Substances KF-1040 and process for producing of the same

Details Substances KF-1040 and process for producing of the same Substances KF-1040 and process for producing of the same

2000-08-08

2002-08-13

Peselev, Elli (Department: 1623)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing compound containing saccharide radical

C435S822000, C514S025000, C536S004100

Reexamination Certificate

active

06432682

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel KF-1040 substance having an inhibitory activity for lipid metabolism as well as to a process for producing such substance.
PRIOR ARTS
There have been known anti-obesity drugs and drugs for hyperlipidemia. For example, centrally acting anorectics will suppress appetite, which may, however, be harmful for health due to reduction of appetite. Therefore, it has been expected to develop a new anti-obesity drug or a therapeutic drug for hyperlipidemia which reveals no side effect.
On the other hand, it has recently been made clear that hydrolysis of sphingomyelin which is one of lipids constituting a biomembrane has involved in the intracellular signal transduction by cytokine, such as interleukin 1&bgr; or tumor necrosis factor &agr; [Y. A. Hannun, J. Biol. Chem., 269, 3125-3128 (1994) and R. Kolesnick & D. W. Golde, Cell, 77, 325-328 (1994)], and in the intracellular signal transduction upon activation of T cells [L. M. Boucher et al, J. Exp. Med., 18, 2059-2068 (1995) and A. Ochi, Medicinal Immunol., 28, 397-401 (1994)] and has a function in the diseases such as arteriosclerosis, inflammations, thrombosis and so on and in the immunoregulation mechanisms therefor. However, any prophylactic or therapeutic medicament for these diseases has not yet been developed in practice from a standpoint of the specific and potential inhibit or for sphingomyelinase, a hydrolase of sphingomyelin.
Problem to be Solved by the Invention
In recent years, increase in the population of patients with life-style related diseases has brought about large problems in the therapeutic and preventive medical sciences. Especially, diseases of obesity and hyperlipidemia by accumulation of triacylglycerols due to recent habit of luxurious diet may often lead to more serious diseases such as arteriosclerosis, fatty liver, hypertension, diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, respiratory problems and some types of cancer.
Obesity refers to a physical state in which the stored fat, constituted mainly of triglycerides, is accumulated excessively in the body, ascribed to an increased synthesis of triacylglycerols causing extraneous accumulation of fat in the adipose tissue. Also triacylglycerolaemia is believed to be triggered by facilitation of triacylglycerol synthesis in intestine and in liver causing, thus, a lipoproteineamia with a high concentration of triacylglycerols in blood. Therefore, it is assumed that any substance exhibiting an inhibitory action onto diacylglycerol:acyltransferase which involves the selective synthesis of triacylglycerols may have an ability for suppressing accumulation of triacylglycerols in adipose tissue and blood and may be effective for the therapy of these diseases.
Under the circumstances, it is believed to be worthwhile in the therapy of obesity and hyperlipidemia and of degenerative diseases, such as arteriosclerosis and so on, originated thererfrom, to provide a substance having an activity of inhibiting diacylglycerol:acyltransferase.
Furthermore, it is also expected that a substance having an activity of inhibiting sphingomyelinase which causes hydrolysis of sphingomyelin, a biomembrane constituting lipid, may be useful as a drug for anti-arteriosclerosis, antithrombosis and antiinflammation and as an immunosuppresant, based on a novel functional mechanism not found heretofore.
Means for Solving Problem
The inventors had conducted researches for metabolic products produced by microorganisms and found that substances which have activities for inhibiting diacylglycerol:acyltransferase and sphingomyelinase were produced in the culture medium on the cultivation of a newly identified fungal strain KF-1040 isolated among sea weed. These active substances capable of inhibiting metabolism of lipids were then isolated from the above-mentioned culture medium and purified, wherefrom the chemical structures thereof were determined as represented by the formulae (I) and (II) given below. Since the substances represented by these formulae (I) and (II) were not known in the past, the inventors have named them as “KF-1040 substance A” and “KF-1040 substance B”, respectively, which are referred to totally as the “KF-1040 substance”.
The present invention has been completed based on the knowledges given above and it relates to the KF-1040 substance comprising the KF-1040 substance A represented by the following formula (I), namely,
and the KF-1040 substance B represented by the following formula (II), namely,
The present invention further relates to a process for producing novel KF-1040 substance comprising culturing a microorganism which belongs to the genus Gliocladium and has an ability of producing KF-1040 substance A and/or KF-1040 substance B in a culture medium, causing to accumulate the resulting KF-1040 substance A and/or KF-1040 substance B in the culture medium and isolating the KF-1040 substance A and/or KF-1040 substance B from the culture medium.
The present invention also relates to a process for producing the KF-1040 substance, wherein the microorganism which belongs to the genus Gliocladium and has an ability of producing KF-1040 substance A and/or KF-1040 substance B is Gliocladium sp. KF-1040(FERM BP-6251). The present invention further relates to a microorganism which belongs to the genus Gliocladium and has an ability of producing KF-1040 substance A and/or KF-1040 substance B.
The microorganism having the ability for producing the KF-1040 substance represented by the formulae (I) and (II)(referred to hereinafter as “KF-1040 material producing fungus”) belongs to the genus Gliocladium and, for example, the fungal strain Gliocladium sp. KF-1040 isolated by the inventors is an example to be utilized at the most effectively according to the present invention. The taxonomical properties of this producing strain KF-1040 are as given below:
1. Morphological Properties
This strain grows relatively good in media containing 50% of seawater (with salt concentration of 3.4%), such as potato glucose agar, cornmeal agar, malt extract agar, Miura agar medium and seawater starch agar, with abundance of conidia.
On microscopic observation of colony grown on a cornmeal agar medium, the hypha is transparent and has a septum. The conidiophore assumes both penicillate and verticillate forms. The penicillate conidiophore (having a length of 100-200 &mgr;m) erects or branches from the basal hypha and forms at the top end or at the branch several penicillate cyclic phialides of sizes of 2.5-3.0 &mgr;m×10-23&mgr;m, on which a conidial mass is formed.
On the other hand, the verticillate conidiophore (having a length of 25-50 &mgr;m) erects from the basal hypha and forms at the top end or at the branch phialides (of sizes of 3.0-5.0 &mgr;m×17-25 &mgr;m) of a form of elongate flask or of cone converging toward the top, from which a sole conidial mass is formed. The conidium is colorless and has a shape of ellipsoid or elongate ellipsoid of a size of 2.5-3.0 &mgr;m×3.0-5.0 &mgr;m, rarely with sharp tip at its one end, for the penicillate conidiophore. For the verticillate, the conidium is colorless and has a ellipsoidal or elongate ellipsoidal form of a size 2.5-3.0 &mgr;m×6.0-8.5 &mgr;m
2. Cultured Properties on Various Media
The results of visual observation of the state of culture of this strain in various culture media at 25° C. for 14 days were as given in the following Table 1.
TABLE 1
Growth condition
on the medium
Color of
Color of
(diameter of
surface of
reverse side
Soluble
Medium
colony)
colony
of colony
pigment
Potate-glucose
good (28-30 mm)
bright gray
bright gray
none
agar medium
floccose, flat
Cornmeal agar
good (24-30 mm)
bright gray
bright gray
none
medium
floccose, stripped
Malt extract
good (20-22 mm)
pale gray
bright gray
none
agar medium
floccose, flat
Miura agar
good (22-24 mm)
bright gray
bright gray
none
medium
floccose, ridged
a few
Seawater starch
good (24-27 mm)
bright gray
white milky
none
agar medium
floccose, flat
3. Physiolo

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