阅读说明：本技术 一种莪术醇衍生物在制备治疗结直肠癌药物中的应用 (Application of curcumenol derivative in preparation of medicine for treating colorectal cancer ) 是由 张兴贤 孟祥伟 聂添情 应宇晨 于 2019-09-20 设计创作，主要内容包括：本发明属于天然药物及药物化学领域,具体公开了一种如下式所示的莪术醇衍生物在制备治疗结直肠癌药物中的应用,其对人结直肠癌细胞株Sw620、HCT116、CaCo2具有显著抑制活性,在制备抗结肠癌药物领域具有巨大的应用前景。上述莪术醇衍生物是以天然产物莪术醇为原料,经结构改造制得得到。另外,该类化合物制备方法简便、易于操作、原料易得且生产成本较低,适于工业化生产应用。<Image he="277" wi="324" file="DDA0002209683160000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the field of natural medicines and medicinal chemistry, and particularly discloses application of a curcumenol derivative shown as the following formula in preparation of a medicine for treating colorectal cancer, wherein the curcumenol derivative has significant inhibitory activity on human colorectal cancer cell strains Sw620, HCT116 and CaCo2, and has a huge application prospect in the field of preparation of anti-colorectal cancer medicines. The curcumenol derivativesIs prepared by taking natural product curcumenol as raw material and modifying the structure. In addition, the compound has the advantages of simple preparation method, easy operation, easily obtained raw materials and lower production cost, and is suitable for industrial production and application.)

1. The application of curcumenol derivatives in preparing medicaments for treating colorectal cancer is characterized in that the curcumenol derivatives have the following structure shown as the following formula (I):

in the formula I, W is selected from dimethylamino, diethylamino, di-n-butylamino, Wherein R is¹Is selected from C₁-C₆Alkyl radical, R²、R³、R⁴Independently selected from hydrogen, C₁-C₆Alkyl, aryl ester group, alkyl ester group, aryl sulfonyl or alkyl sulfonyl, and n is an integer of 1-5.

2. The use of claim 1, wherein R is²、R³、R⁴Independently selected from hydrogen, C₁-C₆Alkyl, phenyl or C₁-C₆Alkyl ester group.

3. The use of claim 1, wherein R is¹Is selected from C₁-C₄Alkyl, said R²、R³、R⁴Independently selected from hydrogen, C₁-C₄Alkyl, phenyl or C₁-C₄Alkyl ester group.

4. The use according to claim 1, wherein the curcumenol derivative has any one of the following formulae (a-01) to (a-15):

5. a drug for treating colorectal cancer, which comprises an effective amount of the curcumenol derivative according to claims 1 to 4.

6. The drug according to claim 5, wherein the drug has the effect of inhibiting the activity of human colorectal cancer cell lines Sw620, HCT116 and CaCo 2.

Technical Field

The invention belongs to the field of natural medicines and medicinal chemistry, and particularly relates to application of a curcumenol derivative, in particular to application of the curcumenol derivative in preparation of a medicine for treating colorectal cancer.

Background

Colorectal cancer (carcinoma of colon and recatum) is a common malignancy in the gastrointestinal tract, second only to gastric, esophageal and primary liver cancers in digestive malignancies. Along with the improvement of the urban modernization degree, the improvement of the living standard of people, the change of the living style and the dietary structure, the increase of the high-calorie, high-fat and high-protein food intake of chicken, duck, fish and meat and the aging process of population, the problem of high colorectal tumor incidence becomes more and more prominent, and the method is worthy of attracting attention.

From the current clinical treatment situation, the incidence rate of colorectal cancer in cities is 2-3, the colorectal cancer rate in the age group below 40 years accounts for about 20% of the total colorectal cancer population, and the colorectal cancer tends to further increase, so that the colorectal cancer is expected to replace lung cancer and become the new king of cancer. Therefore, the search for highly effective and low-toxicity drugs for treating colon cancer is becoming more and more urgent.

The traditional Chinese medicine has rich traditional Chinese medicine resources, in recent years, researchers carry out a large amount of screening on traditional Chinese medicines with tumor activity, and the traditional Chinese medicines have various action mechanisms of regulating the immunity of an organism, inhibiting tumor microangiogenesis, directly killing tumor cells, inducing tumor cell apoptosis, inducing tumor cell differentiation, reversing multiple drug resistance of cancer cells, regulating cell signal conduction, inhibiting telomerase activity and the like, and the traditional Chinese medicines have the characteristics that western medicines such as multiple target spots, multiple links and the like are difficult to have, have wide pharmacological effects, are often integrally regulated, improve the disease resistance of the organism, and achieve the anti-tumor effect through various mechanisms. With the continuous and deep experiment and clinical research on the anti-tumor effect of traditional Chinese medicines, the anti-tumor effect of traditional Chinese medicines is more and more accepted by the international society.

Curcumenol (Curcumol) is an important component of traditional Chinese medicine zedoary volatile oil, and is separated from various plants, and the plants are mostly distributed in southeast Asia, China, Indonesian, India, Peru and the like. Curcumenol (curcumenol), which is called curcumenol and curcumenol, structurally belongs to a guaiane sesquiterpenoids natural product, and is formed by fusing five-membered rings and seven-membered rings, wherein the seven-membered rings form a new five-membered ring and a new six-membered ring through an oxygen bridge of a hemiketal, so that the tension of the three rings is reduced, and a stable compound with a certain rigid structure is formed. According to the reports of documents, the curcumenol has wide biological activities of resisting virus, inflammation, tumor, early pregnancy and the like, and particularly shows potential anticancer activity in the aspect of resisting tumor, such as lung cancer, breast cancer, nasopharyngeal carcinoma, liver cancer, colorectal cancer, ovarian cancer and the like. (see literature Wei W, AzharRasul A S, Sarfraz I, et al. Curcumol: From Plant Roots to Cancer Roots [ J ]. International journal of biological sciences,2019,15(8):1600.)

However, due to the unique chemical structure of the curcumenol, the water solubility is low, the anti-tumor activity is not outstanding, and a great optimization and improvement space exists.

Disclosure of Invention

The invention aims to provide an application of curcumenol derivatives in preparation of drugs for treating colorectal cancer, and the curcumenol derivatives have good inhibition effects on human colorectal cancer cell strains Sw620, HCT116 and CaCo2 under effective doses.

The technical scheme adopted by the invention is as follows:

an application of curcumenol derivatives in preparing drugs for treating colorectal cancer is disclosed, wherein the curcumenol derivatives have the structure shown as the following formula (I):

in the formula I, W is selected from dimethylamino, diethylamino, di-n-butylamino, Wherein R is¹Is selected from C₁-C₆Alkyl radical, R²、R³、R⁴Independently selected from hydrogen, C₁-C₆Alkyl, aryl ester group, alkyl ester group, aryl sulfonyl or alkyl sulfonyl, and n is an integer of 1-5.

Preferably, R is²、R³、R⁴Independently selected from hydrogen, C₁-C₆Alkyl, phenyl or C₁-C₆Alkyl ester group.

Further preferably, R is¹Is selected from C₁-C₄Alkyl, said R²、R³、R⁴Independently selected from hydrogen, C₁-C₄Alkyl, phenyl or C₁-C₄Alkyl ester group.

The above-mentioned "C₁-C₆Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms," C₁-C₄Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms; "C₁-C₆An alkyl ester group "is-COO-alkyl (alkyl is as defined above).

More preferably, the curcumenol derivative has any one of the following formulas (A-01) to (A-15):

on the other hand, the invention also discloses a medicine for treating colorectal cancer, which comprises the curcumenol derivative with effective dose.

The medicine has the function of inhibiting the activity of human colorectal cancer cell strains Sw620, HCT116 and CaCo 2.

In addition, the invention also provides a synthesis method of the curcumenol derivative shown as the formula I, and the specific synthetic route is as follows:

the synthesis method comprises the following steps:

(1) dissolving a compound shown in a formula (II) in an organic solvent A, adding an alkali A, dropwise adding chloroacetyl chloride at a temperature of-5-0 ℃, reacting at a temperature of 0-50 ℃ for 1-6 h after dropwise adding, adding water after the reaction is finished, extracting with ethyl acetate, combining organic phases, washing the organic phases with a saturated sodium chloride solution, concentrating, and performing column chromatography separation and purification to obtain a compound shown in a formula (III);

(2) dissolving the curcuma zedoary in an organic solvent B, adding the compound of the formula (III) under the action of alkali B, reacting for 1-10 h at 30-100 ℃, adding water for quenching after the reaction is finished, extracting with ethyl acetate, concentrating, and performing column chromatography separation to obtain the compound of the formula (I).

Step (one) is as follows:

the organic solvent A is selected from one of the following: tetrahydrofuran, 2-tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane, toluene, acetonitrile or 1, 4-dioxane, preferably tetrahydrofuran or dichloromethane. The dosage of the organic solvent A is 10-50 mL/g based on the mass of the compound of the formula (II).

The base A is selected from organic base or inorganic base, wherein the organic base is selected from triethylamine, tributylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine or 2, 6-dimethylpyridine; the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide or potassium hydroxide.

Preferably, the reaction temperature is 15-25 ℃, and the reaction time is 0.5-2 h.

The amount ratio of the compound of formula (II), chloroacetyl chloride and alkali is 1: 1-2: 1 to 3, preferably 1:1 to 1.2: 1 to 1.5.

(II) in the step (2):

the organic solvent B is toluene, tetrahydrofuran, 2-tetrahydrofuran or 1, 4-dioxane. The dosage of the organic solvent B is 10-50 mL/g calculated by the mass of the curcumenol.

The alkali B is sodium hydride, sodium methoxide, sodium ethoxide, pyridine, potassium tert-butoxide, sodium hydroxide or lithium hydroxide.

Preferably, the reaction temperature is 70-80 ℃, and the reaction time is 5-8 h.

The weight ratio of the curcumenol to the alkali to the feeding substance of the compound shown in the formula (III) is 1: 2-5: 1-3, preferably 1: 2.5-3: 1.5 to 2.

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

(1) the invention obtains a plurality of curcumenol derivatives by modifying the structure of 8-hydroxyl of curcumenol, and in vitro cell experiments show that the curcumenol derivatives show good biological activity to colon cancer cells SW620, HCT116 and Caco2, can be used for preventing or/and treating colorectal cancer, and have great application prospect in the field of medicine.

(2) The synthesis method of the curcumenol derivative disclosed by the invention is simple and convenient, mild in reaction condition, easy to operate, easy in raw material obtaining in the synthesis process, low in production cost and suitable for industrial production and application.

Drawings

FIG. 1 is a nuclear magnetic spectrum of Compound A-09 obtained in example 8;

FIG. 2 is a nuclear magnetic spectrum of Compound A-14 obtained in example 12;

FIG. 3 is a nuclear magnetic spectrum of Compound A-15 obtained in example 13.

Detailed description of the invention

The examples and preparations provided below further illustrate and exemplify the present compounds, and it should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.