Biologically active compounds of Ganoderma pfeifferi DSM 13239

Details Biologically active compounds of Ganoderma pfeifferi DSM 13239 Biologically active compounds of Ganoderma pfeifferi DSM 13239

2001-12-10

2004-04-27

Tate, Christopher R. (Department: 1651)

Drug, bio-affecting and body treating compositions

Extract or material containing or obtained from a...

Reexamination Certificate

active

06726911

ABSTRACT:

DESCRIPTION
The present invention relates to novel biologically active compounds from fungi of the species
Ganoderma pfeifferi
DSM 13239, processes for their preparation, and their use. From the fruit body and mycelium of the species
Ganoderma pfeifferi
DSM 13239, extracts can be obtained which have antimicrobial activity and are suitable as preserving agents, for pharmaceutical and cosmetic preparations, for controlling infections, and for use in fish breeding.
PRIOR ART
Biologically active compounds which can be obtained from certain fungi of the genus Ganoderma by extraction with solvents have long been described and summarized by us in a monograph (U. Lindequist: Ganoderma. In: Hagers Handbuch der pharmazeutischen Praxis/Ed. F. von Bruchhausen, 5th Edition, totally revised, Springer Publishers Berlin, Heidelberg, N.Y., 1998, Supplement Volume 2, Drogen A-K (Ed. W. Blaschek), pages 750-761. In the following, reference is made to the literature stated therein.
To date, commercially utilized drug-supplying species of the genus Ganoderma only include
Ganoderma applanatum
(
Ganoderma applanatum
fruit bodies) and
Ganoderma lucidum
(
Ganoderma lucidum
fruit bodies). Due to its valuable components,
G. lucidum
is grown commercially in various Asian countries (Japan, China, Korea etc.) in large amounts on artificial substrate (Hager, references 20, 25).
For extracting the active substances from
G. lucidum
and
G. applanatum
, various solvents have been employed. To date, dichloromethane and ethyl acetate have not been used.
The most important group of active substances of these fungi are the triterpenes, polysaccharides and sterols. More than 100 triterpenes have been structurally elucidated. They are referred to, inter alia, as ganoderic acids, ganodermic acids, ganoderenic acids, ganolucidic acids, ganosporeric acids, lucidenic acids, ganoderiols, epoxyganoderiols, ganoderals, ganoderols, lucidones, ganodermanonediol, ganodermanonetriol and ganodermatriol. Due to the different designations of a compound in different working groups, there are numerous double usages and unclarities. The basic body is a lanostane, which is mostly unsaturated, often with two conjugated double bonds in the ring system in positions 7 and 9(11), or one double bond in position 8 which is in conjugation with two oxo groups in positions 7 and 11. The acids have a carboxy group at the end of the side chain in position 26. In the trinortriterpenic acids (C27 compounds), the lucidenic acids, the carboxy group is in position 24. Methyl esters of the acids also exist. The hydroxy groups are in part acetylated or dehydrogenated into oxo groups. In some members, there has been degradation of the side chain to as few as two carbon atoms (C23 compounds).
During the development of the fruit bodies, changes in the triterpene pattern of the fungi occur. In the mycelium stage, the ganoderic acids are predominant, but with progressing development of the fruit bodies, lucidenic acids are increasingly occurring (Hager, reference 22). In the polysaccharides, a distinction can be made between glucanes, heteropolysaccharides and protein-bound polysaccharides.
In addition, various proteins, steroids, nucleotides and some further small-molecular compounds have been characterized in
Ganoderma lucidum.
As the main sterols, ergosterol and ergosta-7,22-dienol have been identified (Hager, references 15, 56, 65). In addition, ergosterol peroxide, ergosta-7,22-diene-3&bgr;-yl palmitate (56, 66), 6&agr;- and 6&bgr;-hydroxyergosta-4,7,22-triene-3-one (52), ergosta-7,22-diene-3&bgr;-yl linoleate, 5&agr;,8&agr;-epidioxyergosta-6,22-diene-3&bgr;-yl linoleate and ergosta-7,22-diene-2&bgr;-3&agr;,9&agr;-triol (66) have been identified.
Further components are adenosine in concentrations of from 40 mg/100 g of dried fruit bodies (Hager, reference 67), and 5′-deoxy-5′methylsulfinyladenosine (Hager, reference 68).
From extracts of the cultured mycelium, a polypeptide referred to as Ling Zhi-8 (LZ-8) and consisting of 110 amino acids and having a molecular weight of 12,420 Dalton has been isolated whose amino end is acetylated (Hager, references 69, 70). In addition, a lectin consisting of 2 protein subunits (molecular weights 55,600 and 59,800 Dalton) and a carbohydrate content of 2.56% has been found (Hager, reference 72).
Extracts from
G. lucidum
have long been used as medicaments. The effects of extracts from
Ganoderma lucidum
are very complex and varied, and it was seldom possible to date to assign them unambiguously to individual active substances. The following effects of extracts from
G. lucidum
belong to the prior art.
Extracts having effects on the CNS: An aqueous extract of the fruit bodies has centrally inhibiting and muscle-relaxing effects in mice. In a dose-dependent way, 30, 100 and 300 mg of the lyophilized extract per kg of body weight, s.c., suppress the activity of the animals in a running wheel, the locomotive activity and the centrally stimulating effect of caffeine. The pain threshold in the heat plate test is increased. In the tail pressing test, analgesic effects occur. 300 mg/kg prolongs the time until onset of death after the administration of strychnine (1.5 mg/kg, i.p.) or caffeine (400 mg/kg, i.p.), the spasms induced by the alkaloids not being influenced (Hager, reference 73). In rats, Ganoderma extracts are said to have a sleep-promoting effect (Hager, reference 74).
Extracts having effects on the cardiovascular system: Hexane and methanol extracts of the fruit bodies (1 mg/ml) significantly reduce the contraction rate of cultivated myocardial cells of mice in vitro by 25 and 80%, respectively. The hexane and aqueous extracts increase the contraction amplitude by about 15% at the mentioned concentration. Responsible compounds for the former effect are ganoderic acid S, ganoderal A and ganodermanonetriol. 0.1 mg/ml of this compound will result in a complete stop of the contractions. The increase of the amplitude is caused by ganoderic acid S, portensterol and ganodermanonetriol (Hager, reference 5).
In vivo, a lyophilized aqueous extract was administered to patients with essential hypertension (group I) and to patients with a mild or no hypertension (group II) orally in the form of tablets over a period of 6 months (6 tablets with 240 mg of extract per day). In the patients of group I, a significant decrease of the increased blood pressure occurred while that of patients of group II was not influenced. Side-effects did not occur (Hager, reference 76).
Spontaneously hypertensive rats whose feed contained 5%
Ganoderma lucidum
powder exhibited a significantly reduced systolic blood pressure and a reduced total cholesterol level in the plasma and liver as compared to the control group after 4 weeks with a corresponding diet (Hager, reference 77).
Morigiwa et al. (Hager, reference 39) found inhibition of the angiotensin-converting enzyme in 10 triterpenes in vitro and thus another possible explanation of the antihypertensive effects. The most potent was ganoderic acid F (IC
50
4.7×10
−6
M). Ganoderal A, ganoderols A and B and the ganoderic acids B, D (C), H, K, S and Y were active with an average IC
50
of 10
−5
M.
Extracts having effects on the blood: An aqueous extract (50 &mgr;l of the extract, 5 g of the fungus extracted with 300 ml) inhibits the thrombin-induced aggregation of bovine platelets in vitro. Adenosine has been identified as the responsible active substance (Hager, reference 67). On the other hand, raw extracts do not exhibit an anti-platelet activity in HIV-positive hemophilic patients despite of high adenosine concentrations (Hager, reference 78). Further active substances for which an effect on platelet aggregation has been detected in vitro include 5-deoxy-5-methylsulfinyladenosine (Hager, reference 79) and ganodermic acid S. In a concentration of 50 &mgr;g/ml, the adenosine derivate inhibits the ADP-induced aggregation of rabbit platelets, but not the PAF-stimulated aggregation (Hager, reference 79). Ganodermic acid S has membrane activity and

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