CN110882237A - Application of teprenone and derivatives thereof in preparation of medicines for preventing and treating ovarian cancer - Google Patents
Application of teprenone and derivatives thereof in preparation of medicines for preventing and treating ovarian cancer Download PDFInfo
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- A61K31/12—Ketones
- A61K31/121—Ketones acyclic
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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- A61P35/00—Antineoplastic agents
Abstract
The invention relates to application of all-trans and single-cis teprenone and derivatives thereof (structural formula I) in preparation of medicines for preventing and treating ovarian cancer. The experimental result shows that the activity of all-trans teprenone (5E-GGA) is obviously higher than that of single cis-teprenoneThe activity of the formula teprenone (5Z-GGA) is also higher than that of a mixture of all-trans and single-cis teprenone isomers.
Description
Technical Field
The invention relates to application of teprenone and derivatives thereof in preparing medicaments for preventing and treating ovarian cancer, belonging to the technical field of medicaments.
Background
Ovarian cancer is one of the diseases with higher malignancy degree in gynecological tumor. Statistically, in 2012, 239000 cases of newly diagnosed ovarian Cancer and 152000 cases of patients who died from ovarian Cancer (Prat J., France sch S. Cancer soft term productive organs [ M ]// STEWART BW, WILD CP. world Cancer report2014. Lyon: International age for Research Cancer 2014: 467) are diagnosed. Ovarian cancer has hidden clinical symptoms, and an effective screening means is lacked, about 75 percent of patients are diagnosed with the ovarian cancer in the middle and advanced stages, and the treatment of the advanced ovarian cancer comprises surgical operation and postoperative adjuvant chemotherapy based on platinum and taxol medicaments. Despite clinical remission after surgery and first-line chemotherapy in most ovarian Cancer patients, Overall Survival (OS) of advanced ovarian Cancer remains at a low level due to disease recurrence or drug resistance [ Jelovac d., Armstrong dk.ca Cancer j.clin.2011, 61 (3): 183-203.]. The traditional chemotherapy drugs have the defects of low specificity, more adverse reactions and the like, and the effect of the new chemotherapy drugs on the patients is not satisfactory, so that the search for more effective methods for preventing and treating ovarian cancer is urgent.
Teprenone [ geranylgeranylacetone (GGA), a product of Eisai, Inc. ], i.e., a mixture of all-trans and mono-cis isomers of 6, 10, 14, 18-tetramethyl-5, 9, 13, 17-nonadecatetraen-2-one (weight ratio of 3: 2), is a non-cyclic isoprenoid compound having a retinoid skeleton and has been widely used in the treatment of digestive tract ulcers. Teprenone has been reported to protect cells of various organs, such as the eye, Brain, heart (see IshiiY., et al. invest. Ophthalmol. Vis. Sci.2003, 44: 1982-92; Tanito M., et al. J. Neurosci.2005, 25: 2396-404; Fujiki M., et al., J. Neurotrauma.2006, 23: 1164-78; Yasuda H., et al., Brain Res.2005, 1032: 176-82; Ooie T., et al., Circulation2001, 104: 1837-43; Suzuki S., et al, Kidney Int.2005, 67: 2210-20). There has also been reported (Japanese patent JP-8-133967) that teprenone is used as an active ingredient of a preventive or therapeutic agent for dry eye, asthenopia or dry eye. Japanese patent JP-2000-319170 discloses a clear eye drop containing teprenone, phospholipids, a synthetic surfactant and water. There is also known a drug for treating retinal diseases produced by Eisai corporation, which comprises cis-trans teprenone as an active ingredient in an unknown mixing ratio.
GGA was found to induce the expression of heat shock protein 70 (HSP 70) and thioredoxin (Trx) (Tsuruma T., et al. Transplant Proc.1999, 31 (1-2): 572-. HSP70 is a widely existing stress protein, and its synthesis can provide organism tolerance to various harmful factors (such as ischemia, anoxia and heavy metal, etc.), make cell in stress state, and quickly activate protein gene related to antitoxic, thereby protecting cell and organism. Trx is an effective antioxidant in cells, and can protect cells and relieve damage caused by oxidative stress. Trx can inhibit the activity of p38MAPK and apoptosis signal regulatory kinase I and enhance the anti-apoptosis ability of cells (SaitoM., et al EMBO 1998, 17: 2596-2606; Hashimoto S., et al, biochem. Biophys. Res. Commun.1999, 258: 443-447).
Teprenone, a mixture of all-trans and single-cis isomers (3: 2 in a mixture ratio), produced by Eisai, inc, for the treatment of digestive ulcers has been reported to cause apoptosis of HL-60 cancer cells (Okada s.et al cell struct. funct.1999, 24: 161-168; Kanno t., et al physiol.chem.phys.med.2002, 34: 1-15.) Hashimoto et al reported that GGA can inhibit the progression of ovarian cancer by inhibiting Rho gtpase and Ras-MAPK enzymes (Hashimoto s, et al cancer 2005, 103: 9-1536; Hashimoto s, et al biochem.biophysis.res.com.2007, 356: 72-77).
As is well known, teprenone produced by Eisai Inc. is a mixture of (5E, 9E, 13E) -teprenone and (5Z, 9E, 13E) -teprenone [ in a weight ratio of 3: 2[ see WO 2004/047822, JP-9-169639A, JP-4621326, JP-2006-89393A, The package description of The Japanese Pharmacopoeia (16th Edition), and The antiulcer drug Scheinx (Selbex) ]. Teprenone sold by other companies is also a 3: 2 mixture of (5E, 9E, 13E) -teprenone and (5Z, 9E, 13E) -teprenone (see, for example, MSDS Cat. No. 202-1S; Waka Puree Industries, Ltd.). Thus, the Hashimoto et al report is limited to a mixture of teprenone containing both all-trans and single-cis isomers produced by Eisai, Inc., and the ratio of both all-trans and single-cis isomers is 3: 2. No studies have been reported on mixtures of the two isomers in other ratios and the use of each isomer alone. Since the pharmacological effects and toxic side effects of the two isomers may differ, it is necessary to separately study the effects of all-trans teprenone (5E-GGA), single-cis teprenone (5Z-GGA), and mixtures of the two isomers in other ratios in the prevention and treatment of ovarian cancer.
Disclosure of Invention
The invention aims to provide application of all-trans teprenone and derivatives thereof in preparing medicaments for preventing and treating ovarian cancer.
The all-trans and single-cis isomers refer to that in the structural formula (I), double bonds connected with R groups are trans or cis, and the structures of other double bonds are shown in the structural formula (I). When the double bond attached to R is trans, the entire molecule is referred to as the all-trans isomer (5E-GGA); when the double bond attached to R is cis, the entire molecule is referred to as the single cis isomer (5Z-GGA).
R is selected from the following four groups:
wherein the content of the first and second substances,
x is C, or S;
y is O, or NR6；
R1Is H, alkyl, cycloalkyl, alkoxy, or NR7R8；
R2Is alkyl, cycloalkyl, aryl, OH, NR7R8Or an alkoxy group;
R3is H, alkyl, cycloalkyl, aryl, or alkoxy;
R4and R5Are each H, alkyl, or alkoxy; r4And R5May be linked to form a cyclic compound;
r6，R7and R8Respectively, H, alkyl, OH, or alkoxy.
The proportion of all-trans and single-cis teprenone in the invention refers to the weight ratio between the two.
The application of the teprenone and the derivatives thereof is to prepare the medicine for preventing and treating ovarian cancer by taking all-trans isomer, single cis isomer or the mixture of the two isomers as active ingredients.
The preparation method of all-trans teprenone and single-cis teprenone is characterized by that the commercially available teprenone mixture (all-trans isomer: single-cis isomer ═ 3: 2) is eluted on silica gel column by using n-hexane/ethyl acetate or petroleum ether/ethyl acetate mixed solvent with proper proportion, and each component is concentrated on rotary evaporator to remove solvent so as to obtain all-trans teprenone and single-cis teprenone.
The all-trans teprenone of the present invention can also be obtained by a method reported in the literature [ Bull. Korean chem. Soc.2009, 30 (9): 215-217]. The One-Pot synthesis method reported in the literature is shown as a reaction formula I:
the reaction formula is I,
The preparation of other teprenone derivatives can refer to the synthesis method of related documents and utilize conventional organic synthesis reaction. Synthesis of some specific compounds see the embodiments section; figure 2 lists some representative compounds.
The activity of the all-trans isomer of the teprenone disclosed by the invention is obviously higher than that of a single cis isomer and higher than that of a mixture of two isomers.
The ingredients (or effective ingredients) of the medicine for preventing and treating ovarian cancer are single teprenone isomer or a mixture of two isomers (except a mixture with the ratio of all-trans to single-cis being 3: 2), and one or more pharmaceutically acceptable auxiliary materials can be added to improve the absorption effect of the medicine or facilitate taking, such as capsules, pills, powder, spray, tablets, paste, patches, oral liquid, injection and the like.
The auxiliary materials comprise conventional filling agents, diluents, binding agents, excipients, absorption enhancers, surfactants, stabilizers and the like in the pharmaceutical field, and flavoring agents, pigments, sweeteners and the like can be added as necessary.
The invention provides a new application of teprenone and derivatives thereof, namely an application in preparing medicaments for preventing and treating ovarian cancer. The biological test result shows that: the all-trans teprenone can better inhibit invasion and proliferation of human ovarian cancer cells Caov-3, and the effect of the all-trans teprenone is obviously superior to that of single-cis teprenone and also superior to that of a mixture of two isomers.
The use of all-trans-teprenone (5E-GGA) for preventing and treating ovarian cancer has the following advantages: (1) the curative effect is better; (2) the safety is high.
The application of all-trans teprenone and a high proportion of trans/cis (except for a mixture with a weight ratio of 3: 2) teprenone mixture in the medicine for preventing and treating ovarian cancer is found for the first time, so that the all-trans teprenone is used as an active ingredient to prepare a medicament alone or is used for preventing and treating ovarian cancer by being matched with other active ingredients to prepare the medicament.
Drawings
FIG. 1 shows the general chemical structures of teprenone and its derivatives.
Figure 2 lists some representative compounds.
FIG. 3 shows the results of experiments on the inhibition of proliferation of human ovarian carcinoma cells, Caov-3, by various teprenone preparations. P < 0.01 relative to cancer cells treated with Lysophosphatidic acid (LPA) alone (control).
Detailed Description
The instrument information for NMR and mass spectrometry of the test compounds of the present invention is as follows:
NMR：
instrument owner name: BRUKER
Instrument Model (Model): AVANCE II 400
Instrument frequency: 400MHz
Testing of commonly used deuterated reagents: CDCl3，d6-DMSO
LC-MS：
Instrument owner name: water
Instrument Model (Model): UPLC-SQD
Test of the usual solvent a: 0.1% formic acid + water
Test of the usual solvent B: 0.1% formic acid + acetonitrile.
Unless otherwise stated, the cytostatic assay of this study was performed according to the conventional MTT assay. Some of the major instruments and consumables in the examples are as follows:
caov-3 human ovarian cancer cell ATCC product
Lysophosphatidic acid (LPA) Sigma product
DMEM Medium Gibco product
Fetal Bovine Serum (FBS): gibco products
96-well cell culture plate Corning product
Product of CellTiter 96AQ kit Promega
Thermo product of Multidrop384 cell dispenser
Perkin Elmer product of EnSpire multifunctional plate reader
Example 1: preparation of all-trans and mono-cis teprenone
A commercially available teprenone mixture (5E-GGA: 5Z-GGA ═ 3: 2) was eluted on a silica gel column with an appropriate ratio of n-hexane/ethyl acetate or petroleum ether/ethyl acetate mixed solvent, and each fraction was concentrated on a rotary evaporator to remove the solvent to obtain all-trans teprenone and mono-cis teprenone, LCMS: MS (m/z): 331.3(MH +); 353.3(M + Na). By H-NMR (CDCl)3) It is determined whether the all-trans or the mono-cis isomer is present.
Example 2: synthesis of all-trans teprenone (reaction type one)
The reaction formula is I,
All-trans-teprenone can also be synthesized by literature reported methods [ fill. korean chem. soc.2009, 30 (9): 215-217]. The One-Pot synthesis method reported in the literature is as follows (reaction formula I): a round bottom flask was charged with geranylaryl linalool (r-1) (0.30mL, 0.91mmol), compound r-2(0.39g, 2.28mmol), p-xylene (4.63mL), and aluminum isopropoxide (0.019g, 0.09 mmol). The reaction flask was put in an oil bath at 160 ℃ and heated with stirring for 6 hours. The reaction was then cooled to room temperature and the solvent was rotary evaporated. Saturated aqueous sodium carbonate solution was added to the residue, and extracted with dichloromethane. The organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated and chromatographed on a silica gel column, eluting with n-hexane/ethyl acetate (40: 1 v/v).1H NMR(300MHz，CDCl3)δ1.60(s，12H，20，21，22， 23-CH3)，1.68(s，3H，19-CH3)，2.01(m，12H，7，8，11，12，15，16-CH2)，2.14(s，3H，1-CH3)， 2.26(m，2H，3-CH2)，2.45(m，2H，4-CH2)，5.09(m，4H，5，9，13，17-CH)。
Example 3: preparation of all-trans and single-cis teprenone mixtures in various weight ratios
The all-trans teprenone prepared above and commercially available teprenone are mixed in different proportions to prepare a teprenone isomer mixture with a desired weight ratio, for example, the all-trans/mono-cis isomer ratio is 7: 3, 8: 2, 9: 1, 9.5: 0.5, 9.8: 0.2, 9.9: 0.1, etc. In the three teprenone samples tested, the ratio of the all-trans and the mono-cis isomers was 10: 0(5E-GGA), 3: 2, 0: 10(5Z-GGA), respectively.
Example 4: preparation of 5E, 9E, 13E-teprenone-2-ol (3) (reaction formula II)
The reaction formula II,
5E-GGA (1) (1.66g, 5mmol) was placed in a round bottom flask) And methanol (10mL), nitrogen blanketed. The reaction flask is put into an ice bath, and NaBH is added in batches under stirring4(0.19g, 5 mmol). Stirring was then continued for 1 hour. The reaction flask was quenched with 40mL of distilled water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. Rotary evaporation of the solvent gave 3; LCMS: MS (m/z): 333.3 (MH)+)。
Example 5: preparation of Compound 4 (reaction type III)
Reaction formula III,
Into a nitrogen-purged reaction flask were placed propenol r-3(87mg, 0.3mmol), triethylamine (0.062mL, 0.45mmol) and dichloromethane (1mL), and cooled to 0 ℃ with stirring. A1M solution of acetyl chloride in dichloromethane (0.42mL, 0.042mmol) was added dropwise to the reaction flask. After the addition was complete, the reaction was stirred at room temperature overnight. Then, an aqueous sodium bicarbonate solution was added to the reaction flask, and extracted 3 times with dichloromethane. The combined organic phases were extracted once with water and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation and then subjected to silica gel column chromatography, eluting with a mixed solvent of ethyl acetate and n-hexane (1: 99-2: 98), to obtain a colorless liquid 4. LCMS: MS (m/z): 333.2 (MH)+)。
Example 6: experiment for proliferation inhibition of teprenone preparation on human ovarian cancer cells Caov-3
The inhibition of the teprenone preparation on human ovarian cancer cells Caov-3 is determined by using CellTiter 96AQ kit (Promega) through MTT test, and the specific steps are operated according to the instruction of the kit. Human ovarian cancer cells, Caov-3, were placed in DMEM medium supplemented with 10% (v/v) Fetal Bovine Serum (FBS) and penicillin (10U/ml) -streptomycin (10U/ml) in a 95% air and 5% CO medium2And culturing at 37 ℃ in an incubator. Cells within 15 passages were restricted to use. Three teprenone samples were dissolved in DMSO separately and then diluted to 50 μ M with PBS. Cells (3X 10)3Perwell) was transferred to a 96-well plate, adsorbed for 4.5 hours, and 25. mu.M lysophosphatidic acid (LPA) and 50. mu.M each were addedVarious teprenone solutions were then cultured in DMEM medium containing 2% FBS for 24-72 hours. Then adding a certain amount of tetrazole compound [3- (4, 5-dimethylthiozol-2-yl) -5- (3-carboxymethylethoxy phenyl) -2- (4-sulfophenyl) -2H-tetrazolium inner salt, MTS, to each well]The solution, after 1 hour, the absorbance of the formazan solution formed at 590nm wavelength was read with an ensspire multifunctional plate reader to calculate the number of viable cells, and all experiments were repeated four times. The proliferation results were expressed as the ratio of the absorbance of GGA-treated cells to the absorbance of control cells. P < 0.01 relative to cancer cells treated with Lysophosphatidic acid (LPA) alone (control). (see FIG. 3).
Claims (10)
1. Use of a compound represented by structural formula (I) and pharmaceutically acceptable salts thereof, wherein the ratio of the trans and cis isomers of the double bond linking R is any ratio other than 3: 2, for the preparation of a medicament for the prevention and treatment of ovarian cancer;
r is selected from the following four groups:
wherein the content of the first and second substances,
x is C, or S;
y is O, or NR6；
R1Is H, alkyl, cycloalkyl, alkoxy, or NR7R8；
R2Is alkyl, cycloalkyl, aryl, OH, NR7R8Or an alkoxy group;
R3is H, alkyl, cycloalkyl, aryl, or alkoxy;
R4and R5Are each H, alkyl, or alkoxy; r4And R5Can be connected to form aA cyclic compound;
R6，R7and R8Respectively, H, alkyl, OH, or alkoxy.
2. The use of teprenone and its derivatives according to claim 1 for the preparation of a medicament for the prevention and treatment of ovarian cancer, characterized in that: r in the formula (I) is a group (II) in which X is C, Y is O, R1Is H, R2Is methyl; the weight ratio of all-trans (5E-GGA) to single-cis teprenone (5Z-GGA) in an effective dose of a mixture of teprenones is any ratio other than 3: 2.
3. The use of teprenone according to claim 2 for the preparation of a medicament for the prevention and treatment of ovarian cancer, wherein: in an effective amount of a mixture of teprenone, the weight ratio of all-trans (5E-GGA) to single-cis teprenone (5Z-GGA) is greater than or equal to 95: 5, 96: 4, 97: 3, 98: 2, 99: 1, 99.9: 0.1, or 99.99: 0.01.
4. The use of teprenone according to claim 2 for the preparation of a medicament for the prevention and treatment of ovarian cancer, wherein the teprenone is all-trans teprenone (1), characterized in that: the purity of a therapeutically effective amount of all-trans teprenone (5E-GGA) is greater than or equal to 98% while the content of mono-cis teprenone is negligible.
5. The use of teprenone and its derivatives according to claim 1 for the preparation of a medicament for the prevention and treatment of ovarian cancer, characterized in that: the compound represented by the structural formula (I) is used as an effective ingredient of a medicament, and the preparation of the medicament dosage form comprises (but is not limited to): tablet, capsule, powder, spray, paste, patch, oral liquid, injection, sustained-release preparation, etc.
6. The use of teprenone according to claim 2 for the preparation of a medicament for the prevention and treatment of ovarian cancer, wherein: the teprenone is taken as an effective component of the medicine, and the medicine dosage forms for preparing the teprenone include (but are not limited to): tablets, capsules, powders, sprays, ointments, patches, oral liquids, injections, or sustained-release agents, etc.
7. The use of teprenone according to claim 3 for the preparation of a medicament for the prevention and treatment of ovarian cancer, wherein: the teprenone is taken as an effective component of the medicine, and the medicine dosage forms for preparing the teprenone include (but are not limited to): tablets, capsules, powders, sprays, ointments, patches, oral liquids, injections, or sustained-release agents, etc.
8. The use of teprenone according to claim 4 for the preparation of a medicament for the prevention and treatment of ovarian cancer, wherein: all-trans teprenone is taken as an effective component of a medicine, and the medicine dosage forms for preparing the medicine comprise (but are not limited to): tablets, capsules, powders, sprays, ointments, patches, oral liquids, injections, or sustained-release agents, etc.
9. The use of teprenone according to claim 2 for the preparation of a medicament for the prevention and treatment of ovarian cancer, wherein: a medicament comprising an effective amount of teprenone is administered orally 1, 2, or 3 times daily.
10. The use of teprenone according to claim 4 for the preparation of a medicament for the prevention and treatment of ovarian cancer, wherein: a medicament comprising an effective amount of all-trans teprenone is administered orally 1, 2, or 3 times daily.
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|---|---|---|---|---|
| CN114983988A (en) * | 2022-06-30 | 2022-09-02 | 深圳市乐土生物医药有限公司 | Application of teprenone in preparation of medicine for treating and/or preventing cancer |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06192073A (en) * | 1992-12-24 | 1994-07-12 | Eisai Co Ltd | Cell differentiation-inducing agent |
| US20050013875A1 (en) * | 2001-10-25 | 2005-01-20 | Takeshi Kobayashi | Immunopotentiators in thermotherapy for cancer |
| WO2012026813A2 (en) * | 2010-08-25 | 2012-03-01 | Nyken Holding B.V. | Analogs of geranylgeranylacetone (gga) and uses thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06192073A (en) * | 1992-12-24 | 1994-07-12 | Eisai Co Ltd | Cell differentiation-inducing agent |
| US20050013875A1 (en) * | 2001-10-25 | 2005-01-20 | Takeshi Kobayashi | Immunopotentiators in thermotherapy for cancer |
| WO2012026813A2 (en) * | 2010-08-25 | 2012-03-01 | Nyken Holding B.V. | Analogs of geranylgeranylacetone (gga) and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| KAE HASHIMOTO等: "Geranylgeranylaceton inhibits ovarian cancer progression in vitro and in vivo", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114983988A (en) * | 2022-06-30 | 2022-09-02 | 深圳市乐土生物医药有限公司 | Application of teprenone in preparation of medicine for treating and/or preventing cancer |
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