CN114940696A - Toosendanin derivative and application thereof in breast cancer treatment - Google Patents
Toosendanin derivative and application thereof in breast cancer treatment Download PDFInfo
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- CN114940696A CN114940696A CN202210574559.XA CN202210574559A CN114940696A CN 114940696 A CN114940696 A CN 114940696A CN 202210574559 A CN202210574559 A CN 202210574559A CN 114940696 A CN114940696 A CN 114940696A
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- 208000026310 Breast neoplasm Diseases 0.000 title claims abstract description 20
- 238000011282 treatment Methods 0.000 title claims description 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
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- C07J71/0005—Oxygen-containing hetero ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention provides a toosendanin glucose derivative shown in formula I, pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof:
wherein m is a natural number from 0 to 9, and n is a natural number from 0 to 8. The derivative has better anti-breast cancer activity.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a toosendanin derivative and application thereof in treatment of breast cancer.
Background
Breast cancer, one of the most common malignancies in women, has become a leading cause of female malignant tumor death worldwide, and the incidence of cancer is on the rising trend year by year. Triple-negative breast cancer (TNBC) is a special subtype of breast cancer, accounting for about 15% to 20% of breast cancer, and is negative in all of the tumor cell surface Estrogen Receptor (ER), Progesterone Receptor (PR), and human epidermal growth factor receptor 2 (HER 2). TNBC has special biological behavior and clinical pathological characteristics, high malignancy degree, strong invasiveness, easy occurrence of local relapse and distant metastasis, no use of conventional endocrine and targeted therapy due to negative hormone receptors and HER2 genes, and limited chemotherapy due to drug resistance.
Toosendanin (TSN) is a substitute of Shandao years for imported ascaris-expelling drugs, which was found by separation from cortex meliae and is rapidly becoming the main effective component of clinical ascaris-expelling drugs in China, in the research of Sichuan traditional Chinese medicines in the 50 th century. However, TSN causes hepatotoxicity, limiting its widespread clinical use. Recent studies show that TSN is also effective in inhibiting proliferation of various tumor cells, such as osteosarcoma, colorectal cancer, prostate cancer, pancreatic cancer, breast cancer, liver cancer, lung cancer, and the like.
Pharmacokinetic studies have shown that the bioavailability of TSN is less than 10% and that a large number of metabolites may be a significant cause of hepatotoxicity. It is known that hepatotoxicity caused by drugs is one of the main causes of failure in development of new drugs or withdrawal from the market after marketing, and it is statistically estimated that about 1/3 drugs are withdrawn from the market due to hepatotoxicity. Therefore, how to improve the bioavailability of TSN, reduce the hepatotoxicity of TSN, improve the selectivity of TSN in tumor tissues, and deeply clarify the anti-tumor action mechanism and the direct action target of TSN is very important for TSN to develop into a novel anti-tumor drug.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a toosendanin derivative and application thereof in breast cancer treatment, which can improve the bioavailability of toosendanin, reduce the hepatotoxicity of toosendanin and discover a better anti-tumor drug. The invention uses glucose residue to modify the structure of toosendanin, and finds that the toosendanin derivative shown in the structural formula I has better anti-tumor effect than toosendanin.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
the invention provides a toosendanin glucose derivative shown in formula I, pharmaceutically acceptable salt, hydrate, prodrug or solvate thereof:
in the formula I, m is a natural number from 0 to 9, and n is a natural number from 0 to 8.
Further, the azadirachtin glucose derivative, the pharmaceutically acceptable salt thereof, the hydrate thereof, the prodrug thereof, or the solvate thereof is characterized in that the structural formula of the azadirachtin glucose derivative is shown as a formula II:
the invention also provides application of the toosendanin glucose derivative, the pharmaceutically acceptable salt, the hydrate, the prodrug or the solvate thereof in preparing a medicament for treating breast cancer.
The invention also provides a medicine for treating breast cancer, and the active ingredient of the medicine for treating breast cancer comprises the toosendanin glucose derivative, the pharmaceutically acceptable salt, the hydrate, the prodrug or the solvate thereof.
Furthermore, the medicine for treating breast cancer can be any pharmaceutically acceptable dosage form, and the anticancer medicine also comprises a pharmaceutically acceptable carrier and/or an auxiliary agent.
The invention has the beneficial effects that:
the invention provides the toosendanin derivative with a new structure through structural modification, the toosendanin derivative has better anti-breast cancer effect, low hepatotoxicity and improved bioavailability of the toosendanin.
Drawings
Fig. 1 is a graph of tumor volume as a function of time (n-6) in the present application.
Detailed Description
The invention is further illustrated by the following specific examples, which, however, are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
The invention has been described generally and specifically with respect to materials used in the tests and experimental methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be clear to those skilled in the art that, in the following, the materials used and the methods of operation are well known in the art, unless otherwise specified.
Example 1 Synthesis of Toosendanin glucose derivative Compound 6
(1) Synthesis of Compound 2
beta-D-glucose pentaacetate (16.0g,15mmol) and 2-bromoethanol (2.1g,17mmol) were sequentially charged in a 250mL round bottom flask, dissolved in dichloromethane (100mL), and finally boron trifluoride ether (3.3g,23mmol) was added and reacted at room temperature for 3 hours. TLC showed the reaction was complete and the reaction was poured into a separatory funnel, washed sequentially with saturated aqueous sodium bicarbonate, water, saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the crude product recrystallized from ethanol to yield the white crystalline product compound 2(5.04g, 55%).
Characterization data for compound 2 are as follows:
1 H NMR(400MHz,CDCl 3 )δ5.22(t,J＝9.5Hz,1H),5.13–4.95(m,2H),4.58(d,J＝7.9Hz,1H),4.26(dd,J＝12.3,4.8Hz,1H),4.21–4.07(m,2H),3.82(m,1H),3.72(ddd,J＝10.0,4.8,2.5Hz,1H),3.47(m,2H),2.09(s,3H),2.07(s,3H),2.03(s,3H),2.01(s,3H)。 13 C NMR(100MHz,CDCl 3 )δ170.6,170.2,169.4,169.4,100.9,72.6,71.9,71.1,69.7,68.3,61.8,29.8,20.7,20.5,20.5,20.5。
(2) synthesis of Compound 3
Compound 2(1.4g,3.0mmol) was charged to a 50mL round bottom flask, dissolved in N, N-dimethylformamide (20mL), followed by sodium azide (1.0g,15.4mmol) and the reaction system at 60 deg.C
Stirred under conditions for 6 hours and TLC showed the reaction was complete. The reaction was diluted with water (50mL), poured into a separatory funnel, extracted with ethyl acetate (50mL), and the organic phase was washed with saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was recrystallized from a mixed solvent of ethyl acetate and petroleum ether to give the product compound 3(0.82g, 66%) as white crystals.
Characterization data for compound 3 are as follows:
1 H NMR(400MHz,CDCl 3 )δ5.22(t,J＝9.5Hz,1H),5.10(t,J＝9.7Hz,1H),5.03(dd,J＝9.6,8.0Hz,1H),4.60(d,J＝8.0Hz,1H),4.26(dd,J＝12.3,4.7Hz,1H),4.16(dd,J＝12.3,2.5Hz,1H),4.03(ddd,J＝10.7,4.8,3.5Hz,1H),3.78–3.63(m,2H),3.50(ddd,J＝13.4,8.3,3.5Hz,1H),3.29(ddd,J＝13.4,4.8,3.3Hz,1H),2.09(s,3H),2.05(s,3H),2.03(s,3H),2.01(s,3H。 13 C NMR(100MHz,CDCl 3 )δ170.6,170.2,169.3,169.3,100.6,72.7,71.9,71.1,68.5,68.3,61.8,50.5,20.7,20.6,20.5,20.5。
(3) synthesis of Compound 4
Methanol (10mL) was added to a 50mL round bottom flask, followed by compound 3(400mg,0.97mmol) and sodium methoxide solution (1M in MeOH), and the reaction was stirred at room temperature for 1 hour and then completed by TIC. Adding cation exchange resin (Amberlite IR-120H) + ) Stirring was continued until the pH of the system was no longer basic. Suction filtered, the filtrate was collected and concentrated to give product 4 as a pale yellow viscous liquid (204mg, 85%).
(4) Synthesis of Compound 5
1.15g (2mmol) of the compound TSN and 252mg (3mmol) of 3-butynoic acid are weighed out in 10mL of dichloromethane, 575mg of EDCI and 24mg of DMAP are added in succession, the mixture is stirred overnight at room temperature and the reaction is checked by TLC to completion. Concentration under reduced pressure and preparative plate separation (PE: EA ═ 3:1) gave 950mg of compound 5 in 74.4% yield. MS calcd for C 35 H 42 O 11 [M+H] + :638.3,found:638.5。
(5) Synthesis of Compound 6
639mg Compound 5 and 299mg Compound 4 in 10mL 1:1THF-H 2 Adding 300mg of anhydrous copper sulfate and 40 mg of anhydrous copper sulfate into the O mixed solvent in sequence0mg sodium ascorbate was stirred overnight at rt, concentrated and purified by flash column chromatography (DCM: MeOH ═ 8:1) to give crude, prep-plate separation (DCM: MeOH ═ 8:1) to give 580mg of compound 6 in 65.3% yield. MS calcd for C 35 H 42 O 11 [M+H] + :887.4,found:887.2。
Example 2 in vitro antitumor Activity
MTT method is adopted to detect the proliferation inhibition activity of toosendanin and its derivatives on various breast cancer cells and normal liver cells. The breast cancer cell is selected from MDA-MB-231, MDA-MB-435, MDA-MB-468, HCC1937 and BT20, and the normal liver cell is LO 2. The experimental procedure was as follows: cancer cells were seeded at 2000 cells/well in 96-well plates at 37 ℃ with 5% CO 2 Culturing in the environment for 24h to ensure that the cells are fully attached. Then 100 mu L of toosendanin and derivative solutions with different concentrations are respectively given (cells are cultured by using DMED containing 10% fetal calf serum and 1% streptomycin and treated by diluting a drug stock solution into different concentrations, 6 compound wells are arranged for each concentration, only an equal volume of a culture medium is added into a blank control group, after 48 hours of action, 20 mu L of 5mg/mL MTT solution is added into each well, after 3-4 hours of incubation in a cell culture box, liquid in the well plate is removed, 150 mu L of dimethyl sulfoxide (DMSO) is added into each well, oscillation is carried out on a room-temperature enzyme labeling instrument for 30s, formazan crystals are fully dissolved, the absorbance value A of each well at 570nm is detected by the enzyme labeling instrument, the experiment is repeated for 3 times, the inhibition rate of the growth of tumor cells by the toosendanin and the derivatives thereof is calculated by the following formula, and the half Inhibition Concentration (IC) of the drug is calculated by Graphpad prism 5 50 Value). The results are shown in table 1 below.
The tumor cell inhibition rate is 1- [ (experimental OD mean-blank OD mean)/(cell control OD mean-blank OD mean) ] × 100%.
TABLE 1 in vitro antitumor Activity
As can be seen from table 1, representative compounds have good proliferation inhibitory activity on a variety of TNBC cells tested, superior efficacy to TSN, and lower toxicity to normal hepatocytes LO2 than TSN. The obtained compound is shown to have good antitumor activity and selectivity.
Example 3 in vivo antitumor Activity
According to in vitro experimental data, the compound 6 is found to have the best activity on MDA-MB-231 cells, so that the MDA-MB-231 cells are selected to construct a nude mouse transplanted tumor model, and the in vivo anti-tumor activity of the compound 6 is investigated. The experimental procedure was as follows: culturing appropriate amount of MDA-MB-231 cell line, collecting well-grown cells, making into tumor cell suspension, and mixing 1 × 10 7 Inoculating the cells into subcutaneous tissue of mouse until the tumor grows to 100cm 3 On the left and right, the patients were randomly divided into a saline group, a compound 6 treatment group with different doses and a TSN control group, administered by intraperitoneal injection 1 time a day, and the change of the tumor volume with time was observed, and the results are shown in FIG. 1, in which n is 6.
As can be seen from fig. 1, the antitumor activity of compound 6 is dose-dependent. Compound 6 was administered at a dose of 1mg/kg/d with a therapeutic effect comparable to that of TSN at 2 mg/kg/d. The compound 6 with 2mg/kg/d can remarkably inhibit the growth of tumors, and the tumor inhibition rate is 83 percent.
In conclusion, the anti-breast cancer activity of the azadirachtin derivative synthesized by the method is obviously superior to that of azadirachtin.
It should be apparent to those skilled in the art that while the preferred embodiments of the present invention have been described, additional variations and modifications in these embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. It is therefore intended that the following appended claims be interpreted as including the preferred embodiment and all such alterations and modifications as fall within the scope of the invention. It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the machine equivalent technology of the claims of the present invention, it is intended that the present invention also include such modifications and variations.
Claims (4)
1. A toosendanin glucose derivative represented by formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug thereof, or a solvate thereof:
in the formula I, m is a natural number from 0 to 9, and n is a natural number from 0 to 8.
2. The toosendanin glucose derivative, its pharmaceutically acceptable salt, its hydrate, its prodrug, or its solvate according to claim 1, wherein the toosendanin glucose derivative has a structural formula shown in formula II:
3. use of the toosendanin glucose derivative, its pharmaceutically acceptable salt, its hydrate, its prodrug, or its solvate according to claim 1 or 2 for the preparation of a medicament for the treatment of breast cancer.
4. A drug for treating breast cancer, wherein the active ingredient of the drug for treating breast cancer comprises the azadirachtin glucose derivative, the pharmaceutically acceptable salt thereof, the hydrate thereof, the prodrug thereof, or the solvate thereof according to claim 1 or 2.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1476829A (en) * | 2003-07-16 | 2004-02-25 | 中国科学院上海生命科学研究院 | Application of toosendanin as anti-tumor medicine |
| CN1699400A (en) * | 2005-05-18 | 2005-11-23 | 中国科学院上海生命科学研究院 | Toosendanin derivatives and preparing process and application thereof |
| CN109692178A (en) * | 2017-10-24 | 2019-04-30 | 南京大学 | Toosendanin is preparing the application in anti-breast cancer chemotherapeutic sensitivity drug |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1476829A (en) * | 2003-07-16 | 2004-02-25 | 中国科学院上海生命科学研究院 | Application of toosendanin as anti-tumor medicine |
| CN1699400A (en) * | 2005-05-18 | 2005-11-23 | 中国科学院上海生命科学研究院 | Toosendanin derivatives and preparing process and application thereof |
| CN109692178A (en) * | 2017-10-24 | 2019-04-30 | 南京大学 | Toosendanin is preparing the application in anti-breast cancer chemotherapeutic sensitivity drug |
Non-Patent Citations (10)
| Title |
|---|
| JINGNAN ZHANG,等: "Toosendanin and isotoosendanin suppress triple-negative breast cancer growth via inducing necrosis, apoptosis and autophagy" * |
| 凌泽江: "川楝素衍生物的合成" * |
| 卓实;等: "甘草减轻川楝子肝毒性的实验研究" * |
| 徐美玲;等: "川楝树提取物对人乳腺癌细胞增殖、凋亡、迁移及细胞周期分布的影响" * |
| 李海波;等: "川楝子的化学成分、药理作用及其毒性研究进展" * |
| 王小娟;等: "川楝素抗肿瘤作用机制研究进展" * |
| 童红梅: "柠檬苦素类化合物临床作用的研究应用" * |
| 赵善欢,等: "植物性物质川楝素的研究概况" * |
| 郭育铭;等: "柠檬苦素类似物的研究进展" * |
| 陈培文,等: "川楝素抗肿瘤活性及作用机制的研究进展" * |
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