CN105273031B - Novel triterpene compound and application thereof - Google Patents
Novel triterpene compound and application thereof Download PDFInfo
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- CN105273031B CN105273031B CN201410252758.4A CN201410252758A CN105273031B CN 105273031 B CN105273031 B CN 105273031B CN 201410252758 A CN201410252758 A CN 201410252758A CN 105273031 B CN105273031 B CN 105273031B
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Abstract
The invention discloses a novel triterpene compound and application thereof to treat or prevent kidney diseases. The disclosed novel triterpene compound is capable of reducing biochemical indexes (such as content of urea nitrogen (BUN) or creatinine (CRE) in serum) related to kidney inflammation and improving glomerulus filtration rate (GFR), therefore the novel triterpene compound can be used to manufacture medicines capable of treating or preventing kidney diseases.
Description
Technical field
This disclosure relates to a kind of triterpenoid of novelty and application thereof, and which can be used to prepare one kind to control
Treat the medicine of kidney disease (such as acute renal infringement and chronic kidney disease).
Background technology
Acute renal damages (acute kidney injury, AKI), also known as acute renal failure (acute kidney
Failure), Zhao Yin is destroyed in kidney filtration function rapidly, causes the metabolite of internal nitrogen substance (such as carbamide or creatinine
Acid) accelerated accumulation in blood, thus make it is individual there are the symptoms such as tired, loss of appetite, headache, n or V, it is and adjoint
Amount of urine is reduced.AKI is prevailing in sufferer in hospital, particularly severe case.The reason for causing AKI is a lot, such as tissue ischemia
Re perfusion, severe injury, nephropathy or renal transplantation afterwards.But clinically there is no clearly single-minded curable substance AKI at present, therefore many
(for example, dialysed) using supportive treatment, to mitigate symptom as main purpose.If patient can be past from rehabilitation in above-mentioned disease
Toward can also develop into long-term, Patients with Chronic Kidney Disease, need to rely on and wash kidney for a long time, the patient being in a bad way, or even need kidney
Dirty transplanting.
The current coincident with severity degree of condition for being used for judging AKI patient and the index that whether may enter to transform into CKD are glomerule
Filterability (glomerular filtration rate, GFR).GFR values decline often with blood urea nitrogen (blood
Urine nitrogen, BUN) with serum creatinine acid (serum creatinine, CRE) amount increase, therefore, if a compound or
The combination of multiple compounds can effectively improve GFR, while suppressing BUN and CRE, will potentially useful can treat or prevent to prepare
The lead compound of kidney disease (including that acute renal is damaged and chronic kidney disease) medicine.
The content of the invention
This disclosure is at least partly based on the discovery that a kind of sporophore or bacterium from Ganoderma (Ganoderma lucidum)
Isolated or purification in filament and come novel triterpenoid and the compositionss comprising this novel triterpenoid, which can reduce
With nephritis related biochemical indicator thing content (including blood urea nitrogen and serum creatinine acid content) and raising kidney pompon filterability.
This finds the novel triterpenoid and the compositionss comprising this novel triterpenoid for implying this disclosure, can be used as energy
Treatment or the medicine of prevention kidney disease (including that acute renal is damaged and chronic kidney disease).
Therefore, first purpose of this disclosure is to provide a kind of triterpenoid with lower formula (I) structure,
According to embodiment of the present invention, the triterpenoid of formula (I) structure itself can reduce related to nephritis raw
Change index thing content, including blood urea nitrogen (blood urine nitrogen, BUN) and creatinine (serum
Creatinine, CRE) content；And kidney pompon filterability (glomerular filtration rate, GFR) is improved, therefore
May be utilized in fabricating the medicine that can be treated or prevent kidney disease.
Second purpose of this disclosure is to provide a kind of pharmaceutical compositions to treat or prevent kidney disease.This medicine
Learn triterpenoid, its pharmaceutically acceptable salt class, esters of above-mentioned formula (I) structure of the compositionss comprising a pharmacy effective dose
Or solvate；And its pharmaceutically acceptable carrier.
According to embodiment of the present invention, disclosed pharmaceutical compositions can further include at least another kind of triterpenoid, and which is
In group selected from following material composition：Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid C (lucidenic acid C, LAC), Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid N (lucidenic
Acid N, LAN), Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid E2(lucidenic acid E2,LAE-2), it is lucidenic acid A (lucidenic acid A, LAA), red
Sesame acid B (lucidenic acid B, LAB), Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid D2(lucidenic acid D2,LAD-2) and its combination.
According to a better embodiment, triterpenoid of the disclosed pharmaceutical compositions comprising above-mentioned formula (I) structure with
LAA、LAB、LAC、LAD2、LAE2With the combination of LAN, and its pharmaceutically acceptable carrier.Additionally, the pharmaceutical compositions
In, the triterpenoid of formula (I) structure respectively may be about the 5-15% (weight %) of triterpenoid total amount with the amount of LAC；LAA with
LAD2Amount respectively may be about the 15-30% (weight %) of triterpenoid total amount；LAE2Amount be about triterpenoid total amount 8-
15% (weight %)；The amount of LAN and LAB respectively may be about the 5-12% (weight %) of triterpenoid total amount.
The kidney disease for being adapted to be treated with the pharmaceutical compositions or prevented damages (acute comprising acute renal
Kidney injury, AKI) and chronic kidney disease (chronic kidney disease, CKD).In one example, the kidney
Disease is AKI, such as acute renal inflammation.In another example, the kidney disease be CKD, such as chronic kidney inflammation.
If on the basis of pharmaceuticals or pharmaceutical compositions gross weight, triterpenoid combination total amount of the present invention accounts for the pharmacy
0.1% to 99% (weight %) of composition total weight.In some embodiments, the total amount of triterpenoid of the present invention is at least
It is about the 1% of the pharmaceutical compositions gross weight.In certain embodiments, the total amount of triterpenoid of the present invention is at least about this
The 5% of pharmaceutical compositions gross weight.In other embodiments, the total amount of triterpenoid of the present invention is at least about the pharmacy group
The 10% of compound gross weight.In further embodiments, the total amount of triterpenoid of the present invention is at least about the pharmaceutical compositions
The 25% of gross weight.
3rd purpose of this disclosure is to provide a kind of method for treating kidney disease.Methods described includes controlling needs
The triterpenoid of the individual formula (I) structure of the present invention for applying a therapeutically effective amount for the treatment of；Or above-mentioned pharmaceutical compositions.According to
According to a preferred forms, triterpenoid of the pharmaceutical compositions comprising the formula (I) structure, its pharmaceutically acceptable salt
Class, esters or solvate, and LAA, LAB, LAC, LAD2、LAE2And LAN；With its pharmaceutically acceptable carrier.It is adapted to this
The kidney disease treated by inventive method includes AKI and CKD.In one example, the kidney disease be AKI, such as acute kidney
Dirty inflammation.In another example, the kidney disease be CKD, such as chronic kidney inflammation.It is adapted to be treated in the process of the present invention
Individuality can be mammal, the preferably mankind.
Through further detail below and subsidiary claims by can know more about this disclosure these and other
Feature.The general introduction and further detail below that the above need to be known only is illustrated, and for illustrating this disclosure, and is not used to limit this
The category of disclosure.
Description of the drawings
It is that the above-mentioned of the present invention can be become apparent with other purposes, feature, advantage and embodiment, institute's accompanying drawings are said
It is bright as follows：
Figure 1A is the kidney induced according to the formula (I) compound suppression cisplatin of the present invention shown by an embodiment of the present invention
Dirty apoptotic situation；
Figure 1B is to suppress cisplatin to be lured according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention
The situation of the kidney cell apoptosis sent out；
Fig. 2A is in vivo suppressed according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention
The situation that the serum urea nitrogen content induced by cisplatin increases；
Fig. 2 B are in vivo suppressed according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention
The situation that the serum creatinine acid content induced by cisplatin increases；
Fig. 3 is according to the formula (I) compound of the present invention shown by an embodiment of the present invention and pharmaceutical compositions YKII-10
The situation of blood urea nitrogen increase that lipopolysaccharide induced is reduced respectively in vivo；
Fig. 4 A are in vivo suppressed according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention
The situation that the serum urea nitrogen content induced by Aristolochic Acid increases；
Fig. 4 B are in vivo suppressed according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention
The situation that the serum creatinine acid content induced by Aristolochic Acid increases；
Fig. 5 is in vivo improved according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention
The situation of glomerular filtration rate；And
Fig. 6 is in vivo improved according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention
The situation of renal function.
Specific embodiment
In order that the narration of this disclosure it is more detailed with it is complete, below for embodiments of the present invention with it is concrete
Embodiment proposes illustrative description；But this is not implemented or with the unique forms of the specific embodiment of the invention.Embodiment party
Cover in formula multiple specific embodiments feature and to construction with operate these specific embodiments method and step and its
Sequentially.However, being possible with other specific embodiments to reach identical or impartial function and sequence of steps.
It is below the explanation of specific term used in this specification：
Herein, " treatment (treatment or treating) " word includes pharmacy and/or the life that can cause to be asked
The preventing property (that is, preventative) of reason effect, curative or retentivity are disposed.The effect is preferably referred to medically can be partially or completely
Cure or prevent kidney cell apoptosis.Additionally, " treatment " word here refer to based on partially or completely can mitigating, postpones generation,
Suppression process, one or more symptom for mitigating seriousness, and/or reducing a kind of specified disease, exception and/or medical conditions occur
The purpose of probability, and to tested individuality (or patient), espespecially with a kind of medical conditions, a kind of symptom of the medical conditions, one
The disease for kind causing because of the medical conditions or disease or to can make the situation in advance towards the medical conditions development
Body, applies or applies the compound or pharmaceutical compositions of this disclosure.Also can to not yet occur specified disease, it is abnormal and/or
The individuality of the obvious symptom of medical conditions, and/or early stage symptom is produced to the specified disease, exception and/or medical conditions only
Individuality is treated, to reducing the risk of the pathology for producing the specified disease, exception and/or medical conditions correlation.Herein
In, the symptom, disease, exception and/or medical conditions can be acute renal injury (acute kidney injury, AKI)
Or chronic renal disease (chronic kidney disease, CKD).If in one or more symptom or clinical indices i.e. generation, can be reduced
The table treatment is " effective ".
" prevention (prophylaxis) " here refers to the means anti-processed to a kind of future event.Based on prevention kidney herein
Dirty cell because of poisonous substance or medicine and then hiding the Wen Yi that increased those kidney cell apoptosis, therefore, can be exposed in individuality
Before the poisonous substance or medicine, simultaneously or after, preventive disposal means as herein described are implemented.
" effective dose (an effective amount) " word meaning by for treatment kidney disease purpose, this one use
Amount after during appropriate administration, serum urea nitrogen and creatinine amount can be reduced, reduce kidney cell apoptosis or
It is to improve the purposes such as glomerular filtration rate.According to some embodiments, formula (I) compound or the group comprising formula (I) compound
Compound is to be exposed on toxicant (e.g., chemotherapeutics, the lipopolysaccharide that can cause kidney injury in a tested individuality
(lipopolysaccharide, LPS) or Aristolochic Acid (Aristolochic acid I, AA-I)) before, with preventative
Ground mode is first applied to tested individuality.
" compound (compound) ", " compositionss (composition) " " ", " medicament (agent) " or " pharmaceuticals
The word heres such as (medicine or medicament) " are used interchangeably, and all referring to when an individuality is applied to, (mankind are dynamic
Thing) when, a kind of compound of the pharmacy urgently asked and/or physiological reaction can be induced through local and/or systemic effect
Or compositionss.
" applying (administered, administering or, administration) " word here is referred to
With described compound or compositionss, or premedicant (prodrug) (for example, the ester of reactive compound for applying reactive compound
Class), derivant (derivative), or the like (analog) etc., and the reactive compound can be formed in vivo individuality is applied
A suitable consumption person.
The words such as " individual (subject) " or " patient (patient) " are used alternatingly herein, and which refers to acceptable describedization
The animal (including the mankind) of compound and/or method treatment." individuality " or " patient " here covers male and female two kinds of sexes,
Unless otherwise expressly specified.Therefore " individuality " or " patient " comprising any mammal, includes, but not limited to the mankind, inhuman
The primatess of class, such as mammal, Canis familiaris L., cat, horse, sheep, pig, cattle etc., which can be benefited because treating using the compound.
It is adapted to receive the compounds of this invention and/or the animal of method treatment is preferably the mankind.In general, " patient " word and " individuality "
One word alternating with each other can be used herein.
" effective dose (an effective amount) " or " a pharmacy effective dose (a therapeutically
Effective amount) " both alternate with each other can use, it is intended that the medicable compound of a tool or group are applied to treatment target
The dosage of compound.The measurement of curative effect can be objective (being weighed using some tests or mark) or (treatment target of subjectivity
Which is given to effect and the narration felt).The effective dosage ranges of above-mentioned compound or compositionss can be from about 0.1 milligram/public affairs
Jin/day, to about 100 mg kg days, preferably from 1 mg kg day to about 50 mg kg days, is more preferably from 5 millis
G/kg/day is to about 10 mg kg days.Effective dose also can with the different of route of administration and may other
Medicament different and change.
In this manual, unless separately make it is contrary simply, otherwise " triterpenoid " word cover triterpenoid and its
Pharmaceutically acceptable salt class, esters or solvate.For example, formula (I) compound of this disclosure is a kind of triterpene
Compound, therefore, when formula (I) compound of this disclosure is addressed in description, it is also covered by this disclosure formula (I) chemical combination
The salt of thing, esters or solvate." salt " word is represented using a kind of alkali and one kind acid (for example, this disclosure herein
Novel triterpenoid) salt that formed after reaction, the salt obtained from appropriate alkali includes alkali metal (such as sodium), alkali
The salt of earth metal (such as magnesium), ammonium ion and N (alkyl) 4+." esters " word represents the ester of the triterpenoid of this disclosure
Class, by taking formula (I) compound as an example, the esters are by the carboxyl and a kind of alcohols (e.g., C of straight or branched of formula (I) compound1-6
Alcohols) generated after reaction；Or the hydroxyl by formula (I) compound (R-COOH, wherein R are straight with another kind of organic acid
The C of chain or side chain1-6Alkyl) generated after reaction." solvate (solvate) " word here is represented by a chemical combination herein
Institute after thing (formula (I) compound e.g., in this disclosure) and solvent molecule (e.g., the water, ethanol etc.) interreaction around which
The wrong compound of formation.In one example, the solvate of the triterpenoid is the ethanol solvate of formula (I) structure.
Although being all rough numerical value to the numerical range and parameter that define wider range of the present invention, herein as far as possible
Correlation values in specific embodiment are presented accurately.However, any numerical value substantially inevitably contains because of indivedual tests
Standard deviation caused by method.Herein, " about " typically refer to actual numerical value a special value or scope positive and negative 10%,
5%th, within 1% or 0.5%.Or, " about " word represents actual numerical value and falls within the acceptable standard error of meansigma methodss,
Depending on the consideration of those skilled in the art.In addition to experimental example, or unless explicitly stated, when being appreciated that this place
All scopes, quantity, numerical value and percentage ratio are (such as to describe material usage, time length, temperature, operating condition, number
Amount ratio and other similar persons) through modification " about ".Therefore, unless otherwise contrary explanation, this specification and subsidiary power
Numerical parameter disclosed in sharp claim is all rough numerical value, and visual demand and change.At least should be by these numerical parameters
It is interpreted as pointed number of significant digit and applies mechanically the numerical value obtained by general transfer method.
Unless this specification is defined otherwise, the implication of science and technology vocabulary used herein and those skilled in the art institute
Understand and usual same meaning.Additionally, in the case of context of getting along well conflicts, the singular noun used by this specification covers
The complex number type of the noun；And during plural noun used, also cover the odd number type of the noun.
It is isolated from Ganoderma sporophore or mycelial novel triterpene based on one kind that this disclosure is at least part of
Compound and developed, the novel triterpenoid and the pharmaceutical compositions comprising this novel triterpenoid, with can
Reduce serum urea nitrogen and creatinine level and improve the characteristic of kidney pompon filterability.Therefore, this novel triterpenoid with
Pharmaceutical compositions comprising this novel triterpenoid are potentially useful manufacturing the medicament that can treat or prevent kidney disease.
Therefore, first aspect of this disclosure is to provide a kind of triterpenoid with formula (I) structure,
According to particular implementation of the present invention, the disclosed triterpenoid should with formula (I) structure itself has drop
The low serum urea nitrogen caused by medicine (e.g., cisplatin or Aristolochic Acid) or the elevated ability of creatinine, or recover because of medicine
Kidney cell apoptosis phenomenon caused by thing (e.g., cisplatin or Aristolochic Acid).
Inventor is it has also been found that a kind of novel triterpenoid combination, wherein each triterpenoid is isolated from spirit
Sesame sporophore or mycelium, and this novel triterpenoid combines as above-mentioned formula (I) compound, with can reduce by medicine
Serum urea nitrogen or the elevated ability of creatinine that thing (e.g., cisplatin or Aristolochic Acid) is caused, or recover because of medicine (e.g.,
Cisplatin or Aristolochic Acid) caused by kidney cell apoptosis phenomenon.
Based on this, second purpose of this disclosure is to provide a kind of pharmaceutical composition to treat or prevent kidney disease
Thing.Triterpenoid of this pharmaceutical compositions including at least above-mentioned formula (I) structure of a pharmacy effective dose；And which pharmaceutically may be used
The carrier of acceptance.
According to embodiment of the present invention, disclosed pharmaceutical compositions can further include at least another kind of triterpenoid, and which is
In group selected from following material composition：Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid C (lucidenic acid C, LAC), Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid N (lucidenic
Acid N, LAN), Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid E2(lucidenic acid E2,LAE-2), it is lucidenic acid A (lucidenic acid A, LAA), red
Sesame acid B (lucidenic acid B, LAB), Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid D2(lucidenic acid D2,LAD-2) and its combination.
In some embodiments, in the pharmaceutical compositions, the amount of the triterpenoid of formula (I) structure and LAC is respectively about
5-15% (weight %) for total triterpenoids content, e.g., from about 5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,
10.5th, 11,11.5,12,12.5,13,13.5,14,14.5 or 15% (weight %), this is with contained triterpene compound in compositionss
The total amount of thing is calculated as 100% and is obtained.In a preferred embodiments, the triterpenoid of the formula (I) structure is distinguished with the amount of LAC
About the 10% of triterpenoid total amount.
In other embodiments, LAA and LAD in the pharmaceutical compositions2Amount respectively may be about triterpenoid total amount
15-30% (weight %)；E.g., from about 15,15.5,16,16.5,17,17.5,18,18.5,19,19.5,20,20.5,21,
21.5th, 22,22.5,23,23.5,24,24.525,25.5,26,26.5,27,27.5,28,28.5,29,29.5 or 30% (weight
Amount %), this is obtained so that the total amount of contained triterpenoid in compositionss is calculated as 100%.In one example, LAA with
LAD2Amount respectively may be about 25% of triterpenoid total amount in compositionss.
In other embodiments, LAE in the pharmaceutical compositions2Amount be about triterpenoid total amount 8-15%
(weight %)；(the weight of e.g., from about 8,8.5,9,9.5,10,10.5,11,11.5,12,12.5,13,13.5,14,14.5 or 15%
Amount %), this is to obtain so that the total amount of contained triterpenoid in compositionss is calculated as 100%.In one example, LAE2Amount
It is about 12% (weight %) of triterpenoid total amount in the pharmaceutical compositions.
In some embodiments, in the pharmaceutical compositions, the amount of the LAN and LAB respectively may be about total triterpenoids and contain
The 5-12% (weight %) of amount, e.g., from about 5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,10.5,11,11.5 or 12%
(weight %), this is obtained so that the total amount of contained triterpenoid in compositionss is calculated as 100%.In a preferred embodiments,
The amount of the LAN and LAB respectively may be about 8.5% (weight %) of triterpenoid total amount in the pharmaceutical compositions.
According to a preferred forms, triterpenoid of the disclosed pharmaceutical compositions comprising above-mentioned formula (I) structure, LAC,
LAN、LAE2, LAA, LAB and LAD2, and its pharmaceutically acceptable carrier；And the triterpene compound of wherein above-mentioned formula (I) structure
Thing and LAC, LAN, LAE2, LAA, LAB and LAD2Amount respectively may be about total triterpenoids content about 10%, 10%,
8.5%th, 15%, 25% and 25% (weight %).
The triterpenoid of the present invention, including the triterpenoid and LAC, LAN, LAE of above-mentioned formula (I) structure2、LAA、
LAB and LAD2Can be separated by Ganoderma apoplexy due to endogenous wind according to method disclosed in embodiment 1, such as by Ganoderma lucidum (Leyss. Ex Fr.) Karst. (Ganoderma
Lucidum it is isolated in sporophore) or mycelium.No matter raw material is from Ganoderma sporophore or mycelium, and used divides
It is typically all, with solvent (preferably alcohol solution), to be extracted at temperatures greater than room temperature from purification process, then will extraction
Taking thing carries out col-umn chromatography, and which includes but is not limited to high efficiency liquid chromatography (HPLC) and anti-phase liquid chromatography (Reverse
Phase Liquid Chromatograpy) etc., and concentration, drying and other steps, until obtaining the ganoderma active compound
Till dried powder.
The kidney disease for being adapted to be treated with the pharmaceutical compositions or prevented damages (acute comprising acute renal
Kidney injury, AKI) and chronic kidney disease (chronic kidney disease, CKD).In one example, the kidney
Disease is AKI, such as acute renal inflammation.In another example, the kidney disease be CKD, such as chronic kidney inflammation.
In general, if on the basis of pharmaceuticals or pharmaceutical compositions gross weight, triterpenoid total amount of the present invention is accounted for
0.1% to 99% (weight %) of the pharmaceutical compositions gross weight.In some embodiments, triterpenoid of the present invention is total
Amount is at least about the 1% of the pharmaceutical compositions gross weight.In certain embodiments, the total amount of triterpenoid of the present invention is at least
It is about the 5% of the pharmaceutical compositions gross weight.In other embodiments, the total amount of triterpenoid of the present invention is at least about this
The 10% of pharmaceutical compositions gross weight.In further embodiments, the total amount of triterpenoid of the present invention is at least about the pharmacy
The 25% of composition total weight.
The kidney disease for being adapted to be treated in the process of the present invention includes AKI and CKD.In one example, the kidney disease
For AKI, such as acute renal inflammation.In another example, the kidney disease be CKD, such as chronic kidney inflammation.It is adapted to this
The individuality treated by inventive method can be mammal, the preferably mankind.
Said medicine or pharmaceutical compositions, such as Remington ' s can be prepared according to well-established pharmacy preparation method
Pharmaceutical Sciences(17th edition,ed.Alfonoso R.Gennaro,Mack Publishing
Company, Easton, Pa (1985)) preparation method disclosed in a book.Pharmaceutically acceptable excipient refer to can and medicine
Other compositions compatibilities and person compatible with organism in length of schooling agent.
According to disclosed embodiment, can be disclosed to apply via any appropriate route of administration
Medicine or pharmaceutical compositions, capsule, suspension or the lozenge for example taken through oral cavity, or with without intestines and stomach mode
To apply.Include such as intramuscular injection, vein blood vessel injection, subcutaneous injection or intraperitoneal note without the method for application of intestines and stomach
The systemic administration mode such as penetrate.Or, also can pass through and wear epithelium mode and apply, such as local skin is smeared or imbedibility (e.g., is propped up
Tracheal strips, nasal cavity, in oral cavity or nose drop etc.)；Or internal rectum mode is applied.Can be administered alone during administration or and with known
Pharmaceutically acceptable adjuvant is administered together.In better embodiment, can be via oral way (e.g., through food) by the present inventionization
Compound casts individuality.
If with oral way apply, triterpenoid of the present invention or its novel combination formula can be become include it is various auxiliary
Agent (e.g., Microcrystalline Cellulose, Calcium Carbonate, dicalcium phosphate and glycine)；Various disintegrating agents are (such as starch, alginic acid and specific silicic acid
Salt)；And the lozenge of granule adhesive (e.g., polyvinylpyrrolidone, sucrose, gelatin and Australian gum (acacia)).Except this
Outward, the lubricant of magnesium stearate, sodium lauryl sulphate and Talcum etc. can also be included.Preferred materials related to this include
Sugar and high molecular weight polyethylene glycol in Lactose or milk.Above-mentioned solid dosage also can optionally include coating or shell,
Such as Enteric coatings, and for improving the coating of arbitrary active constituents of medicine rate of release.The example of this type coating has been this
Known to art personnel.In one example, the pharmaceutical compositions are to be become lozenge by formula.In another example, institute
It is to be become to be filled in soft or hard gelatin capsule or be encapsulated in the medicated bag of bioerodible by formula to state pharmaceutical compositions
Granule.When occupation mode is suspension for oral use and/or specific remedy (elixirs), active component can be combined sweet with various
Taste agent or flavoring agent, coloring agent or dyestuff formula together, can also add emulsifying agent and/or suspending agent when needing, and such as water,
The diluent such as ethanol, Propylene Glycol, glycerol.In some embodiments, pharmaceutical compositions of the present invention are to be become suitable mouth by formula
The liquid dosage form of clothes.Such liquid formulations can further include the buffer for maintaining pH value.Also this liquid formulations can be filled in
Flexible glue is intracapsular.This liquid dosage form can be a kind of solution, suspension, emulsion, microemulsion, precipitation or the portability present inventionization
Any liquid medium of compound, its pharmaceutically acceptable derivates, isomeric compound, metabolite, salt or solvate.This liquid can
It is designed to improve the dissolubility of its pharmaceutically-acceptable salts class of the compounds of this invention, it is a kind of containing medicine to be formed
Emulsion or dispersion liquid.When using this dosage form, it is by reactive compound and at least one pharmaceutically acceptable accessory drugss (bag
Include, but be not limited to, above-mentioned accessory drugss) be mixed together after formed.
If being applied in parenteral (parenterally) mode, triterpenoid of the present invention or its novel combination can be matched somebody with somebody
The pharmaceutical compositions of Fang Chengwei liquid, which can be can be with intravenous injection, intramuscular injection, subcutaneous injection or peritoneal injection etc.
Sterile solution or suspension that mode is applied.The diluent that may be utilized in fabricating above-mentioned aseptic injectable solution or suspension includes, but
It is not limited to, 1,3 butylene glycol, Mannitol, water, Ringer's mixture, isotonicity sodium chloride solution.Also can be using fatty acid (e.g., oil
Acid) and its glyceride ester derivatives, or it is natural it is pharmaceutically acceptable oil (e.g., olive oil or Oleum Brassicae campestriss) come manufacture be available for injection
Solution or suspension.Can also include in this kind of oily solution or suspension for the alcohols that dilutes or carboxymethyl cellulose or
Similar dispersant.Other conventional surfactants (e.g., Tweens or Spans is serial) or emulsifying agent, or medicine can also be used
It is commonly used to strengthen the medicament of bioavailability during the manufacture formula of field.
Also above-mentioned pharmaceuticals of the invention or pharmaceutical compositions can be made various suitable for mucosal drug delivery (mucosal
Application dosage form), such as buccal (buccal) and/or Sublingual (sublingual) pharmaceutical dosage unit, to deliver medicine
Through oral mucosa.Various biodegradables and pharmaceutically acceptable macromolecule adjuvant, this kind of adjuvant can be used to cause pharmacy
Compositionss have acceptable adsorption effect and desired drug release pattern, and can be with buccal and/or sublingual medications dosage form
In unit, contained active component to be applied or other compositions are compatible.In general, above-mentioned macromolecule adjuvant includes hydrophilic
Polymer, which can be adhered to the wetted surface of oral mucosa.The embodiment of macromolecule adjuvant includes but is not limited to acroleic acid polymerization
Thing and copolymer (acrylic acid polymers and copolymers)；Hydrolyzed polyvinyl alcohol (hydrolyzed
polyvinylalcohol)；Polyethylene oxide (polyethylene oxides)；Polyacrylate
(polyacrylates)；Ethene polymerss and copolymer (vinyl polymers and copolymers)；Polyvinyl pyrrole
Pyridine；Glucose (dextran)；Guar gum (guar gum)；Pectin (pectins)；Starch；And cellulosic polymer
(cellulosic polymers)。
When it is understood that the dosage of triterpenoid of the present invention or its novel combination can be different because individual, this be not only because
It is specific compound used or compositionss, route of administration, compound (alone or together with one or more medicines) in patient's body
The be intended to difference for the factor such as reacting for being caused, it is also possible to affected by other factorses, for example：The morbid state of symptom to be treated
Or the order of severity；Age of patient, sex or body weight, the health status of patient；And the serious journey of the pathological state to be treated
Degree, patient are in other medical treatment or special diet content for carrying out simultaneously；And the other factorses that those skilled in the art are contemplated that；
And the healthcare givers for being responsible for taking care of finally can judge appropriate dosage based on these factors.Adjustable administration dosage and form
To provide preferably therapeutic response.Therapeutically effective amount also refers to compound or the toxicity caused by compositionss or harmful effect simultaneously
Not as good as the treatment interests brought in which.In preferably situation, when being combined in dispensing of triterpenoid of the present invention should adopt
Appropriate dosage is simultaneously continued for some time, to reduce number of times and/or the order of severity that symptom occur.
When the triterpenoid or pharmaceutical compositions of the present invention of formula (I) structure are administered to an individuality, applied
Effective dose is about between 0.1-100 mg kg day whose body weights.The pharmacy group that can be applied to the individuality daily
The consumption of compound about 0.1,0.5,1,2,5,7,9,10,12,15,17,19,20,22,25,27,29,30,32,35,37,39,
40、42、45、47、49、50、52、55、57、59、60、62、65、67、69、70、72、75、77、79、80、82、85、87、89、
, 95,97,99, or 100 mg kg of body weight 90,92；Preferably about 1-50 mg kg of body weight, e.g., from about 1,2,5,7,8,
9th, 10,12,15,17,19,20,22,25,27,29,30,32,35,37,39,40,42,45,47,49,50 mgs/kg of bodies
Weight；More preferably it is about 5-10 mg kg of body weight, the mg kg of body weight of e.g., from about 5,7,8,9 or 10.These dosage can be with single
Apply or be divided into and repeatedly applied in one day.
3rd purpose of this disclosure is to provide a kind of method for treating kidney disease.Methods described includes controlling needs
The individual for the treatment of applies the medicine or compositionss that can treat kidney disease.Treatment is needed badly when this medicine or compositionss are administered to
When with mammalian subject (the preferably mankind), can pass out the formula (I) structure of the present invention of effective dose triterpenoid or
It is the pharmaceutical compositions of the invention described above.This medicine can be by appropriate approach, such as orally, the passive type such as per nasal, transpulmonary, percutaneous
Transfer mode is administered, or via modes such as intravenous injection, intramuscular injection, subcutaneous injection, internal rectum, ophthalmic being administered.
Following examples are for illustrating this disclosure ad hoc fashion, and help skilled in the art realises that and implementing
This disclosure.But this disclosure category is not limited in these embodiments.
Embodiment
Materials and methods
Cell culture
This research uses MDCK dog kidney cell strains, with 1.5x105The density of individual cell/disk is seeded in the culture in 96- holes
In disk, and cultivate in the improved EagleShi culture medium of Jing DulbeccoShi (Dulbecco ' s modified Eagle ' s
Medium, DMEM) in, and all add in the medium 10% hyclone (fetal calf serum, FCS), 100 units/
The penicillin of ml, the streptomycin (Invitrogen, Carlsbad, CA) of 100ng/ml, 2mM L-Glutamic Acid and inessential ammonia
Base acid and Sodium Pyruvate, and maintain (5%CO under 37 DEG C of wet environment2And 95% air).
Laboratory animal
This experiment uses BLb/c mices, raises in the environment of without pathogen, and room temperature is maintained at 22 ± 3 DEG C, relative humidity
50 ± 20% are held in, day and night cycle maintenance 12/12 hour, and can freely take drinking-water and food.Animal feed is using experiment
Mouse feed 5001 (Laboratory Rodent Diet5001) (is purchased fromNutrition International,
Inc.,MO,USA).Drinking water for animals is then using the tap water for boiling.All zoopery operations, all follow Chinese laboratory animal
The specification of " management of laboratory animal and guide for use " that association publishes.
1 the compounds of this invention of embodiment and pharmaceutical compositions
1.1 separate and purification formula (I) compound
By dry weight for 50g ganoderma lucidum sporocarp with disintegrating machine fragmentation after, Ganoderma lucidum (Leyss. Ex Fr.) Karst. powder is placed in into concussion extraction equipment, and plus
Enter ethanol, its ratio is ganoderma lucidum sporocarp powder dry measure：Alcohol by volume=1：24, then concentrating after 37 DEG C of digestions one day.Even
Continuous to repeat aforementioned extraction step for several times, the extract of gained obtains yield about 10% Jing after filtering, merge and drain with concentrating under reduced pressure
The molten thick extraction thing of 5 grams of ganoderma lucidum sporocarp alcohol.By the ganoderma lucidum sporocarp alcohol of above-mentioned gained molten thick extraction thing, with the vacuum drying of 40 DEG C of constant temperature
System sucking filtration overnight removes residual solvent.
In the molten thick extraction thing of 5.0 grams of ganoderma lucidum sporocarp alcohol of dry weight of above-mentioned gained, the ethyl acetate containing equal-volume water is added
(ethyl acetate) is extracted, and obtains another water layer solution and ethyl acetate extract layer solution, and this ethyl acetate is extracted
After layer solution concentrate drying, residual solvent is removed with the vacuum drying system of 40 DEG C of constant temperature sucking filtration overnight, yield can be obtained and accounted for always
The ganoderma lucidum sporocarp acetic acid ethyl ester extract of molten thick extraction thing dry weight 40% (2 grams) of ganoderma lucidum sporocarp alcohol.
The Ganoderma lucidum (Leyss. Ex Fr.) Karst. acetic acid ethyl ester extract that above-mentioned gained is dried, with ethanol dissolving after, carried out point with half preparation scale HPLC
From mobile phase is cyanogen methane/2% acetic acid (1/2～1/4), can obtain formula (I) compound (8mg), and its yield is 0.4%.
Formula (I) compound13C、1H and heteronuclear multiple-bond knot relatedness nuclear-magnetism frequency spectrum (Heteronuclear Multiple
Bond Correlation, HMBC) data is as follows：
MS(EI,20eV),m/z(rel.int.):460[M+](53.56),442(22.56),339(16.46),322
(100),304(46.41)；
HRMS m/z=460.2834 (C27H40O6Calculating molecular weight：460.2819)
IRmax3445,1736,1707,1661cm-1
UV(MeOH)max252nm
Fusing point：124-1260C
1.2 prepare the pharmaceutical compositions YKII-10 containing formula (I) compound
Formula shown in the specific pharmaceutical compositions YKII-10 systems foundation table 2 below for treating kidney disease in this disclosure,
Embodiment 1.1 detached novel formula (I) compound is mixed into after a homogeneous mixture with other known triterpenoids
And be obtained, those triterpenoid systems can be according to any published isolated or purified method, from Ganoderma sporophore or mycelium
Middle isolated or purified and obtain.
Each component content in 2 pharmaceutical compositions YKII-10 of table
2 formula of embodiment (I) compound and YKII-10 pharmaceutical compositions can effectively alleviate or improve the kidney induced by cisplatin
Inflammation
In the present embodiment, with cisplatin (cisplatin) inducing in vitro or in vivo kidney cell apoptosis, then again
Formula (I) compound of the present invention or YKII-10 compositionss are imposed, to assess effect of its treatment kidney disease.
The kidney cell apoptosis induced by 2.1 cisplatin
With 1 × 105The density of individual cell/culture hole, MDCK dog kidney cells are inoculated in 6 flat hole culture plates,
In incubator, after cell attachment, the cisplatin (Cisplatin) with 50 μM anticipates cell 4 hours to overnight incubation, then divides
Not Jia Ru formula (I) compound (50 μ g/mL or 100 μ g/mL) or embodiment 1 YKII-10 pharmaceutical compositions (25-100 μ g/mL)
To process cell, the DiOC6 stains for directly adding 50nM after 24 hours in culture fluid carry out mitochondrial membrane potential dyeing, 37
React 30 minutes at DEG C, then, the feelings dyeed using handstand fluorescence microscope mitochondrial membrane potential. with PBS cell twice
Shape Taking Pictures recording, the kidney cell of apoptosis cannot be dyeed by DioC6, thereby whether assess apoptosis.As a result show respectively
In 1A and Figure 1B.
As Figure 1A block diagrams show, formula (I) compound (50 μ g/mL) is used alone, you can effectively recover cisplatin and induced
The renal tubular cell transmembrane potential of generation declines, and when concentration brings up to 100 μ g/mL, then reversible transmembrane potential decrease beyond 8 one-tenth, makes
Tend to the transmembrane potential of control group.Similar, if applying the YKII-10 pharmaceutical compositions (25-100mg/Kg) of various dose, equally
Also the decline of renal tubular cell transmembrane potential, and its recovery extent can effectively be recovered with the increase of YKII-10 pharmaceutical compositions dosage
And increase (Figure 1B).It follows that formula (I) compound of the present invention or the pharmaceutical compositions YKII-10 comprising formula (I) compound
Rat tubular cell apoptosis can be effectively reversed, therefore be can be used to alleviate or treated nephritis.
The mouse kidney inflammation induced by 2.2 cisplatin
In the present embodiment, 6 weeks big d C57BL/6 mices are selected, experimental group gives embodiment 1.2 with oral way daily
YKII-10 pharmaceutical compositions (10mL/Kg), continuous 5 days, control group mice then gave distilled water, all animals the 2nd day with
Lumbar injection mode gives test mice cisplatin (15mg/kg, i.p.) once, and mouse blood, blood Jing centrifuging and takings are gathered after 3 days
After serum using biochemistry analyzer (TOSHIBA, TBA-40FR) measurement serum urea nitrogen (blood urine nitrogen,
BUN), the numerical value such as serum creatinine acid (creatinine, CRE), to assess mice renal function situation.As a result it is shown in the 2nd figure.
As Fig. 2A and Fig. 2 B show, the YKII-10 pharmacy of the embodiment of the present invention 1.2 is applied with oral way to laboratory animal
Compositionss (10mL/Kg) can effectively reduce the Biochemical Indices In Serum related to inflammation, including BUN and CRE so as to be close to control
Group, represents that the pharmaceutical compositions of the present invention comprising formula (I) compound can effectively be used to alleviate or treat nephritis.
The YKII-10 pharmaceutical compositions of 3 formula of embodiment (I) compound and embodiment 1 can effectively be alleviated or improve in vivo
The nephritis induced by lipopolysaccharide
In the present embodiment, with lipopolysaccharide (lipopolysaccharide, LPS) inducing mouse kidney inflammation
(kidney inflammation), then imposes formula (I) compound of the present invention or YKII-10 compositionss again, to assess its treatment
Effect of kidney inflammation.
BLb/c mice of this test using 6 week old, tests the previous day, animal is grouped according to body weight, each group is confirmed after packet
Between body weight without statistically significant difference.After on-test, daily by lumbar injection LPS (2.5mg/Kg) to mice body, continuously
Injection 5 days, produces inflammation to induce mouse kidney.Meanwhile, and experimental mice embodiment is given once a day with oral way
1.1 formula (I) compound (100mg/Kg) or the YKII-10 compositionss of embodiment 1.2 (dosage is 250mg/Kg)), control
Group mice then gives distilled water.Gather animals urine within the 5th day and the 10th day after on-test respectively, and with ARKRAY urines point
Analyzer determines urine protein content therein, to assess the renal function of mice.As a result it is shown in Fig. 3.
As Fig. 3 block diagrams show, for LPS induces the mouse kidney inflammation for producing, formula (I) chemical combination no matter is single use
Thing (100mg/Kg) or with other known triterpenoid and with (e.g., giving the YKII-10 pharmaceutical compositions of embodiment 1.2
(250mg/Kg) protein content that), can be effectively reduced in laboratory animal urine, represents formula (I) compound of the present invention or bag
Pharmaceutical compositions YKII-10 containing formula (I) compound can effectively be alleviated or treat nephritis.
The infringement of live body acute renal can effectively be alleviated or be improved to the YKII-10 pharmaceutical compositions of 4 embodiment 1 of embodiment
In the present embodiment, with Aristolochic Acid (Aristolochic acid I, AA-I) come induce mice produce acute kidney
Dirty infringement (acute kidney injury), then imposes the YKII-10 pharmaceutical compositions of the embodiment of the present invention 1.2, again to comment
Estimate effect of its treatment acute renal infringement.
4.1AA-I induction renal function injury zootypes
6 weeks big Balb/c mices are selected, and mice AA-I (2.5mg/kg) are given with oral way daily continuous 5 days, it is real
Test group mice daily i.e. with the YKII-10 pharmaceutical compositions (300mg/kg) of oral way administration embodiment 1.2 in on-test
Once, 12 are continuously given, matched group then gives distilled water.Mouse blood was gathered in the 12nd day, the profit Jing after centrifuging and taking obtains serum
The numerical value such as blood urea nitrogen (BUN), creatinine (Creatinine, CRE) are measured with biochemistry analyzer (TOSHIBA, TBA-40FR), with
Assessment mice renal function.As a result it is shown in 4A and 4B figures.
Shown by the 4th figure result, the YKII-10 pharmaceutical compositions of the embodiment of the present invention 1.2 can effectively reduce AAI and be induced
The BUN and CRE of generation, represents that the pharmaceutical compositions YKII-10 of the embodiment of the present invention 1.2 can effectively be alleviated or treat acute renal
Infringement.
4.2 glomerular filtration rates (glomerular filtration rate, GFR) are tested
In the present embodiment, using the fluorescent labeling inulin (Inulin) with kidney pompon as unique excretion pathway, it is injected into
In mice body, the dissipation rate of fluorescence is monitored by living body fluorescent image detecting instrument and then reflect kidney pompon filter efficiency.
6 weeks big Balb/c mices are selected, YKII-10+AAI experimental mices give medicine (dosage is 300mg/Kg))
Continuous 8 days, in the 4th day lumbar injection AA-I (2.5mg/kg) it is continuous 5 days；YKII-10 experimental mices give medicine (300mg/
Kg) continuous 8 days；After AA-I experimental mices give distilled water 3 days, in lumbar injection AA-I (2.5mg/kg) continuous 5 on the 4th
My god, matched group then gives distilled water.After test carries out 8 days, by fluorescent labeling inulin (GFR-Vivo680) (2x10-9Mole) beat
Enter in mice body, by Perkin Elmer living body fluorescents image detecting instrument (FMT4000) the 1st, 5,15,30,45 after injection
Minute detecting fluoroscopic image, calculates fluorescent labeling inulin (Inulin) concentration of residual in mice body, and then calculates kidney pompon
Filtration curve, compares the glomerular filtration efficiency of four groups of mices.As a result it is shown in Fig. 5.
Fig. 5 block diagrams show when mice be exposed on AAI process under, kidney pompon filterability (GFR) from original normal value (about
250 μ L/ minutes) rapid drawdown 10 again to about 25 μ L/ minutes, if being treated with pharmaceutical compositions YKII-10, though cannot reverse completely
Acute renal infringement caused by AAI, but still about 4 times or so of GFR can be effectively lifted, to about 100 μ L/ minutes.
The YKII-10 pharmaceutical compositions of 5 embodiment 1 of embodiment can effectively be alleviated or improve live body chronic kidney disease
In the present embodiment, by excision laboratory animal part kidney so as to which renal function falls to approximately normal dynamic
The 1/6 of thing, then imposes the YKII-10 pharmaceutical compositions of the embodiment of the present invention 1.2 again, to assess its work(for lifting renal function
Effect, thereby reflects the effect of the YKII-10 pharmaceutical compositions of the embodiment of the present invention 1.2 to treatment chronic kidney disease.
8 weeks big Adult male rats are selected, experimental group and matched group (per group of 3 rats), every group of animal is randomly divided into
With excision left kidney 2/3, after allowing animal to rest one week, then right kidney is cut off, experimental animal decreased renal function is made to about
The 1/6 of intact animal, to simulate the renal function situation of chronic kidney disease trouble.Second postoperative week starts dispensing, test group of animals
The YKII-10 pharmaceutical compositions of the embodiment 1.2 of 300 mg kg of body weight are given daily, and matched group then gives water, while by
Animal afterbody is taken a blood sample, and creatinine level in the blood of determination experiment animal is converted into eGFR (estimated through below equation sequence
GFR), assessing renal function, and the eGFR before being tested as the datum line of 100% renal function：
EGFR (ml/min/1.73 square centimeter)=186x (creatinine numerical value)-1.154x(30)-0.203
Then, blood sampling determines creatinine level every two weeks, and is as a result shown in Fig. 6 into eGFR via same formula scales
As Fig. 6 results show, at the beginning of dispensing, the 44% of the renal function about normal rat of experimental animal, Post operation 6 weeks,
The renal function of dispensing group laboratory animal has been obviously improved to the 59% of normal rat, about increases by 15%, and matched group is then unchanged,
Jing T-test calculate the 6th week experimental group, and there were significant differences with statistical meaning with matched group data.
In sum, the novel triterpenoid (that is, formula (I) compound) of this disclosure and include formula (I) chemical combination
The pharmaceutical compositions of thing are the potentially useful medicines to treat acute or chronic kidney disease.
When being appreciated that above-mentioned embodiment and embodiment only illustrate, and those skilled in the art can carry out various repairing to which
Decorations.The purpose of description proposed above, embodiment and data is to make the structure of this specification complete, and as implementation this
Bright illustration.Although this disclosure is disclosed above with embodiment, so which is not limited to this disclosure, Ren Heben
Art personnel, in the spirit and scope without departing from this disclosure, when can be used for a variety of modifications and variations, therefore originally take off
Show that the protection domain of content is worked as to be defined depending on the defined person of appended claims.
Claims (1)
1. a kind of pharmaceutical compositions to treat acute renal injury or chronic kidney disease, sour by formula (I) compound, Ganoderma lucidum (Leyss. Ex Fr.) Karst.
C, Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid N, Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid E2, lucidenic acid A, Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid B and Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid D2Triterpenoid combine；
Wherein：
The amount of the formula (I) compound and Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid C is respectively the 5- of triterpenoid total amount in the pharmaceutical compositions by weight
15%；
Lucidenic acid A and Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid D2Amount be respectively the 15-30% of triterpenoid total amount in the pharmaceutical compositions by weight；
Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid E2Amount pharmaceutical compositions by weight in triterpenoid total amount 8-15%；
The 5-12% of triterpenoid total amount in amount pharmaceutical compositions by weight of Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid B and Ganoderma lucidum (Leyss. Ex Fr.) Karst. acid N.
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| CN201410252758.4A CN105273031B (en) | 2014-06-09 | 2014-06-09 | Novel triterpene compound and application thereof |
| HK16105967.0A HK1217954A1 (en) | 2014-06-09 | 2016-05-25 | A novel triterpenoid and uses thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5631038A (en) * | 1990-06-01 | 1997-05-20 | Bioresearch, Inc. | Specific eatable taste modifiers |
-
2014
- 2014-06-09 CN CN201410252758.4A patent/CN105273031B/en active Active
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2016
- 2016-05-25 HK HK16105967.0A patent/HK1217954A1/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5631038A (en) * | 1990-06-01 | 1997-05-20 | Bioresearch, Inc. | Specific eatable taste modifiers |
Non-Patent Citations (4)
| Title |
|---|
| Anti-infalmmatory and anti-tumor-promoting effects of triterpene acids and sterols from the fungus ganoderma lucidum;Toshihiro Akihisa等;《Chemistry&Biodiversity》;20071231;第4卷;第225页 * |
| Inhibitory effect on NO production of triterpenes from the fruiting bodies of Ganoderma lucidum;Nguyen The Tung等;《Bioorganic & Medicinal Chemistry Letters》;20130103;第23卷;第1429页 * |
| Interaction of ganoderma triterpenes with doxorubicin and proteomic characterization of the possible molecular targets of ganoderma triterpenes;Qing-Xi Yue等;《Cancer SCI》;20080416;第99卷(第7期);第1462页 * |
| Lucidenic acids P and Q, methyl lucidenate P, and other triterpenoids from the fungus Ganoderma lucidum and their inhibitory effects on Epstein-Barr virus activation;Kenji Iwatsuki等;《J.Nat.Prod》;20030312;第66卷;第1582页 * |
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| HK1217954A1 (en) | 2017-01-27 |
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