Process for preparing FR900482 and compounds analogous thereto

Details Process for preparing FR900482 and compounds analogous thereto Process for preparing FR900482 and compounds analogous thereto

1999-04-22

2001-03-20

Lilling, Herbert J. (Department: 1651)

Chemistry: molecular biology and microbiology

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

Preparing heterocyclic carbon compound having only o, n, s,...

C435S256500, C435S929000

Reexamination Certificate

active

06204031

ABSTRACT:

TECHNICAL FIELD
This invention relates to enzyme technology.
More particularly, the invention relates to a process for oxidizing the alcohol side chain of the following compound (II), which is either a compound elaborated by the microorganism
Streptomyces sandaensis
No. 6897 (FERM BP-792) as such or a chemical transformation product thereof, to thereby transform the compound (II) to the following compound (I) having an aldehyde side chain.
Compound (I) is not only a compound having high antitumoral activity of its own but also a synthetic intermediate of other compounds having antitumoral activity, and there has been a standing demand for a microorganism capable of transforming compound (II) to compound (I) with good efficiency.
DISCLOSURE OF INVENTION
(wherein R
1
represents hydrogen, a lower alkanoyl group or a lower alkyl group; R
2
and R
3
each represents hydrogen or a lower alkanoyl group).
The inventors of this invention explored extensively for a microorganism which would be able to convert the alcohol side chain of compound (II) to an aldehyde side chain. As a result, they discovered novel oxidase-producing microorganisms in the genus Fusarium and succeeded in converting this substrate to the following compound (I) having an aldehyde side chain.
(wherein R
1
, R
2
and R
3
are respectively as defined above).
Among species of compound (I) and compound (II), those compounds having hydrogen for each of R
1
, R
2
and R
3
have been named FR900482 and FR066979, respectively. Those compounds are elaborated by the microorganism
Streptomyces sandaensis
No. 6897 (FERM BP-792) and are known compounds having antitumoral and other activities as disclosed in Kokai Tokkyo Koho S61-10590 in Examples 1 and 8 of its specification. Moreover, FR066979 can be produced by the process described in Kokai Tokkyo Koho H1-101893 as well.
FR900482 and FR066979 are the most preferred object compound and starting compound, respectively, of this invention.
Meanwhile, among species of compound (I), the compound having acetyl for each of R
1
, R
2
and R
3
has been named FR066973, the compound having hydrogen for each of R
1
and R
2
and acetyl for R
3
has been named FR66980, and the compound having methyl for R
1
and acetyl for each of R
2
and R
3
has been named FR073317, and those compounds are described in Kokai Tokkyo Koho S61-10590 in Examples 3, 4 (and 6), and 51, respectively, of its specification.
While compounds (I) and (II) contain asymmetric carbon within their chemical structures, the isomers due to the asymmetric carbon also fall within the scope of compounds (I) and (II) of the invention.
Referring to the above formulae (I) and (II), the following are the more specific definitions and preferred examples.
Unless otherwise indicated, the term “lower” is used in this specification to mean 1~6 carbon atoms.
The preferred “lower alkanoyl group” includes C
1-6
alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc., more preferably C
1-4
alkanoyl groups, and particularly acetyl.
The preferred “lower alkyl group” includes C
1-6
alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., preferably C
1-4
alkyl, and more preferably methyl.
The outstanding features of this invention are now described.
The microorganism according to this invention is first described.
Fusarium sp. No. 122 (Strain F-122):
Characters of Strain F-122
The strain named Fusarium sp. No. 122 (hereinafter abbreviated as Strain No. 122), which is capable of transforming compound (II) to compound (I), was newly isolated from the soil sample collected in Yakushima, Kagoshima-ken. The characters of Strain No. 122 are now described.
This fungus Strain No. 122 was isolated from the soil sample collected in Yakushima, Kagoshima-ken. This microorganism gave broadly diffuse growth on various media and formed white to yellowish white colonies. On various media, Strain No. 122 did not form teleomorphs but formed anamorphs characterized by hyphae bearing phialides (conidiogenous cells) and two types of conidia differing in size, i.e. navicular macroconidia and oval microconidia. The mode of conidiogenesis was phialidic. The mycological characteristics of Strain No. 122 are as follows.
The cultural characteristics on various agar media are summarized in Table 1. On potato dextrose agar, the strain gave broadly diffuse growth, which attained a diameter of 8.0 cm or more by 2 weeks at 25° C. The colony surface was elevated, lanose, and white to yellowish white in color. As to conidia, whereas the microconidia were numerous, the macroconidia were few. The reverse color was yellowish white. On corn meal agar, the strain grew as rapidly as on potato dextrose agar, spreading to a diameter of ≧8.0 cm under the same conditions. The colony surface was protuberant, felty or lanose, and white in color. The conidia, particularly microconidia, were abundantly produced. The reverse color of the colony was white to yellowish white.
The morphological characterization was made on the culture using a sporogenetic medium favoring the formation of macroconidia (medium composition: glycerin 1 g; sodium nitrate 0.5 g; potassium dihydrogen phosphate 0.2 g; yeast extract 0.1 g; agar 15 g; distilled water 1 L). The conidiophores of Strain No. 122 cannot be clearly differentiated from the substrate mycelium, and phialides are directly produced in the form of short branches of the aerial and substrate mycelia. There also are cases in which the substrate hyphae form a dense mass like a sporodochium and phialides occur within or on top of the mass. The phialide is colorless, glabrous, cylindrical to lecythiform, measuring 8~17 (~20)×2~3 &mgr;m, and produces macro- and microconidia from its tip in succession. The macroconidia are colorless, glabrous, 2~4 (~6)-celled, navicular or lunate~allantoid, slightly sinuate and acute at both ends, and measuring 25~35 (~42)×3.5~4.5 (~5.5) &mgr;m. The microconidium is colorless, glabrous, 1 (~2)-celled, slightly sinuate oval (perprolate), and measuring 6~16 (~20)×2.5~4 &mgr;m. The substrate mycelium is glabrous, septate, colorless, and branching. The hypha is cylindrical and 2~3.5 &mgr;m in width. Chlamydospores are not formed. When this strain was cultured on Sabouraud's dextrose agar, a black, globose sclerotium is sometimes formed.
Strain No. 122 is able to grow at 2~31° C., with the optimum temperature for growth being 21~25° C. Those data were generated using potato dextrose agar (Nissui).
The above characteristics of Strain No. 122 were compared with the relevant descriptions in the literature on the classification and nomenclature of fungi such as G. R. Barron: The Genera of Hyphomycetes from Soil, pp. 239-241, Williams & Wilkins, Baltimore, 1968; J. A. von Arx: The Genera of Fungi, Sporulating in Pure Culture, pp. 180-184, J. Cramer, Vaduz, 1974; and K. H. Domsch, W. Gams & T. -H. Anderson: Compendium of Soil Fungi, pp. 517-524, Academic Press, London, 1980. The comparison showed agreements with the described characteristics of Fusarium link (1809), suggesting that Strain No. 122 is a strain of microorganism belonging to the genus Fusarium. Accordingly the strain was named Fusarium sp. No. 122. This strain was deposited with National Institute of Bioscience and Human Technology and assigned with the accession number of FERM P-15763 (date of deposit: Aug. 2, 1996), which was subsequently converted to a deposit under Budapest Treaty and assigned with the accession number of FERM BP-6156 (date of deposit: Oct. 23, 1997).
TABLE 1
Cultural characteristics of Strain No. 122
Medium
Cultural characteristics
Malt extract
Growth: Widely diffuse, ≧8.0 cm in dia.
agar*
Surface: Round, flat, felty to floccose,
abundant conidia, yellowish white (4A2)
Reverse: Yellowish white (3A2) to pale
yellow (3A3)
Potato dextrose
Growth: Widely diffuse, ≧8.0 cm in dia.
agar
Surface: Round, protuberant, lanose,
(Difco 0013)
abundant conidia. White (1A1) to yellowish
white (4A2)
Reverse: Ye

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