Steffimycin

Approaches used to diversify steffimycin and aranciamycin have been successfully applied to elloramycin 47, an anthracycline-like rhamnose-containing compound that falls into tetracenomycin group of antibiotics [70, 81-83] (Fig. 6). 

Olano C, Abdelfattah MS, Gullon S et al (2008) Glycosylated derivatives of steffimycin insights into the role of the sugar moieties for the biological activity. ChemBioChem 9 624-633... 

Well-known examples are novel glycosylated elloramycins (11), staurosporines (12), mithramycins (13), and steffimycins (14) generated by the group of/. Salas, in Oviedo, Spain (73, 99). One additional example concerns the formation of a macrolide in a mutant strain of Saccharopolyspora erythraea. This mutant strain lacks the erythromycin polyketide synthase gene as well as both GT genes required for the transfer of L-mycarose (eryBV) and D-desosamine (eryCII) moieties during the erythromycin biosynthesis, but still it provides the TDP-activated forms of the... 

R is initially hydrogen in steffimycin this position is modified with a -OCH3 moiety. Although the steffimycin biosynthetic cluster has been cloned and sequenced [23], the genes responsible for this modification have not been unequivocally identified, and this modification has not been used in combinatorial biosynthesis. 

Steffimycin has a carbonyl substituent at C-10 [23]. As noted above, in steffimycin biosynthesis is completely removed in connection with cycli-zation therefore this substituent is added by tailoring enzymes apparently after glycosylation. The authors impUcate the cytochrome P450 enzyme StfPI... 

Steffimycin (Struct. 5) is unusual in that the glycosylation at carbon-7 is a neutral deoxysugar, 2-0-methyl rhamnose. 

Removal of the 2-0-methyl moiety from steffimycin by introduction of the S. nogalater ketoreductase and aromatase in S. steffisburgensis has already been described [25]. Interestingly, this change was associated with two other alterations with respect to the parent compound both the 8-0-methyl moiety and the 2 -methylation were missing. This suggests that the enzymes causing these modifications require the presence of the 2-0-methylation in their substrate. 

Gullon and coworkers [23] produced two steffimycin-related aglycones (Scheme 8). 

Biosynthetic modification of anthracycline biosynthesis has produced numerous new molecules, and its potential appears to be by no means exhausted. The research effort also reveals several instances of possible pitfalls, which may also be of interest when modifying other classes of antibiotic molecules Enzyme specificity. The substrate range of the introduced enzyme must include the intermediates available in the host but also the altered molecule must be a substrate for the host s downstream biosynthetic enzymes (as illustrated by the steffimycin hybrids). 

Scheme 1 Structures of anthracyclines doxorubicin, nogalamycin, aclacinomycin A, P-rho-domycin, cosmomycin D, steffimycin and aranciamycin...

The majority of the anthracyclines belong to the class of reduced polyketides, meaning that after formation of the polyketide chain the keto group at C-9 (numbered from the enzyme-bound carboxy termini) is reduced after cyclization of the first ring between C-7 and C-12 by a ketoreductase (Scheme 2, step 2). The ketoreduction occurs in all anthracycline biosynthetic pathways apart from steffimycin, where the lack of this enzymatic step leads... 

Scheme 4 Proposed biosynthetic pathway for the formation of steffimycin, as presented by Gulldn et al. [37]...

The possibiUties of attaching a sugar imit by a modified Marshalk reaction [106] were explored by Shaw et al. [107] as the first step on the route to the anthracyclinones fuUy substituted in ring A. The occurrence of the natural anthracyclines aranciamycin and steffimycin [7], fully substituted with oxygen functions and a methyl group at C-9 in ring A, was an incentive to use the... 

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