Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing saccharide radical
Patent
1999-01-28
2000-11-21
Marx, Irene
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing saccharide radical
435 25, 435119, 435170, C12P 1944
Patent
active
061501409
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the biotransformation, effected by means of selected microbial strains, of colchicinoid compounds, into the respective 3-O-glycosyl derivatives. The process of the present invention provides colchicinoid compounds glycosylated exclusively at C-3 of the aromatic ring A, starting from colchicine, thiocolchicine or the derivatives thereof, in high yields and purity.
BACKGROUND OF THE INVENTION
The colchicinoid compounds glycosylated at C-3 of the benzene ring are of remarkable pharmacological importance for their high effectiveness or for the preparation of new medicaments.
In particular, thiocolchicoside (3-O-glucosylthiocolchicine) is an active ingredient of remarkably important use in the pharmaceutical field, mainly in the therapy of diseases of the muscle-skeletal system, and as starting materials for the preparation of novel antitumor, immunosuppressive, antipsoriasis and antiinflammatory medicaments.
A number of efforts for the preparation of 3-glycosylcolchicinoid compounds have been carried out in the past, either by means of chemical reactions or by biotransformation.
The chemical route consists in sequences of complex, non-specific reactions which lead to a mixture of glycosylated derivatives, some of which are inactive. Therefore, yields of the product specifically glycosylated at C-3 of the aromatic ring, are very low.
The biological approach substantially relates to the biotransformation of thiocolchicine, by culture of Centella asiatica, into monoglycosylated derivatives at C-2 and at C-3 of the aromatic ring; such a transformation is therefore not highly selective and provides scarce yields and productivity (Solet, J. M., et Al., Phytochemistry 33, 4, 817-820, 1993).
Other efforts to biotransform colchicinoid compounds gave simply demethylations of the methoxy groups bound to the aromatic ring (at C-2 and at C-3), and were always characterized by limited yields and productivity and by poor regioselectivity.
Thus, Hufford C. D. et al. (J. Pharm. Sc., 68, 10, 1239-1242, 1979), using Streptomyces griseus and/or Streptomyces spectabilis, and Bellet P. et al., (GB-923421, 1959), using different strains of Streptomyces and of other species of Bacteria and Fungi, tried to transform colchicine and its derivatives into the corresponding 3-demethylated derivatives. The results of these known methods confirm what is stated above in connection with the non-selectivity of the microbial enzymes involved at, for example the C-2, C-3 and C-10 positions of the alkaloid molecule. Moreover, the productivity levels of said catalytic systems are rather poor, due to the low conversion yields, the reduced substrate concentrations which can be used, and the frequent degradation of the tropolone ring.
More recently, Poulev et al. (J. Ferment. Bioeng. 79, 1, 33-38, 1995) have obtained the specific biotransformation using bacterial microorganisms, but still achieve poor yields and productivity.
Enzyme activity from microorganisms similar to the above mentioned ones (Streptomyces, Bacillus, etc.) have been applied to the biotransformation of other compounds, such as maytansinoids (U.S. Pat. No. 4,361,650: Izawa, M., et al., J. Antibiotics, 34, 12, 1587-1590, 1981). In this case the catalysed reaction also consists exclusively of a demethylation, characterized by low conversion yields and productivity.
The glycosyl transferase activity of .alpha.-amylase from Bacillus megaterium has been described (Brumm, P. J., et al., Starch, 43, 8, 319-323, 1991); the acceptor specificity of the transferase reaction (exclusively glucose or glucosides) being particularly high. Cyclodextrin-glucosyl transferases, produced by the same microbial source, catalyse an .alpha.-1,4-transglucosylation of rubusoside (13-O-.beta.-D-glucosyl-steviol .beta.-D-glucosyl ester), starting from starch. Also in this bioconversion the acceptor of the transferase reaction is the substrate glucide fraction (Darise, M., et al., Agric. Bioel. Chem., 48, 10, 2483-2488, 1984). Cyclodextringlycosyl trans
REFERENCES:
patent: 3090729 (1963-05-01), Bellet et al.
patent: 3812011 (1974-05-01), Okada et al.
Poulev et al., J. Ferment. Bioeng., vol. 79, 1, pp. 33-38, 1995.
Chemical Abstracts, vol. 119, No. 19, Nov. 8, 1993, Abstract No. 199644: Solet, Jean Michel et al., "Glucosylation of thiocolchicine by a cell suspension culture of Centella asiatica" (citing Phytochemistry (1993), 33(4), 817-20).
Bombardelli Ezio
Ponzone Cesare
Indena S.p.A.
Marx Irene
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