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Applied and Environmental Microbiology, June 2004, p. 3521-3527, Vol. 70, No. 6
0099-2240/04/$08.00+0     DOI: 10.1128/AEM.70.6.3521-3527.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Specific 12ß-Hydroxylation of Cinobufagin by Filamentous Fungi

Min Ye, Guiqin Qu, Hongzhu Guo, and Dean Guo*

The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, People's Republic of China

Received 30 May 2003/ Accepted 1 March 2004

Biotransformation of natural products has great potential for producing new drugs and could provide in vitro models of mammalian metabolism. Microbial transformation of the cytotoxic steroid cinobufagin was investigated. Cinobufagin could be specifically hydroxylated at the 12ß-position by the fungus Alternaria alternata. Six products from a scaled-up fermentation were obtained by silica gel column chromatography and reversed-phase liquid chromatography and were identified as 12ß-hydroxyl cinobufagin, 12ß-hydroxyl desacetylcinobufagin, 3-oxo-12ß-hydroxyl cinobufagin, 3-oxo-12ß-hydroxyl desacetylcinobufagin, 12-oxo-cinobufagin, and 3-oxo-12{alpha}-hydroxyl cinobufagin. The last five products are new compounds. 12ß-Hydroxylation of cinobufagin by A. alternata is a fast catalytic reaction and was complete within 8 h of growth with the substrate. This reaction was followed by dehydrogenation of the 3-hydroxyl group and then deacetylation at C-16. Hydroxylation at C-12ß also was the first step in the metabolism of cinobufagin by a variety of fungal strains. In vitro cytotoxicity assays suggest that 12ß-hydroxyl cinobufagin and 3-oxo-12{alpha}-hydroxyl cinobufagin exhibit somewhat decreased but still significant cytotoxic activities. The 12ß-hydroxylated bufadienolides produced by microbial transformation are difficult to obtain by chemical synthesis.

* Corresponding author. Mailing address: The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xueyuan Road #38, Beijing 100083, People's Republic of China. Phone: 86-10-8280-1516. Fax: 86-10-8280-2700. E-mail: gda{at}bjmu.edu.cn.

Applied and Environmental Microbiology, June 2004, p. 3521-3527, Vol. 70, No. 6
0099-2240/04/$08.00+0     DOI: 10.1128/AEM.70.6.3521-3527.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.





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