Sch 47554

A method for the asymmetric synthesis of the disaccharide portion of SCH-47554 has been developed in 6 steps. The route is shorter than the reported route to a related disaccharide. The route involves the use of the Noyori reduction to establish the asymmetry of the d- and l-sugar portion of the molecule. Diastereoselective Pd-glycosylation reaction and subsequent post-glycosylation transformation are used to establish the remaining stereocenter.

Sch47554 and Sch47555 are antifungal compounds from Streptomyces sp. SCC-2136. The availability of the biosynthetic gene cluster made it possible to track genes that encode biosynthetic enzymes responsible for the structural features of these two angucyclines. Sugar moieties play important roles in the biological activities of many natural products. An investigation into glycosyltransferases (GTs) might potentially help to diversify pharmaceutically significant drugs through combinatorial biosynthesis. Sequence analysis indicates that SchS7 is a putative C-GT, whereas SchS9 and SchS10 are proposed to be O-GTs. In this study, the roles of these three GTs in the biosynthesis of Sch47554 and Sch47555 are characterized. Coexpression of the aglycone and sugar biosynthetic genes with schS7 in Streptomyces lividans K4 resulted in the production of C-glycosylated rabelomycin, which revealed that SchS7 attached a d-amicetose moiety to the aglycone core structure at the C-9 position. Gene inactivation studies revealed that subsequent glycosylation steps took place in a sequential manner, in which SchS9 first attached either an l-aculose or l-amicetose moiety to 4'-OH of the C-glycosylated aglycone, then SchS10 transferred an l-aculose moiety to 3-OH of the angucycline core.

Saprolmycins A-E are anti-Saprolegnia parasitica antibiotics. To identify the gene cluster for saprolmycin biosynthesis in Streptomyces sp. TK08046, polymerase chain reaction using aromatase and cyclase gene-specific primers was performed; the spr gene cluster, which codes for angucycline biosynthesis, was obtained from the strain. The cluster consists of 36 open reading frames, including minimal polyketide synthase, ketoreductase, aromatase, cyclase, oxygenase, and deoxy sugar biosynthetic genes, as defined by homology to the corresponding genes of the urdamycin, Sch-47554, and grincamycin biosynthetic gene clusters in Streptomyces fradiae, Streptomyces sp. SCC-2136, and Streptomyces lusitanus, respectively. To establish the function of the gene cluster, an expression cosmid vector containing all 36 open reading frames was introduced into Streptomyces lividans TK23. The transformant was confirmed to express the biosynthetic genes and produce saprolmycins by liquid chromatography-mass spectrometry analysis of the extract.