Tumor inhibition (%), body weight, tumor reuse mean ± standard deviation were calculated from weightT-test between each dosing group and negative control group was shown and performed.

The activity of the non-natural ginsenoside 3 beta-O-Glc-DM against lung cancer is evaluated. Explored the growth inhibition effect of the non-natural ginsenoside 3 beta-O-Glc-DM on mouse Lewis lung cancer by single use and combined use with taxol. The results are shown in Table 2, wherein the ginsenoside 3 beta-O-Glc-DM alone has a growth inhibition rate of 41.40% on Lewis lung cancer of mice, and the activity is stronger than that of Rg3 (15.00%) and Compound K (14.49%); when 3β -O-Glc-DM was used in combination with paclitaxel, the inhibition rate reached 70.20%, which was significantly improved compared to paclitaxel alone (51.54%), and the activity was stronger than that of the positive control Rg3 in combination with paclitaxel (57.58%) and the Compound K in combination with paclitaxel (55.77%).

TABLE 23 growth inhibition of Lewis lung carcinoma in mice by β -O-Glc-DM alone and in combination with paclitaxel

* P < 0.01, p < 0.001, compared to the solvent control group; Δp < 0.05, compared to paclitaxel alone.

Example 5 3 beta-O-Glc-DM in vitro anti-colorectal cancer Activity assay

Determination of colorectal cancer cell viability by MTT method: compoundK and Rg3 (purity > 98%, purchased from Nanjing spring and autumn bioengineering Co.) were used as positive controls. Cancer cell lines include colorectal cancer cell lines HCT15, HCT116 and SW48. Cells in logarithmic growth phase are digested with pancreatin to prepare single cell suspension with certain concentration, and the single cell suspension is inoculated into 96 well plates at 1500-3000 times per well according to the difference of cell growth speed, and 100 μl of cell suspension is added into each well. The next day fresh medium containing different concentrations of drug and corresponding solvent controls was added, 100 μl (DMSO final concentration < 0.1%) per well, 3-7 dose groups of test compound I were set, and three parallel wells were set per group. At 37 ℃,5% CO ₂ Culture was continued for 120h and the supernatant was discarded, and 50. Mu.L of freshly prepared MTT (Sigma Chemica) containing 2.0mg/mL was added to each welll) serum-free medium. Continuously culturing for 4h, discarding supernatant, adding 150 μl DMSO into each well to dissolve MTT first hairpin precipitate, mixing uniformly by micro-oscillator oscillation, measuring Optical Density (OD) with enzyme-labeled instrument (Bio-Rad, USA) at detection wavelength of 570nm, using tumor cells treated by solvent contrast as contrast group, calculating inhibition rate of drug on tumor cells according to the following formula, and calculating IC according to the intermediate equation ₅₀ ：

The results are shown in Table 3.

Table 3 3 inhibition of growth of colorectal cancer cell lines by beta-O-Glc-DM

Example 63 evaluation of anti-colon cancer Activity in beta-O-Glc-DM in vivo

The model of the colon cancer C26 of the mice is selected from BALB/C mice (male, 6-8 weeks old) purchased from experimental animal centers of Chinese medicine biological products verification in Beijing city, the mice are fed into SPF-class animal houses, 5-6 animals are fed and managed by professionals per cage. The animal room has enough illumination, good ventilation and air conditioning equipment, the room temperature is 18-25 ℃, and the relative humidity is 50-70%. In the experiment, well-grown tumor tissue was taken, sheared and ground, and diluted into tumor cell suspension (5×10) with sterile physiological saline ⁷ Per ml), each mouse was inoculated with 0.2ml of tumor fluid on the axilla back. Animals were randomly grouped the next day after inoculation, weighed, and dosing was started.

The experiments were divided into 12 groups. Solvent control group (20% peg400, gastric lavage); 30.0mg/kg 5-Fu (once every 3 days, intraperitoneal injection); 10.0mg/kg Rg3 and 10.0mg/kg Compound K (as positive control), and 5.0mg/kg, 10.0mg/kg and 20.0mg/kg 3. Beta. -O-Glc-DM (in 20% PEG400, administered once daily by gastric lavage for 8 consecutive days); 30.0mg/kg of 5-Fu in combination with 10.0mg/kg of Rg3, 10.0mg/kg of Compound K or 5.0mg/kg, 10.0mg/kg, 20.0mg/kg of 3β -O-Glc-DM. Administration of 5-FU in combination with ginsenosideThe time interval is 6h. At the end of the experiment, animals were sacrificed, weighed, tumor tissues were peeled off and weighed. Tumor inhibition (%), body weight, tumor reuse mean ± standard deviation were calculated from weightT-test between each dosing group and negative control group was shown and performed.

The results are shown in Table 4, 3. Beta. -O-Glc-DM has a significant inhibitory effect on the growth of C26 colon carcinoma xenograft tumors. The inhibition of tumor weight was 36.90% in the 10mg/kg dose group with 3β -O-Glc-DM alone, which was significantly higher than in the 10mg/kg Rg3 group (13.36%) and the 10mg/kg Compound K group (2.91%). Furthermore, 3β -O-Glc-DM significantly increased tumor inhibition when treated in combination with 5-FU. The inhibition of 5mg/kg 3. Beta. -O-Glc-DM in combination with 30mg/kg 5-FU was 74.47%, which is much higher than that of the 5-FU (30 mg/kg) alone (41.14%). The combination of 3β -O-Glc-DM with 5-FU was also superior to the combination of 10mg/kg Rg3 with 30mg/kg 5-FU (47.09%) and the combination of 10mg/kg Compound K with 30mg/kg 5-FU (51.59%). Thus, the effect of 3β -O-Glc-DM, whether administered alone or in combination with 5-FU, was superior to that of Compound K and Rg3, consistent with the results of in vitro pharmacological tests. Especially 3β -O-Glc-DM shows a stronger anti-colon cancer activity in combination with 5-FU in therapy even at concentrations below Rg 3. These findings indicate that 3β -O-Glc-DM can be a candidate compound for anti-colon cancer drugs.

TABLE 4 Effect of 3 beta-O-Glc-DM alone and in combination with 5-FU in a C26 colon cancer xenograft model

* p < 0.05, < p < 0.01, < p < 0.001, compared to the solvent control; Δp is less than 0.05, ΔΔΔΔΔp in the range of less than 0.001, compared with 5-FU.

Example 7 detection of 20S-O-Glc-DM in vitro anti-lung cancer Activity

Determination of lung cancer cell viability by MTT method: compoundK and Rg3 (purity > 98%, purchased from Nanjing spring and autumn bioengineering Co.) were used as positive controls. The lung cancer cell lines comprise human non-small cell lung cancer cell strains NCI-H1650, NCI-H1975 and A549. Cells in logarithmic growth phase are digested with pancreatin to prepare single cell suspension with certain concentration, and the single cell suspension is inoculated into 96 well plates at 1500-3000 times per well according to the difference of cell growth speed, and 100 μl of cell suspension is added into each well. The next day fresh medium containing different concentrations of drug and corresponding solvent controls was added, 100 μl (DMSO final concentration < 0.1%) per well, 3-7 dose groups of test compound I were set, and three parallel wells were set per group. At 37 ℃,5% CO ₂ The culture was continued for 120 hours, and the supernatant was discarded, and 50. Mu.L of freshly prepared serum-free medium containing 2.0mg/mL MTT (Sigma Chemical) was added to each well. Continuously culturing for 4h, discarding supernatant, adding 150 μl DMSO into each well to dissolve MTT first hairpin precipitate, mixing uniformly by micro-oscillator oscillation, measuring Optical Density (OD) with enzyme-labeled instrument (Bio-Rad, USA) at detection wavelength of 570nm, using tumor cells treated by solvent contrast as contrast group, calculating inhibition rate of drug on tumor cells according to the following formula, and calculating IC according to the intermediate equation ₅₀ ：

The results are shown in Table 5.

TABLE 5 growth inhibition of 20S-O-Glc-DM on lung cancer cell lines

EXAMPLE 8 evaluation of 20S-O-Glc-DM in vivo anti-lung cancer Activity

The mouse Lewis lung cancer model is selected from C57BL/C mice (male, 6-8 weeks old) purchased from experimental animal center of Chinese medicine biological product verification in Beijing city, and the mice are fed into SPF-class animal house with 5-room per cage6, are fed and managed by professionals. The animal room has enough illumination, good ventilation and air conditioning equipment, the room temperature is 18-25 ℃, and the relative humidity is 50-70%. In the experiment, well-grown tumor tissue was taken, sheared and ground, and diluted into tumor cell suspension (5×10) with sterile physiological saline ⁷ Per ml), each mouse was inoculated with 0.2ml of tumor fluid on the axilla back. Animals were randomly grouped the next day after inoculation, weighed, and dosing was started.

Using Rg3 and Compound K as controls, the experimental animals were divided into 12 groups of 6 mice each using a mouse Lewis lung cancer model. Solvent control group (20% peg400, gastric lavage); paclitaxel 15.0mg/kg single dose group (once every 3 days, intraperitoneal injection); three dose groups (20% PEG400 in, once daily for 11 days) of Rg3 10.0mg/kg, compound K10.0 mg/kg, 20S-O-Glc-DM 5.0mg/kg, 10.0mg/kg, 20.0 mg/kg; paclitaxel 15.0mg/kg was administered in combination with Rg3 (10.0 mg/kg), compound K (10.0 mg/kg), or 20S-O-Glc-DM (5.0 mg/kg, 10.0mg/kg, and 20.0 mg/kg), respectively. The administration time interval of the paclitaxel and ginsenoside combination group is 6h. At the end of the experiment, animals were sacrificed, weighed, tumor tissues were peeled off and weighed. Tumor inhibition (%), body weight, tumor reuse mean ± standard deviation were calculated from weightT-test between each dosing group and negative control group was shown and performed.

The antitumor activity of the unnatural ginsenoside 20S-O-Glc-DM was evaluated. Explored the growth inhibition effect of the non-natural ginsenoside 20S-O-Glc-DM on the Lewis lung cancer of mice by singly using and combining with taxol. As shown in Table 6, the ginsenoside 20S-O-Glc-DM alone has a growth inhibition rate of 43.42% on Lewis lung cancer of mice, and the activity of the ginsenoside is stronger than that of Rg3 (15.00%) and Compound K (14.49%); when 20S-O-Glc-DM is combined with taxol, the inhibition rate reaches 63.93 percent, compared with the taxol which is singly used (51.54 percent), the inhibition rate is obviously improved, and the activity is stronger than that of a positive control Rg3 and taxol combined group (57.58 percent) and a Compound K and taxol combined group (55.77 percent).

TABLE 6 growth inhibition of Lewis lung carcinoma in mice by 20S-O-Glc-DM alone and in combination with paclitaxel

* P < 0.01, p < 0.001, compared to the solvent control group.

Example 9 detection of 20S-O-Glc-DM in vitro anti-colorectal cancer Activity

Determination of colorectal cancer cell viability by MTT method: compoundK and Rg3 (purity > 98%, purchased from Nanjing spring and autumn bioengineering Co.) were used as positive controls. Cancer cell lines include colorectal cancer cell lines HCT15, HCT116 and SW48. Cells in logarithmic growth phase are digested with pancreatin to prepare single cell suspension with certain concentration, and the single cell suspension is inoculated into 96 well plates at 1500-3000 times per well according to the difference of cell growth speed, and 100 μl of cell suspension is added into each well. The next day fresh medium containing different concentrations of drug and corresponding solvent controls was added, 100 μl (DMSO final concentration < 0.1%) per well, 3-7 dose groups of test compound I were set, and three parallel wells were set per group. At 37 ℃,5% CO ₂ The culture was continued for 120 hours, and the supernatant was discarded, and 50. Mu.L of freshly prepared serum-free medium containing 2.0mg/mL MTT (Sigma Chemical) was added to each well. Continuously culturing for 4h, discarding supernatant, adding 150 μl DMSO into each well to dissolve MTT first hairpin precipitate, mixing uniformly by micro-oscillator oscillation, measuring Optical Density (OD) with enzyme-labeled instrument (Bio-Rad, USA) at detection wavelength of 570nm, using tumor cells treated by solvent contrast as contrast group, calculating inhibition rate of drug on tumor cells according to the following formula, and calculating IC according to the intermediate equation ₅₀ ：

The results are shown in Table 7.

TABLE 7 growth inhibition of colorectal cancer cell lines by 20S-O-Glc-DM

EXAMPLE 10 evaluation of 20S-O-Glc-DM in vivo anti-colon cancer Activity

The experiments were divided into 12 groups. Solvent control group (20% peg400, gastric lavage); 30.0mg/kg 5-Fu (once every 3 days, intraperitoneal injection); 10.0mg/kg Rg3 and 10.0mg/kg Compound K (as positive control), and 5.0mg/kg, 10.0mg/kg and 20.0mg/kg 20S-O-Glc-DM (in 20% PEG400, administered once daily by gavage for 8 consecutive days); 30.0mg/kg of 5-Fu in combination with 10.0mg/kg of Rg3, 10.0mg/kg of Compound K or 5.0mg/kg, 10.0mg/kg, 20.0mg/kg of 20S-O-Glc-DM. The administration time interval of the 5-FU and ginsenoside combination is 6h. At the end of the experiment, animals were sacrificed, weighed, tumor tissues were peeled off and weighed. Tumor inhibition (%), body weight, tumor reuse mean ± standard deviation were calculated from weightT-test between each dosing group and negative control group was shown and performed.

The results are shown in Table 8. 20S-O-Glc-DM has an inhibitory effect on the growth of C26 colon carcinoma xenograft tumors. The inhibition of tumor weight was 14.02% in the dose group with 10mg/kg of 20S-O-Glc-DM alone, which was higher than in the 10mg/kg Rg3 treated group (13.36%) and the 10mg/kg Compound K treated group (2.91%). Furthermore, 20S-O-Glc-DM significantly increased tumor suppression when treated in combination with 5-FU. The inhibition rate of 20mg/kg of 20S-O-Glc-DM in combination with 30mg/kg of 5-FU was 60.58%, which is much higher than that of the 5-FU alone (30 mg/kg) dose group (41.14%). The combined effect of 20S-O-Glc-DM with 5-FU was also superior to that of the combination of 10mg/kg Rg3 with 30mg/kg 5-FU (47.09%), and that of 10mg/kg Compound K with 30mg/kg 5-FU (inhibition of 51.59%). Thus, 20S-O-Glc-DM is better than Compound K and Rg3, both alone and in combination with 5-FU, consistent with the results of in vitro primary pharmacological tests. These findings indicate that 20S-O-Glc-DM is a candidate compound for an anti-colon cancer drug.

TABLE 8 Effect of 20S-O-Glc-DM alone and in combination with 5-FU in a C26 colon cancer xenograft model

* P < 0.01, p < 0.001, compared to solvent control; Δp < 0.05, compared to 5-FU.

The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.

In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.

Moreover, any combination of the various embodiments of the invention can be made without departing from the spirit of the invention, which should also be considered as disclosed herein.

Claims

1. The application of the compound II or the pharmaceutically acceptable salt thereof in preparing medicaments for preventing or treating lung cancer, wherein the lung cancer is non-small cell lung cancer,

2. the use according to claim 1, wherein the lung cancer comprises advanced lung cancer and/or metastatic lung cancer.

3. The application of a pharmaceutical composition in preparing a medicament for preventing or treating lung cancer is characterized in that the pharmaceutical composition comprises a compound II or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient, wherein the lung cancer is non-small cell lung cancer,

4. the use according to claim 3, wherein the lung cancer comprises advanced lung cancer and/or metastatic lung cancer.

5. The use according to claim 3 or 4, wherein the dosage form of the pharmaceutical composition comprises tablets, capsules, powders, granules, dripping pills, pastes and powders.