Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing a...
Patent
1998-02-26
2000-11-14
Marx, Irene
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing a...
4352521, C12P 3300
Patent
active
061468444
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a method for hydroxylating cholesterol by the action of microorganisms, and more specifically to a method for preparing one or more of either 25-hydroxycholesterol, 17,25-dihydroxycholesterol or 25,26-dihydroxycholesterol from cholesterol. The invention also relates to the aforementioned new dihydroxycholesterols.
BACKGROUND ART
For a biological method, in particular, a method for preparing hydroxy-derivatives of steroids including cholesterol by means of microorganisms, a method by which cholesterol is converted into 25-hydroxycholesterol using microorganisms of the genus Streptomyces has been disclosed in Japanese Laid-Open Patent Publication No. 123997/95. Also, in the biological conversion, which is interesting, of compounds other than steroids, there are known the methods for preparing 25-hydroxyvitamin D compounds by the hydroxylation of vitamin D compounds using microorganisms, for example, Nocardia autotrophica, Streptomyces roseosporus, Amycolata saturnea, Amycolata autotrophica, Sphingomonas sp. (Japanese Laid-Open Patent Publication Nos. 166090/92, 241197/95).
It is known that cholesterol may be, for example, an intermediate on the chemical synthesis of various kinds of vitamin D compounds (Yuki Gosei Kagaku (Organic Synthetwic Chemistry) 37, 809-829 (1979)), and compounds wherein one or more of the specific sites of cholesterol is/are hydroxylated beforehand may be expected for their use as intermediates on the synthesis of various hydroxylated vitamin D compounds. Indeed, according to the conversion method using microorganisms described in the abovementioned Japanese Laid-Open Patent Publication No. 123997/95, it has been published that cholesterol can be selectively hydroxylated at the 25-position which is preferable in relation to activated vitamin D.
However, the hydroxylation efficiency, according to the method described in said patent publication, is not always satisfactory. From the view point of improving the water-solubility of final compounds derived from cholesterol, for example, vitamin D compounds, it would be also desired to provide not only mono-hydroxylated cholesterols but also further hydroxylated cholesterols, for example, dihydroxylated cholesterols.
The purpose of the present invention is therefore to provide a method for efficiently preparing mono-hydroxylated cholesterols, in particular 25-hydroxycholesterol, and a method for preparing further hydroxylated dihydroxycholesterols, and new dihydroxycholesterols per se.
DISCLOSURE OF INVENTION
In the course of intensive study for the accomplishment of the above purpose, the present inventors have found that microorganisms of genera other than the genus Streptomyces described in the abovementioned Japanese Laid-Open Patent Publication No. 123997/95 hydroxylate cholesterol not only at the 25-position but also at the 17- or 26-position.
Thus, the above purpose can be achieved by providing a method, by which cholesterol having formula (I) ##STR1## is biologically converted into hydroxylated cholesterols of formula (II) ##STR2## (in which R.sup.1 is a hydroxyl radical, and R.sup.2 and R.sup.3 are a hydroxyl radical and a hydrogen atom, respectively, or a hydrogen atom and a hydroxyl radical, respectively), for preparing hydroxylated cholesterols having the formula (II), according to the invention, comprising out, and in which cholesterol having the formula (I) is treated by incubation in the presence of a microorganism, chosen from those that belong to the genus Amycolata and the genus Sphingomonas, or its preparation from cultures and oxygen, and formula (II) is recovered from the incubation-treated solution.
Among the hydroxylated cholesterols having the formula (II), dihydroxycholesterols of formula (II-b) ##STR3## (in which R.sup.2 and R.sup.3 are a hydroxyl radical and a hydrogen atom, respectively, or a hydrogen atom and a hydroxyl radical, respectively) can be also prepared by another method in which 25-hydroxycholesterol is substituted for cholesterol as a starting ma
REFERENCES:
patent: 4204995 (1980-05-01), Barner et al.
Cesario et al., "The absolute configuration of C-25 epimers of 25, 26-dihydroxycholecalciferol by X-ray differaction analysis", Tetrahedron Letters, No. 12, pp. 1097-1098, 1978.
Lam et al., "Synthesis and Biological Activity of 25E, 26-Dihydroxycholecalciferol", Steroids, vol. 25, No. 2, Feb. 1975, pp. 247-256.
Partridge et al., "Synthesis and Structure Proof of a Vitamin D.sub.3 Metabolite, 25(S), 26-Dihydroxycholecalciferol", Journal of the American Chemical Society, vol. 103, No. 5, Mar. 11, 1981, pp. 1253-1255.
Koizumi et al., "Stereoselective Introduction of Hydroxy Groups into the Cholesterol Side Chain. Preparation of (24R)- and (24S)-24, 25-Dihydroxy- and (25R)- and (25S)-25, 26-Dihydroxyvitamin D.sub.3 by Asymmetric Synthesis", Journal of the Chemical Society, Perkin Transactions 1., No. 7, 1983, pp. 1401-1410.
Barner et al., "Configuration of the Vitamin-D.sub.3 -Metabolite 25, 26-Dihydroxycholecalciferol: Synthesis of (25S,26)- and (25R,26)- Dihydroxycholecalciferol", Helvetica Chimica Acta, vol. 64, No. 3, 1981, pp. 915-938.
Ishiguro et al., "Stereoselective Introduction of Hydroxy-groups into the 24-, 25-, and 26- Positions of the Cholesterol Side Chain", Journal of the Chemical Society, Chemical Communications, No. 3, 1981, pp. 115-117.
Sasaki et al., "Manufacture of vitamin D with Actinomycetes", Chemical Abstracts, vol. 118, No. 17, Apr. 26, 1993, Abstract No. 167619 and JP 04 356 190 A.
Database WPI, Section Ch, Week 9304, Derwent Publications Ltd., London, GB; Class B01, AN 93-030367, XP002070167 and JP 04 356 190 A (Taisho Pharm. Co. Ltd.).
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Dobashi Kazuyuki
Takeda Koji
Terasawa Tadashi
Yoshioka Takeo
Marx Irene
Mercian Corporation
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