阅读说明：本技术 柔茎香茶菜甲素o-14苯甲酸酯化衍生物及其制备方法和用途 (O-14 benzoic acid esterified derivative of isodon softescens, preparation method and application thereof ) 是由 可钰 王淙 刘宏民 徐霞 胡天星 郑姿君 王妮 于 2020-06-03 设计创作，主要内容包括：本发明涉及天然产物及药物化学领域,公开柔茎香茶菜甲素O-14苯甲酸酯化衍生物类化合物及其制备方法和应用。其制备方法：以柔茎香茶菜甲素为起始原料,在不破坏其活性中心的前提下,经过与苯甲酸或取代苯甲酸发生O-14位酯化反应,得到柔茎香茶菜甲素O-14苯甲酸酯化衍生物。该类化合物具有抗癌活性和良好的稳定性,可用于制备抗肿瘤药物,应用于临床治疗食道癌、胃癌、原发性肝癌、胰腺癌、乳腺癌以及急性髓系白血病等。其具有如下通式：<Image he="100" wi="203" file="212139DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>。(The invention relates to the field of natural products and pharmaceutical chemistry, and discloses isodon malabarica O-14 benzoate derivative compounds, and a preparation method and application thereof. The preparation method comprises the following steps: the O-14 site esterification reaction is carried out on rabdosia leptandra komarovii A serving as a starting material and benzoic acid or substituted benzoic acid on the premise of not damaging the active center of the rabdosia leptandra komarovii A to obtain the O-14 benzoic acid esterified derivative of rabdosia leptandra komarovii A. The compound has anticancer activity and good activityThe stability of the compound can be used for preparing anti-tumor drugs, and is applied to clinical treatment of esophagus cancer, gastric cancer, primary liver cancer, pancreatic cancer, breast cancer, acute myeloid leukemia and the like. It has the following general formula:)

1. The O-14 benzoic acid esterified derivative of rabdosia leptandra is characterized by having a structure shown in a general formula I:

r is mono-substituted or di-substituted on a benzene ring; selected from hydrogen, linear or branched C1-C10 alkyl, linear or branched C1-C5 alkyl substituted by halogen, methoxy, trifluoromethyl, nitro, hydroxyl, amino, azido and sulfonic group.

2. The isodon softescens O-14 benzoate derivative of claim 1 wherein R is selected from the group consisting of: hydrogen, C1-C3 alkyl, straight-chain C1-C3 alkyl substituted by halogen, methoxy, trifluoromethyl.

3. The isodon softescens O-14 benzoate derivative of claim 2 wherein R is selected from the group consisting of: hydrogen, methyl, fluorine, bromine, chlorine, methoxy, trifluoromethyl, chloromethyl or bromomethyl.

4. The O-14 benzoic acid esterified derivative of isodon softescens according to claim 1, selected from the following compounds:

5. the application of the isodon softescens O-14 benzoic acid esterified derivative in the preparation of the medicine according to claim 1, which is characterized in that the isodon softsoni O-14 benzoic acid esterified derivative is used as an active ingredient to prepare the medicine for treating esophagus cancer, stomach cancer, primary liver cancer, pancreatic cancer, breast cancer or acute myeloid leukemia.

Technical Field

The invention relates to the field of natural products and pharmaceutical chemistry, in particular to a novel isodon softescens O-14 benzoate derivative compound and a preparation method and application thereof.

Background

Rabdosia rubescens, the scientific name of kohlrabi, is a plant of rabdosia of Labiatae, which was originally discovered from folk herbs in Henan Lin county in 1972, and herbs in past generations have not been recorded. The medicinal parts of the plant are stems and leaves, and contain chemical components such as monoterpene, sesquiterpene, diterpene, triterpene, volatile oil, alkaloid, amino acid, polysaccharide, flavone and steroid. The pharmacological activity data indicate that the antitumor active component in rabdosia rubescens is mainly diterpenoid compounds.

On the basis of research and summary of literature work by the inventor, the lead compound of the invention with the framework of ent-kaurene diterpene is obtained by extracting and purifying rabdosia from Jiyuan through a series of methods: isodon komarovii A (Flexiculin A). In vitro activity research shows that the lead compound has good biological activity and a wider anti-tumor spectrum.

The alpha-subunit cyclopentanone structure serving as the anti-tumor active center of the diterpenoid compound is proved to have excellent pharmacological activity, but the poor stability and the relatively mild anti-tumor activity of the compound restrict the clinical application and development of the compound. In addition, the research on the synthesis and structure-activity relationship of the derivative of rabdosia leptinotarsa A is relatively weak. Therefore, the research on the synthesis and the chemical structure modification of the derivative of the rabdosia rubescens A and the research on the structure-activity relationship of the derivative, so that a new chemical entity with more excellent chemical property and higher anti-tumor activity is further searched from the research, and the research has important theoretical significance and practical application value.

Disclosure of Invention

The invention aims to provide a series of isodon softhounsissiliforme A derivatives, and optically active bodies or racemates, diastereoisomer mixtures or pharmaceutically acceptable salts thereof, and improve the anti-tumor effect and stability of the isodon softhounsiiformis A derivatives, so that the possibility is provided for the clinical application of the isodon softhounsiiformis A derivatives.

The invention also aims to provide a preparation method and application thereof in preparing antitumor drugs.

In order to realize the purpose of the invention, the isodon leptostachyos and benzoic acid or substituted benzoate are esterified to obtain a series of derivatives, so that the stability of the derivatives is improved, and the anti-tumor activity of the derivatives is retained or enhanced.

The structural general formula of the O-14 benzoic acid esterified derivative of rabdosia leptandra provided by the invention is as follows:

wherein R is mono-or disubstituted on the benzene ring. Can be hydrogen, linear or branched C1-C10 alkyl, linear or branched C1-C5 alkyl substituted by halogen, methoxy, trifluoromethyl, nitro, hydroxyl, amino, azido, sulfonic acid group, etc.

R is preferably: hydrogen, C1-C3 alkyl, straight-chain C1-C3 alkyl substituted by halogen, methoxy, trifluoromethyl.

More preferably, R is: hydrogen,; methyl, fluoro, bromo, chloro, methoxy, trifluoromethyl, chloromethyl or bromomethyl.

Preferred R-substituted phenyl rings are described below:

the O-14 benzoic acid esterified derivative of rabdosia leptandra is prepared by the following synthetic route:

the isodon softescens (1) is used as a raw material, Dichloromethane (DCM) is used as a solvent, benzoic acid or substituted benzoic acid is respectively added under the stirring condition, then catalysts 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 4-Dimethylaminopyridine (DMAP), N, N-Diisopropylethylamine (DIPEA) are added, and a product 2 (general formula I) is obtained by column chromatography purification.

Wherein R is as defined above.

The invention has the innovation points and advantages that: the rabdosia komarovii A is used as a starting material and undergoes an O-14 site esterification reaction with benzoic acid or substituted benzoic acid on the premise of not damaging an active center of the rabdosia komarovii A to obtain a target product, and the yield is high and reaches over 45%. The compound has good anticancer activity and stability, can be used for preparing antitumor drugs, is clinically used as drugs for treating esophagus cancer, gastric cancer, primary liver cancer, pancreatic cancer, breast cancer, acute myeloid leukemia and the like, and has good development prospect.

Detailed Description

The present invention is further illustrated by the following specific examples, but it should be noted that the scope of the present invention is not limited in any way by these examples.