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ABSTRACT: Second-generation paclitaxel analogues that require replacement of the C-4 acetate by other substituents are in development. An enzyme able to specifically remove the C-4 acetate from paclitaxel could simplify preparation of the analogues. Several strains were isolated from soil samples that contain enzyme activities able to 4-deacetylate 10-DAB (10-deacetylbaccatin III). Selection was made using plates containing 10-DAB as the sole carbon source and screening colonies for deacetylation of 10-DAB. Two strains initially isolated were identified as Rhodococcus sp. and deposited with the A.T.C.C. (Manassas, VA, U.S.A.) as strains 202191 and 202192. Whole cells were able to convert 10-DAB into 4,10-DDAB (4-deacetyl-10-deacetylbaccatin III) in 90% yield. The enzyme activity in these strains was not effective with paclitaxel and 10-deacetylpaclitaxel, although 4,10-DDAB was produced from baccatin III. The activity in these strains was associated with an insoluble fraction of cell extracts. Several additional isolates were obtained that were identified as variants of Stenotrophomonas maltophilia, and a soluble C-4 deacetylase was purified approx. 218-fold from one of them. The activity of this enzyme was limited to 10-DAB, and the enzyme was not effective with paclitaxel or baccatin III.
Biotechnology and Applied Biochemistry 10/2006; 45(Pt 2):81-5. · 1.53 Impact Factor
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Journal of Medicinal Chemistry 09/2004; 47(18):4339-51. · 5.25 Impact Factor
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ABSTRACT: 6-alpha-Hydroxy-7-deoxy-10-deacetylbaccatin-III is an intermediate that is potentially useful for synthesis of analogues of paclitaxel. Screening of microbial strains identified an enzyme activity in Nocardioides luteus SC 13912 (A.T.C.C. 55426) which converted 7-deoxy-10-deacetylbaccatin-III into 6-hydroxy-7-deoxy-10-deacetylbaccatin-III with a maximum yield of 44%.
Biotechnology and Applied Biochemistry 05/2004; 39(Pt 2):209-14. · 1.53 Impact Factor
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ABSTRACT: A C-8 keto pleuromutilin derivative has been synthesized from the biotransformation product 8-hydroxy mutilin. A key step in the process was the selective oxidation at C-8 of 8-hydroxy mutilin using tetrapropylammonium perruthenate. The presence of the C-8 keto group precipitated interesting intramolecular chemistry to afford a compound (10) with a novel pleuromutilin-derived ring system.
Bioorganic & Medicinal Chemistry Letters 06/2003; 13(10):1751-3. · 2.55 Impact Factor
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ABSTRACT: Biotransformation of mutilin and pleuromutilin by microbial cultures was investigated to provide a source of 8-hydroxymutilin or 8-hydroxypleuromutilin. LC/MS analysis of culture broths showed that several strains gave M+16 products from mutilin and one culture gave an M+16 product from pleuromutilin, suggesting addition of oxygen. Biotransformation products were extracted from culture broths with ethyl acetate, dried, and purified by chromatography on silica gel. Streptomyces griseus strains SC 1754 and SC 13971 (ATCC 13273) converted mutilin to (8S)-, (7S)-, and (2S)-hydroxymutilin. Cunninghamella echinulata SC 16162 (NRRL 3655) gave (2S)-hydroxymutilin or (2R)-hydroxypleuromutilin from biotransformation of mutilin or pleuromutilin, respectively. The biotransformation of mutilin by S. griseus strain SC 1754 was scaled up in 15-, 60-, and 100-L fermentations to produce a total of 49 g of (8S)-hydroxymutilin (BMS-303786), 17 g of (7S)-hydroxymutilin (BMS-303789) and 13 g of (2S)-hydroxymutilin (BMS-303782) from 162 g of mutilin.
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