Journal
CHEMBIOCHEM
Volume 9, Issue 14, Pages 2295-2304Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.200800299
Keywords
aureolic acid; deoxysugars; polyketides; Streptomyces
Funding
- Spanish Ministry of Education and Science [BMC2002-03599, BIO2005-04715]
- US National Institutes of Health [CA 91901]
- Red Tematica de Investigacion Cooperative de Centros de Cancer (Ministry of Health, Spain) [ISCIII-RETIC RD06/ 0020/0026]
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Mithramycin is an antitumor drug produced by Streptomyces argillaceus. It consists of a tricyclic aglycone and five deoxyhexoses that form a disaccharide and a trisaccharide chain, which ore important for target interaction and therefore for the antitumor activity. Using a combinatorial biosynthesis approach, we have generated nine mithramycin derivatives, seven of which are new compounds, with alterations in the glycosylation pattern. The wild-type S. argillaceus strain and the mutant S. argillaceus M7U1, which has altered D-oliose biosynthesis, were used as hosts to express various sugar plasmids, each one directing the biosynthesis of a different deoxyhexose. The newly formed compounds were purified and characterized by MS and NMR. Compared to mithramycin, they contained different sugar substitutions in the second (D-olivose, D-mycarose, or D-boivinose instead Of D-oliose) and third (D-digitoxose instead of o-mycarose) sugar units of the trisaccharide as well as in the first (D-amicetose instead of D-olivose) sugar unit of the disaccharide. All compounds showed antitumor activity against different tumor cell lines. Structure-activity relationships are discussed on the basis of the number and type of deoxyhexoses present in these mithramycin derivatives.
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