Tetracenomycins

Reaction of 2-129 with NaCN followed by treatment with NaH and TIPSC1 led to the anthracene 2-130 in 68% yield (Scheme 2.30). The desired lactam 2-131 was then obtained by reduction of the cyano group and ring closure using CoCl2/ NaBH4. Quite recently, this procedure has also been used for a formal total synthesis of tetracenomycin [63]. 

Figure 12.5 A. Comparison of the CHS monomer (left) and P-ketoacyl synthase monomer (right). The structurally conserved secondary structure of each monomer s upper domain is colored in blue (a-helix) and gold (P-strand). Portions of each protein monomer forming the dimer interface are colored purple. The side-chains of the catalytic residues of CHS (Cysl64, His303, Asn336) and P-ketoacyl synthase (Cysl63, His303, His340) are shown. B. Sequence conservation of the catalytic residues of CHS, 2-PS, p-ketoacyl synthase (FAS II), and the ketosynthase modules of 6-deoxyerythronolide B synthase (DEBS), actinorhodin synthase (ActI) and tetracenomycin synthase (TcmK). The catalytic residues are in red.

Hutchinson CR (1997) Biosynthetic studies of daunoru-bicin and tetracenomycin C. Chem Rev 97, 2525-2535. 

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). 

Perez M, Lombo F, Zhu L et al (2005) Combining sugar biosynthesis genes for the generation of l- and D-amicetose and formation of two novel antitumor tetracenomycins. Chem Commun 12 1604—1606... 

A. Actinorhodin, Tetracenomycin, Doxorubicin, and Other Bacterial Aromatic Polyketide Synthases... 

Figure 3 Aromatic PKS gene clusters and actinorhodin biosynthesis. Partial gene clusters for the polyketides actinorhodin (act), tetracenomycin (tcm), and doxorubicin (dps) are shown. Reconstitution of combinations of act genes in a PKS clean host have led to a proposed pathway by which the early stages of actinorhodin biosynthesis occur.

Figure 10 Examples of unnatural aromatic polyketides. Libraries of aromatic poly-ketides have been generated using combinations from the actinorhodin, tetracenomycin, frenolicin, griseusin, and whiE spore pigment gene clusters.

W Bao, E Wendt-Pienkowski, CR Hutchinson. Reconstitution of the iterative type II polyketide synthase for tetracenomycin F2 biosynthesis. Biochemistry 37 8132-8138, 1998. 

Figure 6 Cell-free biosynthesis of tetracenomycin F2. A strain of Streptomyces glaucescens in which the tetracenomycin-minimal PKS genes and an ARO/CYC activity had been overexpressed produced tetracenomycin F2, a precursor to the natural product tetracenomycin A (the remainder of the pathway is indicated by dashed arrows). The same result has been achieved using purified proteins in vitro.

F2 was restored. More recently, the biosynthesis of tetracenomycin F2 has been achieved with fully purified proteins [17],... 

HC Gramajo, J White, CR Hutchinson, MJ Bibb. Overproduction and localization of components of the polyketide synthase of Streptomyces glaucescens involved in the production ofthe antibiotic tetracenomycin C. JBacteriol 173 6475-6483,1991. 

B Shen, RG Summers, H Gramajo, MJ Bibb, CR Hutchinson. Purification and characterization of the acyl carrier protein of the Streptomyces glaucescens tetracenomycin C polyketide synthase. JBacteriol 174 3818-3821, 1992. 

SUMMERS, R.G., WENDT-PIENKOWSKI, E., MOTAMEDI, H HUTCHINSON, C.R., Nucleotide sequence of the tcmll-tcmlV region of the tetracenomycin C biosynthetic gene cluster of Streptomyces glaucescens and evidence that the tcmN gene encodes a multifunctional cyclase-dehydratase-O-methyl transferase, J. Bacteriol., 1992,174, 1810-1820. 

Perez M, Lombo E, Zhu L, Gibson M, Brana AF, Rohr J, Salas JA, Mendez C (2005) Combining Sugar Biosynthesis Genes for the Generation of L- and o-Amicetose and Formation of Two Novel Antitumor Tetracenomycins. Chem Conimun 1604... 

MAT has stringent specificity toward malonyl-CoA, which is reflected in the exclusive utilization of malonyl extender units by Type n PKS 7 Together, these four enzymes consist of the smallest set of enzymes required for the synthesis of a complete polyketide chain. For example, the minimal PKS from the actinorhodin (act) biosynthetic pathway synthesizes an octaketide (Cjg) backbone from eight malonyl-CoA equivalents, the tetracenomycin (tan) minimal PKS synthesizes a decaketide (C20) backbone from ten equivalents of malonyl-CoA (Figure 8A), and the pradimycin (pms) minimal PKS synthesizes a dodecaketide (C24) backbone from twelve equivalents of malonyl-CoA. ... 

Additional fused ring streptomycete polyketides shown in Figure 1 include the tetracyclic decaketides aclacinomycin (19), tetracenomycin C (20) and the angucycline vineomycin Ai (21), " which are formed by mode S folding. Although the incorporation of [ C2]acetate into cetocycline (13) and tetracenomycin C (20) does not appear to have been studied per se, the proposed folding mode of 13 is supported by the... 

Figure 2 illustrates the established distribution of intact C2-units in the [ Ci] acetate-derived carbon skeletons of the fungal polyketides dihydrofusarubin (25), rubrofusarin (26), averufin (28), islandicin (29) and hypomycetin (30) also the probable distribution of Ca-units in the streptomycete products tetracenomycin C (35) and cetocycline (36). The full structures of these compounds are shown in Figure 1 and Scheme 4. The carbon skeletons of other products for which [ Cajacetate incorporation patterns have been determined include the fungal metabolite bikaverin (27) and the streptomycete products actinorhodin (31), spectomycin A (33), RM18 (32) and aloesaponarin II (34) (RM18 and aloesaponarin II are formed by streptomycete recombinant strains).

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