WO2022142160A1 - Icetexane型松香烷二萜在制备结直肠癌治疗药物中的应用 - Google Patents
Icetexane型松香烷二萜在制备结直肠癌治疗药物中的应用 Download PDFInfo
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- WO2022142160A1 WO2022142160A1 PCT/CN2021/099949 CN2021099949W WO2022142160A1 WO 2022142160 A1 WO2022142160 A1 WO 2022142160A1 CN 2021099949 W CN2021099949 W CN 2021099949W WO 2022142160 A1 WO2022142160 A1 WO 2022142160A1
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- acid
- icetexane
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- rosinane
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- A—HUMAN NECESSITIES
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Definitions
- the invention relates to the technical field of medicines, in particular to the application of Icetexane-type rosinane diterpenes in the preparation of medicines for the treatment of colorectal cancer.
- Icetexane-type rosinane diterpenes are a kind of B-ring-expanded rosinane diterpenoids. There are about 70 kinds of natural products of this type that have been reported, which are widely distributed and found in plants of many families.
- the dimeric Icetexane-type rosinane diterpene biperovskatone and the Icetexane-type C18 norperovskatone which were isolated from the genus Herba, possess anti-HBV activity.
- a dimer of C23 terpenoids and Icetexane diterpenoids was isolated from Salvia chinensis, and claryone A was effective in various tumor cell lines HL-60, SMMC-7721, A-549, MCF -7, SW480, Beas-2B have significant cytotoxic activity.
- Dimeric Icetexane-type diterpene Premnalatifolin A has significant cytotoxic activity against various tumor cell lines HT-29, A-431, Hep-G2, PC-3, A-549, MCF-7, among which MCF-7
- the IC50 can reach 1.11 ⁇ 0.23 ⁇ g/mL. Icetexane-type rosinane diterpenes demethylsalvicanol, Brussonol and their derivatives have certain cytotoxic activity against leukemia cell line P388.
- Icetexane-type rosinane diterpenes in the field of anti-tumor only focuses on its cytotoxic activity, and there is no report on its mechanism of action.
- the technical problem to be solved by the present invention is: the application of Icetexane-type rosinane diterpenes in the preparation of colorectal cancer therapeutic drugs.
- the technical solution provided by the present invention is: the application of Icetexane-type rosinane diterpenes in the preparation of colorectal cancer therapeutic drugs, and the Icetexane-type rosinane diterpenes include general formulae (I), (II) And at least one of the compounds shown in (III) and their derivatives or their pharmacologically acceptable salts:
- R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from hydrogen or hydroxyl;
- R 1 and R 3 form a double bond
- R 1 and R 4 form a double bond
- R 1 and R 2 form epoxy
- R 1 and R 4 form epoxy
- R 6 and R 7 form epoxy
- R is selected from any one of hydrogen, acetyl and acetonide.
- the Icetexane-type rosinane diterpenes include at least one of compounds 3 to 14 represented by the following structural formulas and derivatives or pharmacologically acceptable salts thereof:
- the pharmacologically acceptable salts of the present invention include salts formed with inorganic acids, organic acids, alkali metals, alkaline earth metals and basic amino acids.
- the inorganic acid includes at least one of hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.
- the organic acid includes among maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid and tannic acid at least one of.
- the alkali metal includes at least one of lithium, sodium and potassium.
- the alkaline earth metal includes at least one of calcium and magnesium.
- the basic amino acid comprises lysine.
- the compound 1 (carnosic acid) is obtained by separation and purification from rosemary extract, and the structural formula of the compound 1 is as follows:
- the Icetexane-type rosinane diterpenes are compounds that up-regulate the level of the chaperone BiP in the endoplasmic reticulum, promote the transfer of BiP from the cytoplasm to the nucleus, and induce apoptosis.
- Icetexane-type rosinane diterpene when used as a medicine, it can be used directly or in the form of a pharmaceutical composition.
- the pharmaceutical composition includes the Icetexane-type rosinane diterpenes.
- the preparation material of the colorectal cancer therapeutic drug further includes a pharmaceutical carrier.
- the pharmaceutical carrier is a conventional pharmaceutical carrier in the pharmaceutical field.
- the pharmaceutical carrier includes diluents, excipients, fillers, binders, wetting agents, disintegrating agents, absorption enhancers, surfactants, adsorption carriers, lubricants, sweeteners at least one of an agent and a flavoring agent.
- the excipient includes water.
- the bulking agent includes at least one of starch and sucrose.
- the binder includes at least one of cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone.
- the humectant comprises glycerin.
- the disintegrant includes at least one of agar, calcium carbonate and sodium bicarbonate.
- the absorption enhancer comprises a quaternary ammonium compound.
- the surfactant comprises cetyl alcohol.
- the adsorption carrier includes at least one of kaolin and bentonite.
- the lubricant includes at least one of talc, calcium stearate, magnesium stearate, and polyethylene glycol.
- the mass fraction of Icetexane-type rosinane diterpenes in the colorectal cancer therapeutic drug is 0.1% to 99%.
- the mass fraction of Icetexane-type rosinane diterpenes in the colorectal cancer therapeutic drug is 0.5-95%.
- the mass fraction of Icetexane-type rosinane diterpenes in the colorectal cancer therapeutic drug is 10%-20%.
- the dosage standard of the colorectal cancer therapeutic drug is: Icetexane-type rosinane diterpene 0.1 mg/day to 1000 mg/day.
- the dosage form of the drug is various conventional dosage forms in the field, preferably in the form of solid, semi-solid or liquid, can be an aqueous solution, a non-aqueous solution or a suspension, more preferably a tablet preparations, capsules, soft capsules, granules, pills, oral liquids, dry suspensions, dropping pills, dry extracts, injections or infusions.
- the administration mode of the medicament can be conventional in the art, including but not limited to injection administration or oral administration.
- the injection administration can be intravenous injection, intramuscular injection, intraperitoneal injection, intradermal injection or subcutaneous injection.
- administered dose is an amount capable of ameliorating or delaying the progression of a disease, degenerative or damaging disorder. This may depend on the particular disease being treated, as well as other factors including age, weight, health status, severity of symptoms, route of administration, frequency of treatment and whether other drugs are concomitant during treatment.
- treating refers to reducing the extent of colorectal cancer and its complications, or curing and normalizing colorectal cancer and its complications, or slowing the progression of colorectal cancer and its complications.
- the present invention provides a new use of Icetexane-type rosinane diterpenes for colorectal cancer therapeutic drugs, and the inventors have discovered through a large number of scientific research and creative work. Icetexane-type rosinane diterpenes and their derivatives have potent anti-colorectal cancer activity, and their mechanism of action is to up-regulate the level of the chaperone protein BiP (Binding immunoglobulin protein) in the endoplasmic reticulum, which promotes the transfer of BiP protein from the cytoplasm to the nucleus. , which induces apoptosis.
- the invention further expands the application range of Icetexane-type rosinane diterpenes and derivatives thereof.
- Fig. 1 is the test result of the third embodiment of the present invention.
- Fig. 2 is the test result (0 ⁇ mol/L) under four different concentrations of the embodiment of the present invention
- Fig. 3 is the test result (10 ⁇ mol/L) under four different concentrations of the embodiment of the present invention.
- Fig. 4 is the test result (20 ⁇ mol/L) under the embodiment four of the present invention under different concentrations;
- Fig. 5 is the test result of the fifth embodiment of the present invention.
- FIG. 6 is the test result of the sixth embodiment of the present invention.
- Icetexane type rosinane diterpenes and derivatives thereof are synthesized according to the manufacturing route shown in the following chemical reaction formula:
- Embodiment 1 of the present invention is: the preparation method of Icetexane-type rosinane diterpenes and derivatives thereof, comprising the following steps:
- reaction solution After the reaction is complete, slowly add sodium sulfate decahydrate to the reaction solution at 0 ° C until no bubbles are generated, the reaction solution is suction filtered with diatomaceous earth, and the filtrate is spin-dried and then subjected to silica gel column chromatography (the volume ratio of PE and EA is 10: 1) to obtain 458 mg of compound 2 (white solid, 72% yield).
- the dichloromethane layer was dried by adding anhydrous sodium sulfate, rotary evaporated, evaporated to dryness, and subjected to silica gel column chromatography (PE The volume ratio to EA was 12:1), yielding 1.42 g of compound 4 (white solid, 92% yield).
- reaction solution After the reaction is complete, slowly add sodium sulfate decahydrate to the reaction solution at 0°C until no bubbles are generated, the reaction solution is suction filtered with diatomaceous earth, and the filtrate is spin-dried and then subjected to silica gel column chromatography (the volume ratio of PE and EA is 6: 1) to obtain 372 mg of compound 6 (white solid, 78% yield).
- the second embodiment of the present invention is: MTT method to measure the cytotoxic activity of Icetexane-type rosinane diterpenes and derivatives thereof, including the following steps:
- the tumor cells in the logarithmic growth phase were taken and evenly seeded in a 96-well plate at a density of 3000 cells per well, and cultured in a 37°C, 5% CO 2 cell incubator for 12 h. After the cells adhered on the next day, the cells were administered in groups of 3 duplicate wells, and cultured in a 37°C, 5% CO 2 cell incubator for 72 h. Then aspirate all the wells, add 100 ⁇ L of 10% MTT (thiazolyl blue) diluted with DMEM medium to each well, incubate at 37°C, 5% CO 2 in a cell incubator for about 2.5 hours, and then use enzyme The absorbance value at 490 nm of each well was detected by a standard meter.
- MTT thiazolyl blue
- cell survival rate (%) in each well (OD value of administration well - OD value of blank group)/(OD value of normal well - OD value of blank group)*100.
- the tumor cell inhibition curve was fitted according to the data, and the drug concentration when half of the tumor cells died was calculated, which was the IC 50 value of the drug.
- Table 1 shows the test results of the second part of the compounds of the embodiment of the present invention.
- the IC 50s of compounds 3 to 14 are known from Table 1; it is known from the IC 50 that each compound has good antitumor activity.
- the third embodiment of the present invention is: a plate clone formation test to determine the ability of Icetexane-type rosinane diterpenes and their derivatives to inhibit cell proliferation, including the following steps:
- HCT116 human colon cancer cells
- HCT116 human colon cancer cells
- DMEM medium with 10% fetal bovine serum. spare.
- 5 ⁇ M, 2.5 ⁇ M, 1.25 ⁇ M and 0 ⁇ M (blank control) (+)-Grandione (compound 9) were added to each well in a gradient, and placed in a cell incubator at 37°C, 5% CO 2 and saturated humidity.
- the fourth embodiment of the present invention is: Western Blot method to determine the influence of Icetexane-type rosinane diterpenes and derivatives thereof on the BiP protein of HCT-116 cells, including the following steps:
- HCT116 cells in logarithmic growth phase were taken, digested with 0.25% trypsin and pipetted into single cells, 5*10 5 cells per well were seeded in 6-well plates, cultured in an oven overnight, and 20 ⁇ M was added to each well. , 10 ⁇ M, 5 ⁇ M, 0 ⁇ M (blank control) (+)-Grandione, incubated for 6 h. Discard the supernatant, wash with PBS, collect the cells, add 100 ⁇ L of cell lysate to each well and lyse on ice for 10 min, use the BCA kit to measure the total protein concentration of the extracted cells, take 100 ⁇ g of total protein for loading, and use a mass fraction of 10%.
- Polyacrylamide gel separation (20 mA).
- the protein was transferred to PVDF membrane (80V, 1.5h), blocked with 5% nonfat milk powder at room temperature for 2h, washed three times with TBST buffer, added BiP and ⁇ -actin primary antibodies, and incubated overnight at 4°C.
- the PVDF membrane was washed 3 times with TBST, the secondary antibody was added, and after 2 h incubation at room temperature, the membrane was washed 3 times with TBST.
- the PVDF membrane was uniformly dripped with a chemiluminescence developer, and the exposure of the strip was detected with an imager and photographed.
- the fifth embodiment of the present invention is: flow cytometry to determine the effect of (+)-Grandione on BiP protein translocation in HCT-116 cells
- HCT116 cells in logarithmic growth phase were taken, digested with 0.25% trypsin and pipetted into single cells, 5*10 5 cells per well were seeded into 6-well plates, and cultured in an oven overnight to adhere. 20 ⁇ M, 10 ⁇ M, 5 ⁇ M, and 0 ⁇ M (blank control) (+)-Grandione were added, and incubated for 24 h. Cells were collected, centrifuged at 1000rpm at 4°C for 10min, and the supernatant was discarded.
- the sixth embodiment of the present invention is: immunofluorescence assay to determine the effect of (+)-Grandione on the translocation of BiP protein in HCT-116 cells
- HCT116 cells in logarithmic growth phase were taken, digested with 0.25% trypsin and pipetted into single cells, 5*10 5 cells per well were seeded into 6-well plates (including cell slides), and incubated overnight in an oven. Walls, 20 ⁇ M, 10 ⁇ M, 5 ⁇ M and 0 ⁇ M (blank control) (+)-Grandione were added, respectively, and incubated for 24 h.
- Example 3 of the present invention The test results of Example 3 of the present invention are shown in Figure 1. It can be seen from Figure 1 that compared with the blank control, (+)-Grandione can significantly inhibit the growth of HCT116 cells at a concentration of 1.25 ⁇ M.
- Example 4 of the present invention The test results of Example 4 of the present invention are shown in Figures 2 to 4. It is known from Figures 2 to 4 that compared with the blank control ( Figure 2), (+)-Grandione at concentrations of 10 ⁇ M ( Figure 3) and 20 ⁇ M (Fig. 4), apoptosis of HCT116 cells could be significantly induced.
- Example 5 of the present invention The test results of Example 5 of the present invention are shown in FIG. 5 . It can be seen from FIG. 5 that with the increase of the concentration of (+)-Grandione, the nuclear translocation of BiP protein can be significantly increased.
- Example 6 of the present invention The test results of Example 6 of the present invention are shown in Figure 6. It can be seen from Figure 6 that with the increase of drug concentration, the enhancement of green fluorescence is incorporated into the nucleus, indicating that (+)-Grandione can dose-dependently increase the nucleus of HCT116 level of intra-BiP.
- the present invention provides a new use of Icetexane-type rosinane diterpenes for the treatment of colorectal cancer.
- the inventors have discovered through a lot of scientific research and creative work that Icetexane-type rosinane diterpenes and their derivatives have strong properties. Its mechanism of action is to up-regulate the level of the chaperone BiP in the endoplasmic reticulum, promote the transfer of BiP protein from the cytoplasm to the nucleus, and then induce apoptosis.
- the invention further expands the application range of Icetexane-type rosinane diterpenes and derivatives thereof.
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Abstract
本发明公开了Icetexane型松香烷二萜在制备结直肠癌治疗药物中的应用,其作用机制为上调了内质网中伴侣蛋白BiP(Binding immunoglobulin protein)水平,促进了BiP蛋白从胞浆转移到胞核,进而诱导了细胞凋亡。本发明进一步扩大了Icetexane型松香烷二萜及其衍生物的应用范围。
Description
本发明涉及药物技术领域,具体涉及Icetexane型松香烷二萜在制备结直肠癌治疗药物中的应用。
Icetexane型松香烷二萜是一种B环扩环型松香烷二萜类成分,目前已经报道的该类天然产物约有70余种,分布较为广泛,在多个科的植物中均有发现。
从分药花属植物中分离得到的二聚型Icetexane型松香烷二萜biperovskatone及Icetexane型C18降松香烷二萜Norperovskatone的具备抗HBV活性。从甘西鼠尾草中分离得到一个C23萜类化合物与Icetexane类二萜化合物的二聚体甘西鼠尾草酮A对多种肿瘤细胞株HL-60、SMMC-7721、A-549、MCF-7、SW480、Beas-2B具有显著的细胞毒活性。二聚型Icetexane型二萜Premnalatifolin A对多种肿瘤细胞株HT-29、A-431、Hep-G2、PC-3、A-549、MCF-7具有显著的细胞毒活性,其中对MCF-7的IC50可达到1.11±0.23μg/mL。Icetexane型松香烷二萜demethylsalvicanol、Brussonol及其衍生物对白血病细胞株P388具有一定细胞毒活性。从植物Premma tomentosa中分离获得多种具有新颖Icetexane类型型松香烷二萜,其对MCF-7、HT-29,Hep-G2、A-431、A-549等多种肿瘤株具有显著的细胞毒活性。
目前,关于Icetexane型松香烷二萜在抗肿瘤领域的应用仅关注其细胞毒活性,尚无其作用机制方面的报道。
发明内容
本发明要解决的技术问题为:Icetexane型松香烷二萜在制备结直肠癌治疗药物中的应用。
为解决上述技术问题,本发明提供的技术方案为:Icetexane型松香烷二萜在制备结直肠癌治疗药物中的应用,所述Icetexane型松香烷二萜包括如通式(I)、(II)和(III)所示的化合物及其衍生物或其药理学上容许的盐中的至少一种:
其中,R
1、R
2、R
5、R
6、R
7、R
8和R
9均独立选自氢或羟基;
或R
1、R
3组成双键;
或R
1、R
4组成双键;
或R
4、R
5组成双键
或R
1、R
2组成环氧;
或R
1、R
4组成环氧;
或R
6、R
7组成环氧;
或R
8,R
9组成环氧;
R选自氢、乙酰基和丙酮叉中的任意一种。
根据本发明的一些实施方式,所述Icetexane型松香烷二萜包括下述结构式所示的化合物3至14及其衍生物或其药理学上容许的盐中的至少一种:
根据本发明的一些实施方式,本发明所述药理学上容许的盐包括与无机酸、有机酸、碱金属、碱土金属和碱性氨基酸形成的盐。
根据本发明的一些实施方式,所述无机酸包括盐酸、硝酸、硫酸、磷酸、氢溴酸中的至少一种。
根据本发明的一些实施方式,所述有机酸包括马来酸、富马酸、酒石酸、乳酸、柠檬酸、乙酸、甲磺酸、对甲苯磺酸,己二酸,棕榈酸和单宁酸中的至少一种。
根据本发明的一些实施方式,所述碱金属包括锂、钠和钾中至少一种。
根据本发明的一些实施方式,所述碱土金属包括钙和镁中至少一种。
根据本发明的一些实施方式,所述碱性氨基酸包括赖氨酸。
根据本发明的一些实施方式,所述化合物1(鼠尾草酸)是从迷迭香提取物中分离纯化获得的,所述化合物1的结构式如下:
根据本发明的一些实施方式,所述Icetexane型松香烷二萜为具有上调内质网中伴侣蛋白BiP水平,促进BiP从胞浆转移到胞核,诱导细胞凋亡的化合物。
根据本发明的一些实施方式,所述Icetexane型松香烷二萜用作药物时,可以直接使用,或者以药物组合物的形式使用。
根据本发明的一些实施方式,所述药物组合物包括所述Icetexane型松香烷二萜。
根据本发明的一些实施方式,所述结直肠癌治疗药物的制备原料还包括药用载体。
根据本发明的一些实施方式,所述药用载体为药学领域常规的药物载体。
根据本发明的一些实施方式,所述药用载体包括稀释剂、赋形剂、填充剂、黏合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、甜味剂和香味剂中的至少一种。
根据本发明的一些实施方式,所述赋形剂包括水。
根据本发明的一些实施方式,所述填充剂包括淀粉和蔗糖中的至少一种。
根据本发明的一些实施方式,所述黏合剂包括纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮中的至少一种。
根据本发明的一些实施方式,所述湿润剂包括甘油。
根据本发明的一些实施方式,所述崩解剂包括琼脂、碳酸钙和碳酸氢钠中的至少一种。
根据本发明的一些实施方式,所述吸收促进剂包括季铵化合物。
根据本发明的一些实施方式,所述表面活性剂包括十六烷醇。
根据本发明的一些实施方式,所述吸附载体包括高岭土和皂黏土中的至少一种。
根据本发明的一些实施方式,所述润滑剂包括滑石粉、硬脂酸钙、硬脂酸镁和聚乙二醇中的至少一种。
根据本发明的一些实施方式,所述结直肠癌治疗药物中Icetexane型松香烷二萜的质量分数为0.1%~99%。
根据本发明的一些实施方式,所述结直肠癌治疗药物中Icetexane型松香烷二萜的质量分数为0.5~95%。
根据本发明的一些实施方式,所述结直肠癌治疗药物中Icetexane型松香烷二萜的质量分数为10%~20%。
根据本发明的一些实施方式,所述结直肠癌治疗药物的给药量标准为:Icetexane型松香烷二萜0.1mg/天~1000mg/天。
根据本发明的一些实施方式,所述药物的剂型为本领域常规的各种剂型,优选地为固体、半固体或液体的形式,可以为水溶液、非水溶液或混悬液,更优选地为片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、干混悬剂、滴丸剂、干浸膏剂、注射剂或输注剂。
根据本发明的一些实施方式,所述药物的给药方式可以为本领域常规的给药方式,包括但不限于注射给药或口服给药。所述注射给药可以为静脉注射、肌肉注射、腹腔注射、皮内注射或皮下注射等途径。
本文所述的术语“给药剂量”为能够缓解或延迟疾病、退化性或损伤性病症进展的量。可以随被治疗的具体疾病以及其它因素而定,其它因素包括年龄、体重、健康状况、症状的严重程度、给药途径、治疗的频率和在治疗期间是否伴随其它的药物。
本文所述的术语“治疗”是指减轻结直肠癌及其并发症的程度,或者治愈结直肠癌及其并发症使之正常化,或者减缓结直肠癌及其并发症的进程。
根据本发明实施方式的所述的应用,至少具备如下有益效果:本发明提供了Icetexane型松香烷二萜用于结直肠癌治疗药物的新用途,发明人通过大量科学研究和创造性的劳动发现了Icetexane型松香烷二萜及其衍生物具有强效抗结直肠癌活性,其作用机制是上调了内质网中伴侣蛋白BiP(Binding immunoglobulin protein)水平,促进了BiP蛋白从胞浆转移到胞核,进而诱导了细胞凋亡。本发明进一步扩大了Icetexane型松香烷二萜及其衍生物的应用范围。
图1为本发明实施例三的测试结果;
图2为本发明实施例四不同浓度下的测试结果(0μmol/L);
图3为本发明实施例四不同浓度下的测试结果(10μmol/L);
图4为本发明实施例四不同浓度下的测试结果(20μmol/L);
图5为本发明实施例五的测试结果;
图6为本发明实施例六的测试结果。
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。
为了更好的理解本发明的实质,下面结合附图,用本发明的实施例来进一步说明本发明的实质性内容,但并不以此来限定本发明。根据本发明的实质对本发明进行的改进都属于本发明的范围。
本发明的实施例中Icetexane型松香烷二萜及其衍生物按照下述化学反应式所示的制造路线来合成:
本发明的实施例一为:Icetexane型松香烷二萜及其衍生物的制备方法,包括以下步骤:
S1、化合物2的制备:
称取1.0g(3mmol)化合物1(鼠尾草酸)置于100mL圆底烧瓶中,加入12.5mL甲苯和2.5mL甲醇溶解,0℃下缓慢滴加3mL三甲基硅基重氮甲烷的正己烷溶液(2.0mol/L,6mmol)。TLC监测,反应完全后向反应液中滴加1mL冰醋酸,旋转蒸发除去反应溶剂,加入50mL饱和食盐水,用乙酸乙酯萃取(3×30mL),乙酸乙酯层用无水硫酸钠干燥,进行硅胶柱层析(PE(石油醚)与EA(丙烯酸乙酯)的体积比为10:1),得到945mg中间体(黄色固体,产率91%)。
1H NMR(400MHz,CDCl
3)δ7.52(s,1H),6.59(s,1H),5.87(s,1H),3.71(s,3H),3.35(dd,J=11.1,2.7Hz,1H),3.25(dt,J=13.8,6.9Hz,1H),2.85(dd,J=9.4,4.5Hz,2H),2.39–2.27(m,1H),1.94–1.87(m,1H),1.74(dt,J=14.0,3.3Hz,1H),1.69–1.64(m,1H),1.61(dd,J=12.7,1.9Hz,1H),1.54–1.47(m,1H),1.37(dd,J=13.3,4.6Hz,1H),1.31(dd,J=9.2,4.2Hz,1H),1.25(dd,J=6.9,4.4Hz,6H),1.05(s,3H),0.84(s,3H).
称取228mg(6mmol)氢化铝锂置于干燥的两口瓶中,加入5mL无水四氢呋喃,0℃下滴加10mL溶解了692mg(2mmol)化合物1的无水四氢呋喃,N
2保护下回流。反应完全后,0℃下向反应液中缓慢加入十水合硫酸钠至没有气泡产生,反应液用硅藻土抽滤,滤液旋干后进行硅胶柱层析(PE与EA的体积比为10:1),得到458mg化合物2(白色固体,产率72%)。
1H NMR(400MHz,DMSO)δ9.74(s,1H),7.52(s,1H),6.57(s,1H),6.35(s,1H),4.26(d,J=10.0Hz,1H),3.72(d,J=10.0Hz,1H),3.20(d,J=13.7Hz,1H),3.09(dd,J=13.8,6.9Hz,1H),2.74(dd,J=8.7,3.7Hz,2H),1.74–1.60(m,2H),1.53–1.41(m,3H),1.24(d,J=5.3Hz,2H),1.12(dd,J=6.9,4.3Hz,6H),1.00(dd,J=13.4,10.6Hz,1H),0.94(s,3H),0.88(s,3H).
S2、化合物3的制备:
称取636mg(2.0mmol)化合物2和786mg三苯基膦(3.0mmol)置于100mL干燥的圆底烧瓶中,加入20mL无水四氢呋喃溶解,0℃下滴加606mg DIAD(3.0mmol)。室温下反应10min左右。反应完全后,旋干反应液,进行硅胶柱层析(PE与EA的体积比为10:1),得到552mg化合物3(棕 色油状物,产率92%)。
1H NMR(400MHz,CDCl
3)δ6.54(s,1H),5.53(d,J=3.1Hz,1H),5.17(d,J=49.9Hz,2H),3.70(d,J=15.0Hz,1H),3.16–3.04(m,2H),2.89–2.70(m,2H),2.09–1.91(m,3H),1.83(dd,J=11.7,4.3Hz,1H),1.41–1.35(m,1H),1.27(dd,J=6.9,4.3Hz,6H),1.23–1.16(m,1H),1.12(ddd,J=12.9,6.1,2.4Hz,1H),0.94(s,3H),0.90(s,3H).
S3、化合物4的制备:
称取1.2g(4.0mmol)化合物3置于100mL圆底烧瓶中,加入20mL二氯甲烷溶解,0℃下加入0.83mL(8.8mmol)乙酸酐,1.67mL三乙胺(12mmol)和48.8mg(0.4mmol)DMAP,室温下反应,TLC监测。反应完全后,向反应液中加入50mL饱和食盐水,加入二氯甲烷萃取(3×30mL),二氯甲烷层加入无水硫酸钠干燥,旋转蒸发,蒸干溶剂,进行硅胶柱层析(PE与EA的体积比为12:1),得到1.42g化合物4(白色固体,产率92%)。
1H NMR(500MHz,CDCl
3)δ6.95(s,1H),5.39(s,1H),3.44(d,J=15.2Hz,1H),3.06(d,J=15.2Hz,1H),2.93(dt,J=13.3,7.4Hz,2H),2.86–2.78(m,1H),2.33(d,J=8.9Hz,6H),2.02(ddd,J=25.4,15.5,7.4Hz,3H),1.82(d,J=11.4Hz,1H),1.41–1.36(m,1H),1.27(d,J=5.3Hz,1H),1.22(t,J=7.2Hz,6H),1.11(dd,J=12.8,5.4Hz,1H),0.92(s,3H),0.91(s,3H).
S4、化合物5的制备:
称取768mg(2mmol)化合物4置于50mL圆底烧瓶中,加入10mL二氯甲烷溶解,加入346mg(2mmol)间氯过氧苯甲酸,室温下反应,TLC监测。反应完全后,依次向反应液中加入10mL饱和硫代硫酸钠水溶液和20mL饱和碳酸氢钠水溶液,搅拌10min,加入二氯甲烷萃取(3×30mL),二氯甲烷层用饱和食盐水洗涤,并用无水硫酸钠干燥,旋干溶剂,进行硅胶柱层析(PE与EA的体积比为7:1),得到696mg化合物5(白色固体,产率87%)。
1H NMR(400MHz,CDCl
3)δ7.00(s,1H),3.33–3.23(m,2H),3.19(s,1H),2.95(dt,J=13.8,6.9Hz, 1H),2.71–2.64(m,1H),2.41(d,J=17.4Hz,1H),2.31(d,J=10.9Hz,6H),1.99–1.85(m,2H),1.80–1.72(m,1H),1.71–1.68(m,1H),1.65(s,1H),1.49–1.39(m,1H),1.23(dd,J=10.6,6.9Hz,6H),0.91(dd,J=9.2,4.0Hz,1H),0.87(s,3H),0.76(s,3H).
S5、化合物6的制备:
称取171mg(4.5mmol)氢化铝锂置于干燥的两口瓶中,加入5mL无水四氢呋喃,0℃下滴加10mL化合物5(600mg,1.5mmol)的无水四氢呋喃溶液,N
2保护下回流3h。反应完全后,0℃下向反应液中缓慢加入十水合硫酸钠至没有气泡产生,反应液用硅藻土抽滤,滤液旋干后进行硅胶柱层析(PE与EA的体积比为6:1),得到372mg化合物6(白色固体,产率78%)。
1H NMR(400MHz,CDCl
3)δ6.59(s,1H),5.77(s,1H),3.18(dq,J=13.0,6.6Hz,1H),3.05(d,J=14.5Hz,1H),2.80–2.56(m,3H),2.02(dd,J=14.0,7.5Hz,1H),1.89–1.68(m,3H),1.57–1.49(m,1H),1.48–1.41(m,2H),1.35(dd,J=12.4,2.3Hz,1H),1.25(dd,J=13.5,6.9Hz,6H),1.16(d,J=13.1Hz,1H),0.94(s,3H),0.87(s,3H).
S6、化合物7的制备:
称取318mg(1mmol)化合物6置于50mL圆底烧瓶中,加入5mL二氯甲烷溶解,加入464mg(2mmol)氧化银,室温下反应,TLC监测。反应完全后,反应液抽滤,滤液旋干,得到307mg化合物7(红棕色固体,产率97%)。
1H NMR(400MHz,CDCl
3)δ6.60(s,1H),3.05(d,J=14.7Hz,1H),2.92(dd,J=13.6,6.8Hz,1H),2.62(d,J=12.7Hz,1H),2.48(dd,J=14.4,6.8Hz,1H),2.18(d,J=14.7Hz,1H),1.88(d,J=6.7Hz,1H),1.82–1.77(m,1H),1.72(d,J=2.2Hz,1H),1.59–1.52(m,2H),1.44(dd,J=7.9,4.1Hz,3H),1.29(d,J=2.4Hz,1H),1.12(t,J=6.5Hz,6H),0.93(s,6H).
S7、化合物8、化合物9和化合物10的制备:
称取63.2mg(0.2mmol)化合物7置于50mL圆底烧瓶中,加入1mL二氯甲烷溶解,加入300mg 300-400目硅胶,室温下放置,TLC监测。反应完全后,加入10mL二氯甲烷,震摇,过滤,二氯甲烷洗涤滤渣,旋干二氯甲烷,进行硅胶柱层析(DCM(二氯甲烷)与EA的体积比为30:1),得到化合物8(棕色固体)、化合物9(黄色固体)、化合物10(棕色固体)。
化合物10的核磁谱图如下:
1H NMR(500MHz,CDCl
3)δ6.49(s,1H),4.50(d,J=6.8Hz,1H),2.97(dt,J=13.8,6.8Hz,1H),2.50(d,J=18.6Hz,1H),2.20(d,J=18.7Hz,1H),2.16–2.05(m,2H),1.98(dd,J=18.1,10.8Hz,1H),1.80(d,J=6.4Hz,3H),1.59(m,1H),1.51(dt,J=13.3,6.8Hz,1H),1.21–1.16(m,1H),1.13(d,J=6.8Hz,6H),0.99(s,3H),0.87(s,3H).
S8、化合物11的制备:
称取960mg(3.2mmol)化合物3置于反应管中,加入2mL 2,2-DMP溶解,再加入55mg(0.32mmol)对甲苯磺酸,60℃反应,TLC监测。反应完全后,加入0.1mL三乙胺,旋干溶剂,进行硅胶柱层析(PE洗脱),得到910mg化合物11(无色油状物,产率83%)。
1H NMR(400MHz,CDCl
3)δ6.45(s,1H),5.50(s,1H),3.56(d,J=14.9Hz,1H),3.07(d,J=14.9Hz,1H),2.97(dt,J=13.9,6.9Hz,1H),2.88–2.70(m,2H),2.04(ddt,J=38.6,33.9,10.5Hz,3H),1.82(dd,J=11.6,3.8Hz,1H),1.70(d,J=4.5Hz,6H),1.39(ddd,J=12.8,10.8,6.4Hz,1H),1.26(dd,J=6.9,2.0Hz,6H),1.24–1.17(m,1H),1.15–1.08(m,1H),0.94(d,J=13.1Hz,6H).
S9、化合物12的制备:
称取680mg(2mmol)化合物11置于100mL圆底烧瓶中,加入20mL二氯甲烷溶解,加入519mg(3mmol)间氯过氧苯甲酸,室温下反应,TLC监测。反应完全后,依次向反应液中加入10mL饱和硫代硫酸钠水溶液和20mL饱和碳酸氢钠水溶液,搅拌10min,加入二氯甲烷萃取(3×30mL),二氯甲烷层用饱和食盐水洗涤,并用无水硫酸钠干燥,旋干溶剂,进行硅胶柱层析(PE与EA的体积比为20:1),得到535mg化合物12(无色油状物,产率75%)。
1H NMR(500MHz,CDCl
3)δ6.47(s,1H),3.32(d,J=17.1Hz,1H),3.21(s,1H),3.16(dd,J=17.7,7.5Hz,1H),2.97(dt,J=13.8,6.9Hz,1H),2.61(dd,J=10.0,4.0Hz,1H),2.46(d,J=17.1Hz,1H),2.01–1.87(m,2H),1.80–1.74(m,1H),1.70–1.64(m,7H),1.45(dd,J=9.1,3.6Hz,1H),1.27(d,J=7.7Hz,6H),1.25(s,1H),0.95(dd,J=9.0,3.7Hz,1H),0.90(s,3H),0.77(s,3H).
S10、化合物13的制备:
称取60mg(0.17mmol)化合物12置于反应管中,加入1mL双(N,N-二甲基氨基)膦酰氯溶解,加入1滴去离子水,140℃下反应,TLC监测。反应完全后,向反应液中加入10mL去离子水,用乙酸乙酯萃取(3×10mL),有机相用饱和食盐水洗涤,加入无水硫酸钠干燥,旋干溶剂,进行硅胶柱层析(石油醚洗脱),得到35mg化合物13(无色油状物,产率62%)。
1H NMR(400MHz,CDCl
3)δ6.45(s,1H),6.41(s,1H),6.28(d,J=9.8Hz,1H),5.75–5.67(m,1H),2.98(dt,J=13.9,6.9Hz,1H),2.76–2.62(m,2H),2.34(dd,J=12.1,4.6Hz,1H),2.24(ddd,J=18.2,9.1,4.3Hz,1H),2.10–1.92(m,2H),1.71(d,J=3.0Hz,6H),1.64(d,J=3.0Hz,1H),1.27(d,J=7.0Hz,6H),1.02(s,3H),0.83(s,3H).
S11、化合物14的制备
称取33.8mg化合物13(0.1mmol)和17.2mg对甲苯磺酸(0.1mmol)置于反应管中,加入0.8mL乙腈和0.2mL水,80℃下反应,TLC监测。反应完全后,向反应液中加入10mL饱和食盐水,用乙酸乙酯萃取(3×10mL),乙酸乙酯层用无水硫酸钠干燥,进行硅胶柱层析(PE与EA的体积比 为10:1),得到18mg化合物14(棕黄色固体,产率60%)。
1H NMR(400MHz,CDCl
3)δ6.63(s,1H),6.39(s,1H),6.34(d,J=9.7Hz,1H),5.84–5.76(m,1H),3.23(dt,J=13.8,6.9Hz,1H),2.55(ddd,J=13.4,5.6,2.9Hz,1H),2.48–2.38(m,1H),2.22–2.02(m,3H),1.87(dd,J=17.9,5.5Hz,1H),1.77(tdd,J=12.5,6.3,2.9Hz,1H),1.30(d,J=7.1Hz,3H),1.27(d,J=7.1Hz,3H),0.88(d,J=6.6Hz,6H).
以下通过本实施例所制备的Icetexane型松香烷二萜及其衍生物药效学试验来进一步阐述本发明所具有的有益效果。
本发明的实施例二为:MTT法测定Icetexane型松香烷二萜及其衍生物的细胞毒活性,包括以下步骤:
取对数生长期的肿瘤细胞,按照每孔3000个细胞的密度均匀种于96孔板中,在37℃,5%CO
2细胞培养箱中培养12h。次日细胞贴壁后,按照细胞分组进行给药,每组3个复孔,在37℃,5%CO
2细胞培养箱中继续培养72h。然后吸弃所有孔药液,每孔添加用DMEM培养基稀释过的质量分数为10%MTT(噻唑蓝)100μL,在37℃,5%CO
2细胞培养箱中培养2.5小时左右,后用酶标仪检测各孔490nm处吸光度值。
数据的分析与IC
50值的计算:各孔细胞存活率(%)=(给药孔OD值-空白组OD值)/(正常孔OD值-空白组OD值)*100。根据数据拟合肿瘤细胞抑制曲线,计算肿瘤细胞死亡一半时药物浓度,即为该药物的IC
50值。
本发明实施例二部分化合物的测试结果如表1所示。
表1本发明实施例二部分化合物的测试结果
从表1中得知化合物3至14的IC
50;由IC
50得知各化合物均具有较好的抗肿瘤活性。
本发明的实施例三为:平板克隆形成试验测定Icetexane型松香烷二萜及其衍生物抑制细胞增殖能力,包括以下步骤:
取对数生长期的HCT116(人结肠癌细胞)细胞,分别用质量分数为0.25%胰蛋白酶消化并吹打成单个细胞,并把细胞悬浮在质量分数为10%胎牛血清的DMEM培养液中备用。将细胞悬液倍数稀释,六组细胞以每个培养皿100个细胞密度分别接种含2mL培养液的培养皿中,并轻轻转动,使细胞分散均匀。待细胞贴壁后每孔按梯度加入5μM、2.5μM、1.25μM和0μM(空白对照)(+)-Grandione(化合物9),置于37℃,5%CO
2及饱和湿度的细胞培养箱中培养14天。终止培养,弃去上清液,用PBS(磷酸盐缓冲液)小心浸洗2次。再添加质量分数为4%多聚甲醛液2mL固定细胞,固定时间为60min。然后去固定液,加结晶紫染色液2mL,然后用PBS缓慢洗去染色液,在空气干燥。将平皿倒置并于镜下拍照。
本发明的实施例四为:Western Blot法测定Icetexane型松香烷二萜及其衍生物对HCT-116细胞BiP蛋白的影响,包括以下步骤:
取对数生长期的HCT116细胞,分别用质量分数为0.25%胰蛋白酶消化并吹打成单个细胞,每孔5*10
5个细胞接种于6孔板中,于烘箱中培养过夜,分别加入20μM、10μM、5μM、0μM(空白对照)(+)-Grandione,孵育6h。弃去上清液,PBS洗涤,收集细胞,每孔加入100μL细胞裂解液冰上裂解10min,用BCA试剂盒测定所提取的细胞总蛋白浓度,取100μg总蛋白上样,用质量分数为10%聚丙烯酰胺凝胶分离(20mA)。将蛋白转移到PVDF膜上(80V,1.5h),用质量分数为5%脱脂奶粉室温封闭2h后,TBST缓冲液洗涤3次,分别加入BiP以及β-actin一抗,于4℃孵育过夜。PVDF膜用TBST洗3次,加入二抗,室温孵育2h后,用TBST洗涤3次。PVDF膜均匀滴加化学发光显影液,用成像仪检测条带曝光度,拍照。
本发明的实施例五为:流式细胞法测定(+)-Grandione对HCT-116细胞BiP蛋白转位影响
取对数生长期的HCT116细胞,分别用质量分数为0.25%胰蛋白酶消化并吹打成单个细胞,每孔5*10
5个细胞接种于6孔板中,于烘箱中培养过夜贴壁。分别加入20μM、10μM、5μM、0μM(空白对照)(+)-Grandione,孵育24h。收集细胞,1000rpm 4℃离心10min,弃去上清液。用冷的PBS洗涤细胞三次,加入200μL的binding buffer工作液(1×Annexin V结合缓冲液)重悬细胞,细胞悬液中加入10μL的Annex in V-FITC轻轻混匀,避光室温反应15分钟。加入300μL的binding buffer以及5μL PI(碘化丙啶),用流式细胞仪检测。
本发明的实施例六为:免疫荧光法测定(+)-Grandione对HCT-116细胞BiP蛋白转位影响
取对数生长期的HCT116细胞,用0.25%胰蛋白酶消化并吹打成单个细胞,每孔5*10
5个细胞接种于6孔板中(内含细胞爬片),于烘箱中培养过夜贴壁,分别加入20μM、10μM、5μM和0μM(空白对照)(+)-Grandione,孵育24h。PBS洗涤3次后,用固定液(质量分数为4%多聚甲醛的 PBS溶液)在4℃固定12h,再用PBS洗3次,用Triton-X100(曲拉通)的PBS溶液通透10min后,后用PBS洗3次,5%BSA的PBS溶液封闭60min后,加入BiP抗体,湿盒4度过夜。次日,用PBS洗3次,每次5min,然后加入AlexaFluor 488 goat anti-rabbit IgG二抗,37避光孵育2h,再用PBS洗3次,加入200μL Hoechest33342染液,室温避光染5-10min,用PBS洗3次后载玻片上滴加抗荧光淬灭剂,爬片反盖于载玻片上,显微镜观察,拍照。
本发明实施例三的测试结果如图1所示,从图1中得知,与空白对照相比,(+)-Grandione在浓度为1.25μM时即可显著抑制HCT116细胞的生长。
本发明实施例四的测试结果如图2~4所示,从图2~4中得知,与空白对照(图2)相比,(+)-Grandione在浓度为10μM(图3)和20μM(图4)时,可显著诱导HCT116细胞的凋亡。
本发明实施例五的测试结果如图5所示,从图5中得知,随着(+)-Grandione浓度的升高,可显著增加BiP蛋白的核转位。
本发明实施例六的测试结果如图6所示,从图6中得知,随着药物浓度的增加,绿色荧光的增强并入核,说明(+)-Grandione可剂量依赖性升高HCT116核内BiP的水平。
综上所述,本发明提供了Icetexane型松香烷二萜用于结直肠癌治疗药物的新用途,发明人通过大量科学研究和创造性的劳动发现了Icetexane型松香烷二萜及其衍生物具有强效抗结直肠癌活性,其作用机制是上调了内质网中伴侣蛋白BiP水平,促进了BiP蛋白从胞浆转移到胞核,进而诱导了细胞凋亡。本发明进一步扩大了Icetexane型松香烷二萜及其衍生物的应用范围。
上面结合附图对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
Claims (10)
- 根据权利要求1或2所述的应用,其特征在于:所述药理学上容许的盐包括与无机酸、有机酸、碱金属、碱土金属和碱性氨基酸形成的盐;优选地,所述无机酸包括盐酸、硝酸、硫酸、磷酸和氢溴酸中的至少一种;优选地,所述有机酸包括马来酸、富马酸、酒石酸、乳酸、柠檬酸、乙酸、甲磺酸、对甲苯磺酸、己二酸、棕榈酸和单宁酸中的至少一种;优选地,所述碱金属包括锂、钠和钾中至少一种;优选地,所述碱土金属包括钙和镁中至少一种;优选地,所述碱性氨基酸包括赖氨酸。
- 根据权利要求1所述的应用,其特征在于:所述Icetexane型松香烷二萜为具有上调内质网中伴侣蛋白BiP水平,促进BiP从胞浆转移到胞核,诱导细胞凋亡的化合物。
- 根据权利要求1所述的应用,其特征在于:所述结直肠癌治疗药物的制备原料还包括药用载体。
- 根据权利要求5所述的应用,其特征在于:所述药用载体包括稀释剂、赋形剂、填充剂、黏合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、甜味剂和香味剂中的至少一种;优选地,所述赋形剂包括水;优选地,所述填充剂包括淀粉和蔗糖中的至少一种;优选地,所述黏合剂包括纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮中的至少一种;优选地,所述湿润剂包括甘油;优选地,所述崩解剂包括琼脂、碳酸钙和碳酸氢钠中的至少一种;优选地,所述吸收促进剂包括季铵化合物;优选地,所述表面活性剂包括十六烷醇;优选地,所述吸附载体包括高岭土和皂黏土中的至少一种;优选地,所述润滑剂包括滑石粉、硬脂酸钙、硬脂酸镁和聚乙二醇中的至少一种。
- 根据权利要求1所述的应用,其特征在于:所述结直肠癌治疗药物中Icetexane型松香烷二萜的质量分数为0.1%~99%;优选地,质量分数为0.5~95%。
- 根据权利要求1所述的应用,其特征在于:所述结直肠癌治疗药物的给药量标准为:Icetexane型松香烷二萜0.1mg/天~1000mg/天。
- 根据权利要求1所述的应用,其特征在于:所述药物的剂型为固体、半固体或液体的形式;优选为水溶液、非水溶液或混悬液。
- 根据权利要求1所述的应用,其特征在于:所述药物的剂型为片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、干混悬剂、滴丸剂、干浸膏剂、注射剂或输注剂。
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