WO2022052055A1 - Utilisation d'une composition comprenant de l'antrocinol dans la préparation de médicaments destinés à inhiber la croissance de cellules cancéreuses du foie ou de cellules souches de cancer du foie - Google Patents

Utilisation d'une composition comprenant de l'antrocinol dans la préparation de médicaments destinés à inhiber la croissance de cellules cancéreuses du foie ou de cellules souches de cancer du foie Download PDF

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WO2022052055A1
WO2022052055A1 PCT/CN2020/114853 CN2020114853W WO2022052055A1 WO 2022052055 A1 WO2022052055 A1 WO 2022052055A1 CN 2020114853 W CN2020114853 W CN 2020114853W WO 2022052055 A1 WO2022052055 A1 WO 2022052055A1
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cells
liver cancer
androxenol
antrocinol
composition
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PCT/CN2020/114853
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English (en)
Chinese (zh)
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曾耀铭
杨震
叶淇台
吴骏翃
龚建贤
常青
曾德毓
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毓维生物科技股份有限公司
甘肃安卓幸制药有限公司
新加坡绿色化学工程有限公司
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Priority to PCT/CN2020/114853 priority Critical patent/WO2022052055A1/fr
Publication of WO2022052055A1 publication Critical patent/WO2022052055A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the use of a composition for preparing a drug for inhibiting the growth of liver cancer cells or liver cancer stem cells, in particular to the use of a composition comprising Antrocinol for preparing a drug for inhibiting the growth of liver cancer cells or liver cancer stem cells .
  • Liver cancer is a malignant tumor that occurs in the liver or starts from the liver. It is also the fifth most common cancer in the world and the second most deadly cancer. Its incidence is relatively high in Asian countries.
  • the cause of liver cancer may be caused by B. Hepatitis C, hepatitis C, or alcoholic cirrhosis, or diseases including aflatoxins or non-alcoholic fatty liver disease.
  • Sorafenib a multi-kinase inhibitor (MKI) developed by Bayer, as the first-line molecular target drug for patients with advanced HCC; Established in June 1906, it is the first anti-cancer drug approved for nearly 100 years.
  • MKI multi-kinase inhibitor
  • Antrodia cinnamomea (scientific name: Antrodia cinnamomea) has anti-inflammatory, antioxidant and anti-angiogenesis functions, and has been widely used in anti-cancer and liver-protecting health food. It is an effective antagonist of lung cancer and breast cancer, etc., and can affect non-small lung cancer cells by inhibiting the JAK/STAT3 signaling pathway.
  • the present invention has synthesized a new small molecule compound Antrocinol (Antrocinol; (3aS, 4R, 6aS, 10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphthol [ 1,8a-c]furan-1-one), which is a hydroxyl group added to the No. 12 carbon atom of Antrocin.
  • the present invention is the first to discover the anticancer ability of Antrocin in liver cancer.
  • the present invention is the use of a composition for preparing a drug for inhibiting the growth of liver cancer cells or liver cancer stem cells, wherein the composition comprises an effective amount of a compound of formula (I) (Chinese name: Antrocinol; English name: Antrocinol; Chemical formula: (3aS,4R,6aS,10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphthol[1,8a-c]furan-1-one) or its mutual Variant forms, stereoisomers thereof, racemates thereof, metabolites thereof, polymorphs thereof, salts thereof, or solvates thereof.
  • formula (I) Choinese name: Antrocinol; English name: Antrocinol; Chemical formula: (3aS,4R,6aS,10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphthol[1,8a-c]furan-1-one
  • the action mechanism for inhibiting the growth of liver cancer cells or liver cancer stem cells has the same effect as the disclosed anti-cancer action mechanism of the compound of formula (I).
  • composition further comprises a pharmaceutically acceptable salt or carrier.
  • the drug is a drug for treating or preventing metastasis or recurrence of liver cancer cells or liver cancer stem cells.
  • the effective amount of the compound of formula (I) is 0.01 ⁇ M to 1000 ⁇ M.
  • the effective amount of the compound of formula (I) is 0.5 ⁇ M to 1000 ⁇ M.
  • the effective amount is 0.08 mg/kg to 0.8 mg/kg (0.08 mg/kg BW to 0.8 mg/kg BW) of the compound of formula (I) or a tautomeric form thereof per kilogram of body weight administered to a human , its stereoisomers, its racemates, its metabolites, its polymorphs, its salts, or its solvates.
  • the effective amount is 0.24mg/kgBW ⁇ 0.64mg/kgBW of the compound of formula (I) or its tautomeric form, its stereoisomer, its racemate, Its metabolites, its polymorphs, its salts, or its solvates.
  • the effective amount is 0.4 mg/kg BW of the compound of formula (I) or its tautomeric form, its stereoisomer, its racemate, its metabolite, its Polymorphs, their salts, or their solvates.
  • the drug is administered orally, by inhalation or by injection.
  • composition of the present invention can be mixed with carbolic acid, thymol, cineole, benzalkonium chloride, cetylpyridinium chloride, methylparaben, hydrogen peroxide, dumefene, fluoride, biological enzymes, calcium, water, Sweeteners (such as sorbitol, sucrose, sucralose, sodium saccharin and xylitol) and the like are mixed to prepare liquid or paste preparations, such as mouthwash, toothpaste or oral topical preparations.
  • carbolic acid thymol, cineole
  • benzalkonium chloride cetylpyridinium chloride
  • methylparaben hydrogen peroxide
  • dumefene dumefene
  • fluoride fluoride
  • biological enzymes calcium, water
  • Sweeteners such as sorbitol, sucrose, sucralose, sodium saccharin and xylitol
  • liquid or paste preparations such as mouthwash, toothpaste or oral topical preparations.
  • composition of the present invention can be mixed with a moisturizing agent (such as propylene glycol, propylene glycol), an emulsifier (such as: polysorbate, lanolin), etc. to be used in the form of a spray, and can further form a layer on the medical device Antibacterial film.
  • a moisturizing agent such as propylene glycol, propylene glycol
  • an emulsifier such as: polysorbate, lanolin
  • compositions of the present invention can be in the form of solids, solutions, emulsions, dispersions, micelles, liposomes, and other products such as compositions containing one or more of the ingredients of the present invention as active ingredients, or with organic or Inorganic carriers or excipients are mixed to be suitable for enteral or parenteral administration.
  • the active ingredient may be mixed, for example, with pharmaceutically acceptable generally nontoxic vehicles such as tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other suitable form for use.
  • Carriers that can be used include dextrose, lactose, acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silicon dioxide, potato starch, urea, medium chain triglycerides , dextran, and other carriers suitable for use in the preparation of formulations, solid, semi-solid or liquid forms, in addition, stabilizers, thickening agents and coloring and flavoring agents may also be used as auxiliaries.
  • compositions of the present invention may be in oral form, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions for oral use may be prepared according to various known methods of preparing pharmaceutical compositions, and the compositions may contain one or more sweetening agents such as sucrose, lactose or saccharin, such as peppermint, oil of wintergreen or cherry, etc. Flavoring agents, coloring agents and preservatives to provide pharmaceutical aesthetics and taste. Tablets incorporating the active ingredient with non-toxic pharmaceutically acceptable excipients can also be manufactured by known methods.
  • Excipients that can be used are: (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) ) binders such as tragacanth, cornstarch, gelatin or acacia, and (4) lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer duration of action. For example, time delay materials such as glyceryl monostearate or glyceryl distearate can be used, and can also be coated by techniques such as those described in US Pat. Osmotic therapeutic tablet.
  • inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn
  • compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin.
  • an aqueous or oily medium such as peanut oil, liquid paraffin or olive oil.
  • composition embodiments of the present invention may also be in the form of sterile injectable suspensions.
  • This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty acid carriers Such as ethyl oleate or the like. Buffers, preservatives, antioxidants, etc. can be combined as desired.
  • composition embodiments of the present invention can also be mixed with a moisturizing agent (eg: urea; PCA-Na) and a base, and applied to the skin in the form of an ointment.
  • a moisturizing agent eg: urea; PCA-Na
  • Figure 1 is android ((3aS,4R,6aS,10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphthol[1,8a-c]furan-1- ketone) chemical structure diagram.
  • Figure 2 shows the results of Antrocinol inhibiting the proliferation of liver cancer cells
  • Figure 2A shows the toxicity of Antrocinol to HCC cells
  • Figure 2B shows that in Huh7 cells, the effect of Antrocinol as an antiproliferative agent is better than that of Antrocinol Sorafenib and Stivarga
  • Figure 2C shows that androxenol inhibits Huh7 cell proliferation in a time- and dose-dependent manner
  • Figure 2D shows that androxenol dose-dependently down-regulates cell proliferation and cell cycle Relevant biomarkers
  • Figure 2E and Figure 2F show that android inhibits cell number and cell population formation of Huh7 cells; all experimental results are repeated in triplicate and are expressed as mean ⁇ standard deviation.
  • Fig. 3 is to further understand the enhanced information transmission pathway of Andrewsinol in sensitive cells, referring to Fig. 3A, the present invention compares the relationship between the most sensitive cells (Huh7) and the less sensitive cells (SNU387). Gene expression.
  • the gene expression maps of the two cells were obtained from the cBioportal website, and were analyzed using the Gene Set Enrichment Analysis GSEA 4.0.3 software (Broad Institute). The results are shown in Figure 3B.
  • the KRAS/MAPK information transmission pathway is in Huh7 Cells were significantly up-regulated, and RAS would bind to and activate the protein kinase receptor upstream of the MAPK information transmission pathway;
  • Figure 3C and Figure 3D show that android can significantly inhibit the KRAS/MAPK information transmission pathway in Huh7 cells.
  • Figure 4 shows that Andrews can induce apoptosis of liver cancer cells
  • Figure 4A and Figure 4B show that Annexin A5 (Annexin V) analysis results prove that Andrews can promote the apoptosis of Huh7 cells in a dose-dependent manner
  • Figure 4C shows that The apoptosis biomarkers Caspase-3, Caspase-7, Bak and Bax increased with increasing doses of androxanthin; while the expression of anti-apoptotic biomarkers Bcl2 and Bcl-xL decreased
  • Figure 4D shows the Bsx/Bcl2 ratio It reflects the situation of cell apoptosis; the experimental results were repeated in triplicate and expressed as mean ⁇ standard deviation, * means p ⁇ 0.05, ** means p ⁇ 0.01, *** means p ⁇ 0.001; NS means no significant difference.
  • Fig. 5 shows that Andrewsinol inhibits cancer cell stemness of hepatoma cells; Fig. 5A shows that androidxantol can reduce the size of Huh7 cell Tumor spheres; Fig. 5B shows that androidxantol can reduce the size of Tumor spheres in a dose-dependent manner.
  • Figure 5C shows that the inhibitory effect of androxenol is related to the reduction of protein markers of cancer stem cells; the experimental results were repeated in triplicate and expressed as mean ⁇ standard deviation.
  • Figure 6 shows that android inhibits the tumorigenesis of hepatocellular carcinoma in mice.
  • Figure 6A shows tumor burden versus time for different treatments for Huh7 mice with spherical tumors, compared with control and Sorafenib groups, androxanthinol Treatment significantly inhibited tumor growth, while the combination treatment group of android and Sorafenib had the most significant effect, with the lowest tumor burden among all groups;
  • Figure 6B shows the relationship between average body weight and time, the results show that all groups The weight of the mice all appeared to be normal, with no sudden loss or increase, indicating that none of the treatments caused cytotoxicity;
  • Figure 6C is an immunohistochemical staining showing that, compared with the control group, both the android and combination treatment groups observed The expression of ERK and AKT was reduced, while the expression of BAX was increased;
  • Figure 6D is a comparison of the formation ability of spherical tumor cells.
  • the novel small molecule Antrocinol of the present invention (Antrocinol; (3aS, 4R, 6aS, 10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphthol [1,8a- c] Furan-1-one) is based on the synthesis of one of the intermediate products of the asymmetric synthesis series of compounds with a given stereo configuration disclosed in the previous literature (Chem. Commun., 2016, 52: 12426-12429) "Androsinol" The method was synthesized by adding a hydroxyl group on the 12th carbon atom of Antrocin.
  • the android has the following chemical structural formula:
  • cryopreserved cells The activation principle of cryopreserved cells is to thaw quickly to avoid ice crystals recrystallizing and causing damage to cells, leading to cell death. Normal (eg production of monoclonal antibodies or other proteins).
  • the method for quick thawing of cryopreserved cells is as follows: take the cryovial out of the liquid nitrogen or dry ice container, immediately place it in a 37°C water bath for rapid thawing, and gently shake the cryovial to thaw it all within 3 minutes. Wipe the outside of the preservation tube with % alcohol, move it into a sterile cell operating table, take out the thawed cell suspension, slowly add it to the culture container containing the medium (dilution ratio is 1:10 ⁇ 1:15), mix well, Then put it into a CO 2 incubator and change the medium every other day.
  • Human HCC cell lines SNU387, Mahlavu, Hep3B, Huh7 and J5 were obtained from American Type Culture Collection (American Type Culture Collection; ATCC; Manassas, VA, USA).
  • Cells were grown in RPMI 1640 medium containing 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (Invitrogen brand from Life Technologies, Carlsbad, CA) at 37°C and 5% humidity In a carbon dioxide incubator, cells were passaged when they had grown to 95% confluence, or the medium was changed every 72 hours.
  • FBS fetal bovine serum
  • penicillin/streptomycin Invitrogen brand from Life Technologies, Carlsbad, CA
  • TCA Trichloroacetic acid
  • HRP horseradish peroxidase
  • ECL enhanced chemiluminescence
  • the immunodeficient mice used in the present invention were purchased from Lesco Biotechnology Co., Ltd. (NOD/SCID female mice about 4-6 weeks old), and were raised under standard experimental animals without specific pathogens, and were domesticated for one week. After that, start the test.
  • the Huh7 cells were treated with 0.05% trypsin-ethylenediaminetetraacetic acid (trypsin-EDTA) for 3 to 5 minutes to make the cells in a suspended state, and serum-containing medium was added to neutralize the effect of trypsin, and the cells were heated at 1000rpm and 20°C. , Centrifuge for 5 minutes, then remove the supernatant, gently disperse the precipitated cells, then dissolve the cells back into an appropriate volume of culture medium and mix evenly, take a little cell fluid, count the cells with a hemocytometer, and dilute the cells into At a concentration of 10 7 cells per milliliter, approximately 0.15 milliliters were aliquoted into small 1.5 milliliter centrifuge tubes.
  • trypsin-EDTA trypsin-ethylenediaminetetraacetic acid
  • NOD/SCID mice (5/4 treatment groups) with 0.5 x 106 Huh7 hepatoma cells in 0.5 ml PBS, were treated between days 7 and 10 when tumors reached an average size of ⁇ 150 mm3 .
  • Treatment group 1 consisted of 5 mg/kg androxenol in 0.5 ml PBS injected three times per week for up to 4 weeks; treatment group 2 consisted of 10 mg intraperitoneal (ip) injected in 0.5 ml PBS three times per week /kg Sorafenib for up to 4 weeks; Treatment Group 3 consisted of three weekly intraperitoneal (ip) injections of 5 mg/kg androxitol combined with 10 mg/kg Sorafenib for up to 4 weeks; and Control group Treatment group 4 consisted of three weekly intraperitoneal (ip) injections of PBS.
  • the tumor size was measured once a week, and the longest and shortest diameters of the tumor were measured with a cursor ruler. To ensure the accuracy of the measurement, the same person measured the tumor size during the experiment. The tumor tissue was photographed and archived, and then fixed with formalin.
  • the longest diameter is a
  • the shortest diameter is b
  • tumor size (a ⁇ b 2 )/2. Changes in tumor size are graphed as fold calculations.
  • the fold change in tumor volume tumor size (N)/tumor size (N-1).
  • N is the number of weeks.
  • FIG. 1 The chemical structure of the novel small molecule Antrocinol of the present invention is shown in FIG. 1 .
  • the present invention discovers for the first time the anti-cancer ability of androxenol in liver cancer (HCC).
  • Dopaphenol B (SRB) cell viability analysis as shown in Figure 2A, the maximal half-inhibitory dose (IC 50 ) of Andrews in these cell lines were SNU387 (5 ⁇ M), Mahlavu (4.9 ⁇ M), Hep3B (4.6 ⁇ M) and J5 (4.4 ⁇ M); it is worth noting that the Huh7 cell line was the most sensitive to androxenol with an IC50 of 3.8 ⁇ M.
  • the present invention found that the effect of Antrocin as an anti-proliferative agent for liver cancer cells or liver cancer stem cells was unexpectedly stronger than that of "Antrocin” (IC 50 : 9 ⁇ M), "Antrocin;Stivarga””(IC 50 : 11 ⁇ M) and “Sorafenib;Sorafenib” (IC 50 : 12.5 ⁇ M) were both good, and the results in Figure 2C also proved that androxenol inhibited Huh7 cells in a time- and dose-dependent manner. proliferation.
  • the present invention compares the gene expression between the most sensitive cells (Huh7) and the less sensitive cells (SNU387),
  • the gene expression profiles of both cells were obtained from the cBioportal website and analyzed using the Gene Set Enrichment Analysis GSEA4.0.3 software (Broad Institute), and the results showed that the KRAS/MAPK signaling pathway was significantly upregulated in Huh7 cells (Fig. 3B).
  • RAS binds to and activates protein kinase receptors upstream of the MAPK signaling pathway. Androsinol could significantly inhibit the KRAS/MAPK signaling pathway in Huh7 cells ( Figure 3C and Figure 3D).
  • the MAPK messaging pathway is an evolutionarily conserved kinase that regulates basic biological processes, including cell survival and apoptosis.
  • the present invention treats Huh7 cells with different doses of Andrews (0 ⁇ M, 5 ⁇ M, 10 ⁇ M, 20 ⁇ M and 40 ⁇ M) respectively, and uses apoptosis analysis to evaluate the apoptosis rate and Western blotting (Western blot) to analyze the apoptosis rate.
  • Andrews ⁇ M, 5 ⁇ M, 10 ⁇ M, 20 ⁇ M and 40 ⁇ M
  • apoptosis analysis to evaluate the apoptosis rate
  • Western blotting Western blotting
  • LCSCs Liver cancer stem cells
  • HCC Liver cancer stem cells
  • Figure 6A shows the results of different treatments for Huh7 mice with spherical tumors.
  • the androxantol treatment group significantly inhibited tumor growth, although the The treatment of rafenib (Sorafenib) also showed a certain degree of inhibition, but the inhibitory effect was worse than that of the androxenol group, and the best effect could be observed in the combination treatment group of androxenol + sorafenib (Sorafenib). Delayed tumor growth effect, it is worth noting that none of the treatment regimens used in the present invention resulted in significant weight loss in mice ( Figure 6B), indicating that all treatments were not cytotoxic to animals throughout the experiment.
  • Andrews can more effectively inhibit the growth of Huh7 cells than Stivarga or even Sorafenib, and the ERK/AKT protein information transmission pathway in Huh7 cells is Andrews.
  • the present invention is the first invention to propose the anticancer ability of androxenol on hepatocellular carcinoma (HCC), and proves that androxenol is more effective in inhibiting liver cancer cells or liver cancer stem cells than sorafenib.
  • HCC hepatocellular carcinoma

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Abstract

La présente invention concerne une utilisation d'une composition comprenant de l'antrocinol ((3aS,4R,6aS,10aR)-4-(hydroxyméthyl)-7,7-diméthyl décahydro-1H-naphthol[1,8a-c]furan-1-one) dans la préparation de médicaments destinés à inhiber la croissance de cellules cancéreuses du foie ou de cellules souches de cancer du foie. La composition comprend une dose efficace d'antrocinol.
PCT/CN2020/114853 2020-09-11 2020-09-11 Utilisation d'une composition comprenant de l'antrocinol dans la préparation de médicaments destinés à inhiber la croissance de cellules cancéreuses du foie ou de cellules souches de cancer du foie WO2022052055A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109700799A (zh) * 2018-07-06 2019-05-03 北京大学深圳研究生院 牛樟芝素及其微纳米颗粒在制备肿瘤免疫治疗药物中的应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109700799A (zh) * 2018-07-06 2019-05-03 北京大学深圳研究生院 牛樟芝素及其微纳米颗粒在制备肿瘤免疫治疗药物中的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HUANG SHENG-HAN, LIANG KAI-HSIANG, LU JIA-SYUN, CHANG WEI-SHENG, SU MING-DER, YANG TE-FANG: "Total Synthesis of (+)-Antrocin and Its Diastereomer and Clarification of the Absolute Stereochemistry of (−)-Antrocin", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 82, no. 18, 15 September 2017 (2017-09-15), pages 9576 - 9584, XP055910435, ISSN: 0022-3263, DOI: 10.1021/acs.joc.7b01600 *

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