WO2016107582A1 - Compounds from antrodia camphorata, method for preparing the same and use thereof - Google Patents

Compounds from antrodia camphorata, method for preparing the same and use thereof Download PDF

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WO2016107582A1
WO2016107582A1 PCT/CN2015/099894 CN2015099894W WO2016107582A1 WO 2016107582 A1 WO2016107582 A1 WO 2016107582A1 CN 2015099894 W CN2015099894 W CN 2015099894W WO 2016107582 A1 WO2016107582 A1 WO 2016107582A1
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hexane
ethyl acetate
cancer
fraction
silica gel
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French (fr)
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Chiung-Lin LIU
Wei-Tse Tsai
Kai-Hsin HSIEH
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Oneness Biotech Co Ltd
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Priority to JP2017535086A priority patent/JP6896630B2/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/21—Acetic acid esters of hydroxy compounds with more than three hydroxy groups
    • 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
    • A61K31/21—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
    • C07C49/577—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to compounds purified from Antrodia camphorata, the methods for preparing the same and the use thereof; particularly the compounds inhibit proliferation of cancer cells and angiogenesis, and are utilized for treatment of cancer.
  • Antrodia camphorata (originally named as Antrodia cinnamomea) is a Taiwanese endemic fungus growing in the hollow trunk of Cinnamomum kanchirai Hayata, Lauraceae. In folk medicine, Antrodia camphorata is a useful antidote for the intoxication of food or pesticide; it is also used for treatment of hepatitis or other liver diseases. Regarding its high medical value, difficulty in culturing, and slow growth rate, several researches in genomics and metabolomics were published for further understanding about the medical use and culturing method of Antrodia camphorata (Lu et al. 2014 PNAS ⁇ Lin et al. 2011 J Agr Food Chem) .
  • Antrodia camphorata comprises an amount of bioactive compound which is capable of medical use, including large molecule polysaccharide and small molecule terpenes.
  • the polysaccharide consist of various monosaccharide units, most of which is 1, 3- ⁇ -D-glucan, identified by spectrometry. It was reported that polysaccharides of Antrodia camphorata have diverse medical use, such as inhibiting angiogenesis (Yang et al. 2009 J Ethnopharmacol ⁇ Cheng et al. 2005 Life Sci) , inhibiting immune response (Meng et al. 2012 Nutrition) , modulating immune response and inhibiting asthma (Liu et al. 2010 Immunology) , inhibiting hepatitis B (Lee et al.
  • triterpenoids is also a major group of medical compounds from Antrodia camphorata.
  • Cherng et al. reported 3 novel ergostane, a group of triterpenoid compounds: antcins A-C (Cherng et al. 1995 J Nat Prod) , and other 4 novel triterpenoids compounds: antcins E-F ⁇ methyl antcinate G ⁇ methyl antcinate H (Cherng et al. 1996 Phytochemistry) ; following those reports, tens of triterpenoids compounds was reported to be applicable to therapeutic use, such as inhibition of cancer cell proliferation (Wu et al. 2010 J Nat Prod) , inhibition of inflammation (Liaw et al. 2013 J Nat Prod) , treatment of liver cancer and hepatitis (Lien et al. 2014 Molecules) , anti-fatigue (Huang et al. 2012 Evid Based Complement Altern Med) .
  • US7109232 discloses 5 novel compounds purified from Antrodia camphorata and the use, including anti-inflammation and anti-cancer; US7732482 discloses that the said 5 compounds are effective in suppressing fibrosis of organisms.
  • US7342137 discloses a novel group of compounds from Antrodia camphorata, inhibiting various cancer cell lines.
  • US7745647 demonstrates the novel diterpenes from fruiting body of Antrodia camphorata and their use as a neuroprotective agent.
  • US7994158 provides the dehydrosulphurenic acid purified from Antrodia camphorata inhibits the proliferation of cancer, especially leukemia and pancreatic cancer; futhermore, US7531627 provides a 29kDa novel protein ACA1 from Antrodia camphorata, which enhances inflammation and has potential for treatment of cancer.
  • Antrodia camphorata has an amount of substances having potential for treating cancers, some of which were proved to be effective against various cancers. However, little is known about ifthere are still other undiscovered novel compounds and its anticancer effect.
  • Present invention extracts a number of compounds from Antrodia camphorata, identifies their structures and investigates their effects on various diseases.
  • the present invention provides the compound shown as AC007-H1
  • the present invention provides the compound shown as AC009-H1
  • the present invention provides the compound shown as AC012-H1
  • the present invention provides a pharmaceutical composition for treatment of cancer comprising the therapeutically effective amount of compound selecting from the group consisting of AC006, AC007, AC009, AC011, AC012, AC007-H1, AC009-H1 and AC012-H1 or the combination of at least two of the said compounds, and pharmaceutically acceptable vehicles, salts, or prodrugs.
  • the vehicles include excipients, diluents, thickeners, fillers, binders, disintegrants, lubricants, oil or non-oil agents, surfactants, suspending agents, gelling agents, adjuvants, preservatives, antioxidants, stabilizers, coloring agents, or spices thereof.
  • the treatment of cancer is via inhibition of cancer cell proliferation.
  • the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration.
  • the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.
  • the present invention provides a method for treatment of cancer by administering an effective dosage of pharmaceutical composition, wherein the pharmaceutical composition comprises the compound according to the aforementioned composition.
  • the cancer is selected from the group consisting of prostate cancer, liver cancer, melanoma, brain cancer, and colorectal cancer.
  • the cancer is colorectal cancer and liver cancer.
  • the pharmaceutical composition is administered via intravenous injection, subcutaneous injection, oral administration, or topical administration.
  • the present invention provides a method of preparing bioactive compounds and its derivatives from mycelium of Antrodia camphorata, comprising the steps of:
  • fraction F1 eluting with n-hexane/ethyl acetate gradient solutions to obtain fraction F1, F2 and F3, wherein the gradient was 17-22%ethyl acetate, 23-27%ethyl acetate and 28-33%ethyl acetate, respectively, wherein F3 is divided into F3-1, F3-2, F3-3 by retention time;
  • fraction F3-2 with a normal phase MPLC silica gel column, using CH 2 Cl 2 /Acetone gradient solutions (100% ⁇ 0%to 70% ⁇ 30%) as the mobile phase and collecting the fraction of 95% ⁇ 5%to 85% ⁇ 15%and divide into three fractions F3-2-1 to F3-2-3;
  • collecting the fraction of 1%formic acid in H 2 O/Methanol 28/72-22/78 for purification by silica gel column chromatography with n-hexane/Ethyl acetate as the mobile phase and gradient elution (80% ⁇ 20%to 50% ⁇ 50%) , and obtaining AC012 with the elution solution of n-hexane/Ethyl acetate (75% ⁇ 25%-65% ⁇ 35%) .
  • the compounds AC006, AC007, AC009, AC011 and AC012 are the bioactive compounds of Antrodia camphorata.
  • the said compound is further manufactured to obtain bioactive derivatives of hydroxyl group substitution on C4 of the compounds by the steps comprising:
  • the product is eluted out at approximately 1 ⁇ 1 ratio of the gradient solution
  • present invention also provides an anti-angiogenic and anti-proliferative composition
  • an anti-angiogenic and anti-proliferative composition comprising of the abovementioned substances of Antrodia camphorata, proper diluent, excipient, or vehicle; moreover, the composition can inhibit proliferation of highly proliferative cells.
  • Fig. 1 shows the anti-angiogenic effect of the extract AC012 in vitro and (A) control group, (B) AC012 0.1 ⁇ g/ml, (C) AC012 0.3 ⁇ g/mi and (D) AC012 1 ⁇ g/ml was separately added to EPC cell culture.
  • treatment′′ , ′′under treatment′′ and similar terms refer to the methods which ameliorate, improve, reduce or reverse the patient′s disease or any relevant symptoms caused by the disease, or methods which can prevent onset of such diseases or any resulting symptoms.
  • inventive composition can be prepared into a dosage form for suitable application of the inventive composition by using technology commonly understood by a person skilled in the art through formulating the abovementioned compound (s) with a pharmaceutically acceptable vehicle, wherein the excipients include, but are not limited to, solution, emulsion, suspension, powder, tablet, pill, lozenge, troche, chewing gum, slurry, and other suitable forms.
  • the “pharmaceutically acceptable vehicle” may contain one or several reagents selecting form the following list: solvents, emulsifiers, suspending agents, decomposers, binding agents, excipients, stabilizing agents, chelating agents, diluents, gelling agents, preservatives, lubricants, surfactants and other agents suitable for use in the invention.
  • compositions one or more dissolving aids, buffers, preservatives, colorants, fragrances, flavoring agents and the like, which are commonly used for formulation can be added as desired.
  • pharmaceutically acceptable excipients′′ refers to substances known by persons skilled in the art, which are physiologically inert, pharmacologically inactive and are compatible with the physical as well as chemical characteristics of provided compound (s) .
  • Pharmaceutically acceptable excipients include, but are not limited to, polymers, plasticizers, fillers, lubricants, diluents, binders, disintegrants, solvents, co-solvents, surfactants, preservatives, sweetening agents, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents.
  • composition is used to describe solid or liquid compositions in a form, concentration and purity that are suitable for administration in patients and can induce desired physiological changes following administration.
  • Pharmaceutical compositions are typically sterile and non-pyrogenic.
  • the term “effective dosage” as used herein refers to the necessary dosage to cause, elicit, or contribute to the expected biological response.
  • the effective dosage of a pharmaceutical composition varies depending on the following factors, including desired biological endpoint, the drug to be delivered, the composition of the encapsulating matrix, the target tissue, etc.
  • Example 1 preparation of the active substances from Antrodia camphorata
  • the mycelium media of Antrodia camphorata was extracted twice with reflux using hexane for 1-3 hrs each time and the two hexane extracts were combined after vacuum filtration.
  • a column was prepared using silica gel (70-230 mesh) and mycelia and eluted with n-hexane/Ethyl acetate gradient solutions to obtain fraction F1, F2 and F3 and the corresponding gradient elution was 17-22%Ethyl acetate, 23-27%Ethyl acetate and 28-33%Ethyl acetate, respectively.
  • the resulting fraction F3 was divided into F3-1 ⁇ F3-3 three fractions by retention time.
  • fraction F3-1 by silica gel column chromatography (from 50 ⁇ 1 to 20 ⁇ 1 gradient elution) using CH 2 Cl 2 /Acetone as the mobile phase and collect the fraction of 40 ⁇ 1-15 ⁇ 1 for further purification with a normal phase semi-preparative HPLC column and use n-Hexane/Ethyl acetate (4 ⁇ 1) to obtain purified AC006.
  • the extracts AC006, AC007, AC009, AC011 and AC012 are the bioactive compounds of Antrodia camphorata.
  • the compounds were identified by spectroscopic methods, including 1D and 2D nuclear magnetic resonance (NMR) and mass spectral analyses.
  • the structure is shown in below.
  • the purified compounds were subsequently modified to substitute the substituent of C4 and C3.
  • the method of modification is described in the following.
  • the new compounds with hydroxyl group (-OH) on C4 are marked “H1” ;
  • the new compounds with hydroxyl group on C4 and additionally dimethoxy group on C3 are marked “H2”
  • AC012 was hydrolyzed in 1 N (equivalent mole) of NaOMe (sodium methoxide) and anhydrous methanol, respectively. During the hydrolyzation, the reaction was monitored by TLC (thin layer chromatography) until the reaction had been completed. After completion, acidic amberlite was added to neutralize and then was filtered by filter membrane to obtain the intermediate product.
  • NaOMe sodium methoxide
  • anhydrous methanol anhydrous methanol
  • the intermediate product was eluted by normal phase silica gel chromatography, using silica gel as separating resin, gradient of hexane and ethyl acetate as mobile phase, wherein the eluting gradient of hexane: ethyl acetate is from 4 ⁇ 1 to 1 ⁇ 1.
  • the mixture of products AC012-H1 and AC012-H2 was eluted out at approximately 1 ⁇ 1 ratio of the gradient solution, and then was collected and condensed.
  • the retention time to collect AC012-H1 was from 31 to 25 minutes; the retention time to collect AC012-H2 was from 39 to 43 minutes.
  • AC012-H1 and AC012-H2 are shown in the following:
  • the retention time to collect AC007-H1 was from 36 to 43 minutes; AC007-H2, from 47 to 53 minutes.
  • the retention time to collect AC009-H1 was from 27 to 32 minutes; AC009-H2, from 35 to 40 minutes.
  • SRB assay and matrigel capillary tube formation assay were performed to evaluate the anti-angiogenic effect of the purified compounds.
  • Endothelial progenitor cell 5x10 3 cells/well
  • EPCs Endothelial progenitor cell
  • SRB Sulforhodamine B
  • Matrigel was added to 15-well-plates (ibidi) in a total volume of 10 ⁇ l in each well. Plates were stood at 37°C for 30 min to form a gel layer. After gel formation, EPCs (5 x 10 3 cells) treated with or without AC012 (0.1, 0.3, 1 ⁇ g/ml) in presence of VEGF (20 ng/ml) were applied to each well, and plates were incubated for at 37°C 16 hr with 5%CO 2 . After incubation, the inverted contrast phase microscope (Nikon, Japan) was used for subject observation.
  • the inhibitory concentrations of 50%EPC cell proliferation was 29 ⁇ g/ml. In 1 ⁇ g/ml concentration, AC012 was able to inhibit 31.89%tube formation.
  • the anti-angiogenic effect of the purified compounds implicates anti-proliferative effect on cancer cell; SRB assay was performed to further investigate the anti-proliferative effect of purified compound in various cell lines.
  • the purpose of the in vitro experiment is to evaluate the effect of AC006, AC007, AC009, AC011 and AC012 on cell proliferation in various cell lines.
  • SRB Sulforhodamine B
  • the bioactive compounds were purified to definite constituent and were shown to have inhibitory effects on angiogenesis at very low concentrations.
  • Such compound not only can be purified from Antrodia camphorata mycelium by liquid fermentation, but also can be produced through chemical synthesis.
  • This novel process can significantly reduce the cost of preparation and solve the issue of high demand for scarce Antrodia camphorata.
  • the present invention provides a novel application of bioactive substances which are to be used as drugs through its anti-angiogenesis activity and anti-proliferative on highly proliferating cells, i.e. cancer cells. Furthermore, by modifying the substituent, the bioactive compounds display more effective properties of anti-proliferation and anticancer.
  • AC012-H1 shows extraordinary effectiveness against colorectal cancer cell, the proliferation of which was significantly inhibited by AC012-H1, implying that the modification of substituent is successful in enhancing the efficacy against cancer cells, especially colorectal cancer cells, wherein the feature of HCT116 cell line is low expression of Bax (Wang et al. 2012) , growth factor (TGF ⁇ and EGFR) -independent (Howell et al. 1998) . Additionally, some compounds show excellent effectiveness against the proliferation of liver cancer cell, specifically, Huh-7, epithelial-like tumorigenic cells derived from an Asian, carrying a HFE mutation (Vecchi et al. 2009) .
  • present invention presents an original approach for extraction of bioactive compounds and further identified their multifunctional properties in terms of anti-angiogenesis and anti-proliferation.

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PCT/CN2015/099894 2014-12-30 2015-12-30 Compounds from antrodia camphorata, method for preparing the same and use thereof Ceased WO2016107582A1 (en)

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PL15875258T PL3240772T3 (pl) 2014-12-30 2015-12-30 Związki z antrodia camphorata, sposoby ich otrzymywania i ich zastosowanie
EP15875258.4A EP3240772B1 (en) 2014-12-30 2015-12-30 Compounds from antrodia camphorata, method for preparing the same and use thereof
ES15875258T ES2869904T3 (es) 2014-12-30 2015-12-30 Compuestos de Antrodia camphorata, método para prepararlos y uso de los mismos
JP2017535086A JP6896630B2 (ja) 2014-12-30 2015-12-30 牛樟芝化合物、その製造方法及び用途

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CN106063800B (zh) * 2016-08-01 2020-02-18 上海交通大学 牛樟芝在抗前列腺增生药物中的应用
ES2941463T3 (es) 2016-11-18 2023-05-23 Golden Biotechnology Corp Composiciones para el tratamiento de la dermatitis atópica
CN108409571A (zh) * 2018-03-23 2018-08-17 中国药科大学 从金刚纂中提取的用于治疗癌症的化合物
WO2020176436A1 (en) * 2019-02-25 2020-09-03 Arjil Biotech Holding Company Limited Method and composition for inhibiting virus infection
CN113831221B (zh) * 2021-09-18 2023-04-07 云南民族大学 一种倍半萜类化合物及其制备方法与应用
CN114487252B (zh) * 2021-12-28 2024-03-26 陕西嘉禾生物科技股份有限公司 一种用于区别牛樟芝和牛樟木的薄层色谱鉴别方法

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