阅读说明：本技术 樟脑基缩氨基硫脲类化合物的制备及其抗肿瘤活性 (Preparation of camphor thiosemicarbazone compound and antitumor activity thereof ) 是由 王石发 张燕 徐徐 王忠龙 谷文 杨益琴 徐海军 匡红波 周新成 于 2018-05-30 设计创作，主要内容包括：本发明公开了樟脑基缩氨基硫脲类化合物及其制备方法和抗肿瘤活性研究。本发明利用樟脑为原料,在碱性催化条件下,分别与不同的芳香醛进行羟醛缩合反应得到系列α,β-不饱和酮,再经浓盐酸催化,与硫代氨基脲缩合得到系列樟脑基缩氨基硫脲类化合物,并对所有目标产物进行了抗肿瘤活性的研究。实验表明,樟脑基缩氨基硫脲类化合物对人多发性骨髓瘤细胞(RPMI-8226)、人乳腺癌细胞(MDA-MB-231)和人非小细胞肺癌细胞(A549)具有较好的抑制活性,且对正常细胞人胃粘膜细胞(GES-1)毒性较小,因此具有潜在的抗肿瘤应用价值。(The invention discloses camphor thiosemicarbazone compounds, a preparation method thereof and antitumor activity research. According to the invention, camphor is used as a raw material, and is subjected to aldol condensation reaction with different aromatic aldehydes under the alkaline catalysis condition to obtain a series of alpha, beta-unsaturated ketones, and is subjected to concentrated hydrochloric acid catalysis and condensation with thiosemicarbazide to obtain a series of camphor-based thiosemicarbazone compounds, and research on anti-tumor activity of all target products is carried out. Experiments show that the camphor thiosemicarbazone compound has good inhibitory activity on human multiple myeloma cells (RPMI-8226), human breast cancer cells (MDA-MB-231) and human non-small cell lung cancer cells (A549), and has low toxicity on normal cell human gastric mucosal cells (GES-1), so that the camphor thiosemicarbazone compound has potential anti-tumor application value.)

1. The camphor thiosemicarbazone compound is characterized in that the structural general formula of the compound is as follows:

in the formula: r is respectively 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-bromophenyl, 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 2-pyridyl, 4-dimethylaminophenyl, phenyl, 2, 4-dichlorophenyl, 2, 3, 4-trimethoxyphenyl, 4-anthracenylphenyl, 2-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl and 3-methoxy-4-hydroxyphenyl.

2. A process for the preparation of the camphorthiosemicarbazone compound of claim 1 comprising the process steps of:

(1) Camphor is used as a starting material, potassium tert-butoxide is used as a catalyst, and the camphor and different aromatic aldehydes are subjected to aldol condensation reaction to obtain a 3-arylmethylene camphor compound;

(2) The condensation reaction of the 3-arylmethylene camphor compound and the thiosemicarbazide is carried out under the catalysis of concentrated hydrochloric acid to obtain the camphor thiosemicarbazone compound.

3. The method for preparing 3-arylmethylidene camphor compounds according to claim 2, wherein the step (1) comprises the following steps:

1) sequentially adding camphor (8mmol), tert-butyl alcohol (35mL) and potassium tert-butoxide (8-16 mmol) into a 50mL three-neck flask provided with a magnetic stirrer, a thermometer and a reflux condenser tube, and starting the stirrer;

2) Adding aromatic aldehyde (10mmol) after the camphor and the potassium tert-butoxide are dissolved, heating and refluxing for reaction for several hours until the conversion rate of the camphor reaches more than 95 percent (GC tracking detection);

3) After the reaction is finished, concentrating the reaction liquid to remove tert-butyl alcohol, adding ethyl acetate, washing the reaction liquid with distilled water and saturated saline water respectively to be neutral, drying the reaction liquid with anhydrous Na ₂ SO ₄, and filtering and concentrating the reaction liquid to obtain a crude product of the 3-arylmethylidene camphor compound;

4) recrystallizing the crude product with methanol to obtain the 3-arylmethylidene camphor compound.

4. the method for preparing camphor thiosemicarbazone according to claim 2, characterized in that in the step (2), the specific synthetic steps are as follows:

1) adding thiosemicarbazide (2mmol) and ethanol (35mL) in sequence into a 50mL three-neck flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, and starting stirring to dissolve the thiosemicarbazide;

2) adding 3-arylmethylidene camphor (2mmol), heating to 90 ℃, dropwise adding 3 drops of concentrated hydrochloric acid, continuously refluxing for reaction for several hours, and tracking and detecting by adopting TLC;

3) After the reaction is finished, concentrating the reaction liquid to remove ethanol to obtain a crude thiosemicarbazone compound product;

4) And purifying the crude product by column chromatography to obtain the camphor thiosemicarbazone compound.

5. the camphor thiosemicarbazone compound according to claim 1 has good inhibitory activity on human multiple myeloma cells (RPMI-8226), human breast cancer cells (MDA-MB-231) and human non-small cell lung cancer cells (A549), and can be used as a potential antitumor compound.

Technical Field

The invention belongs to the technical field of organic synthesis and pharmaceutical synthesis, and relates to preparation and antitumor activity of camphor thiosemicarbazone compounds.

Background

Tumors are the most serious diseases harming human health, and because tumor cells are easy to migrate, have high propagation speed and are easy to mutate, the morbidity and mortality of cancers are always high. The most common means for treating cancer is chemotherapy, but the toxic and side effects of chemotherapy are large, and many auxiliary anticancer drugs have limitation in clinical application due to the large toxicity, so that efforts are still needed to develop some anticancer drugs with low toxicity and high efficiency. Due to the diversity of natural product structures and wide physiological activity, obtaining anti-tumor drugs from natural products becomes a popular field for developing anti-tumor drugs at home and abroad. The camphor is a natural product with high yield in China, and the camphor and the derivatives thereof are widely applied in the field of medicines besides the application in the aspect of chiral catalysis.

the thiosemicarbazone is Schiff base obtained by condensing thiosemicarbazone and aldehyde or ketone, the compound contains N, S heteroatom and C ═ N active group, and when the left side is connected with different chemical structures or groups, the compound has wide biological activity, such as antibacterial, antiviral, insect-resistant and anti-tumor activity, therefore, the thiosemicarbazone fragment is connected into low-toxicity natural products, and the compound has the prospect of developing anti-tumor drugs.

disclosure of Invention

the purpose of the invention is as follows: aiming at the defects in the prior art, the invention aims to search for thiosemicarbazone compounds which are prepared from natural product camphor serving as a raw material, have potential anti-tumor activity and low toxicity. The invention also aims to provide a preparation method of the camphor thiosemicarbazone compound. The invention also aims to provide an application of the camphor thiosemicarbazone compound.

The technical scheme is as follows:

The camphor thiosemicarbazone compound has a structural general formula as follows:

in the formula: r is respectively 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-bromophenyl, 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 2-pyridyl, 4-dimethylaminophenyl, phenyl, 2, 4-dichlorophenyl, 2, 3, 4-trimethoxyphenyl, 4-anthracenylphenyl, 2-hydroxy-3-methoxyphenyl, 2-hydroxy-4-methoxyphenyl and 3-methoxy-4-hydroxyphenyl.

the preparation method of the camphor thiosemicarbazone compound comprises the following process steps:

(1) Camphor is used as a starting material, potassium tert-butoxide is used as a catalyst, and the camphor and different aromatic aldehydes are subjected to aldol condensation reaction to obtain a 3-arylmethylene camphor compound;

(2) The condensation reaction of the 3-arylmethylene camphor compound and the thiosemicarbazide is carried out under the catalysis of concentrated hydrochloric acid to obtain the camphor thiosemicarbazone compound.

The preparation method of the 3-arylmethylene camphor compound is characterized in that in the step (1), the specific synthetic steps are as follows:

1) Sequentially adding camphor (8mmol), tert-butyl alcohol (35mL) and potassium tert-butoxide (8-16 mmol) into a 50mL three-neck flask provided with a magnetic stirrer, a thermometer and a reflux condenser tube, and starting the stirrer;

2) Adding aromatic aldehyde (10mmol) after the camphor and the potassium tert-butoxide are dissolved, heating and refluxing for reaction for several hours until the conversion rate of the camphor reaches more than 95 percent (GC tracking detection);

3) After the reaction is finished, concentrating the reaction liquid to remove tert-butyl alcohol, adding ethyl acetate, washing the reaction liquid with distilled water and saturated saline water respectively to be neutral, drying the reaction liquid with anhydrous Na ₂ SO ₄, and filtering and concentrating the reaction liquid to obtain a crude product of the 3-arylmethylidene camphor compound;

4) Recrystallizing the crude product with methanol to obtain the 3-arylmethylidene camphor compound.

The preparation method of the camphor thiosemicarbazone compound is characterized in that in the step (2), the specific synthetic steps are as follows:

1) Adding thiosemicarbazide (2mmol) and ethanol (35mL) in sequence into a 50mL three-neck flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, and starting stirring to dissolve the thiosemicarbazide;

2) adding 3-arylmethylidene camphor (2mmol), heating to 90 ℃, dropwise adding 3 drops of concentrated hydrochloric acid, continuously refluxing for reaction for several hours, and tracking and detecting by adopting TLC;

3) After the reaction is finished, concentrating the reaction liquid to remove ethanol to obtain a crude thiosemicarbazone compound product;

4) And purifying the crude product by column chromatography to obtain the camphor thiosemicarbazone compound.

The camphor thiosemicarbazone compound has good inhibitory activity on human multiple myeloma cells (RPMI-8226), human breast cancer cells (MDA-MB-231) and human non-small cell lung cancer cells (A549), and can be used as an anti-tumor compound with potential.

The invention has the advantages that:

(1) The camphor raw material is cheap and easy to obtain, the source is rich, the preparation process of the product camphor thiosemicarbazone compound is simple, and the industrial production is facilitated;

(2) Compared with positive control etoposide, the camphor thiosemicarbazone compound has equivalent activity but lower toxicity than etoposide.

Detailed Description

The present invention will be further described with reference to the following specific examples.