The structure of a novel antitumor antibiotic, saframycin A

Arai, Tadashi; Takahashi, Katsuhiro; Nakahara, Shinsuke; Kubo, Akinori

doi:10.1007/bf01965946

Cited by 68 publications

(29 citation statements)

References 7 publications

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“…In addition, the ecteinascidins and their biosynthetic precursors are present in trace amounts in the tunicate extract. Despite these intrinsic challenges, information about the biosynthesis of these alkaloids has been partially obtained, owing largely to the structural similarity between the ecteinascidins, specifically Et-743, and other THIQ family members, including saframycin B ( 2 ), 44 saframycin Mx1 ( 3 ), 45 safracin A ( 4 ), 46 naphthyridinomycin ( 5 ), 47 and quinocarcin ( 6 ) (Figure 6). 48, 49 …”

Section: Biosynthesis Of the Ecteinascidinsmentioning

confidence: 99%

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

et al. 2015

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The Ecteinascidin family comprises a number of biologically active compounds, containing two to three tetrahydroisoquinoline subunits. Although isolated from marine tunicates, these compounds share a common pentacyclic core with several antimicrobial compounds found in terrestrial bacteria. Among the tetrahydroisoquinoline natural products, Ecteinascidin 743 (Et-743) stands out as the most potent antitumor antibiotics that it is recently approved for treatment of a number of soft tissue sarcomas. In this article, we will review the backgrounds, the mechanism of action, the biosynthesis, and the synthetic studies of Et-743. Also, the development of Et-743 as an antitumor drug is discussed.

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Section: Biosynthesis Of the Ecteinascidinsmentioning

confidence: 99%

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

et al. 2015

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“…[4][5][6][7][8] The antitumor activity of a novel antibiotic, saframycin A, with a unique structure consisting of a dimer of 6-methyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline-5,8-dione, as the basic skeleton, has been reported . [9][10][11][12] In our studies on the microbial conversion of SA into antibiotics possessing antitumor spectra different from those of the parent compound (SA), reduction of the side chain carbonyl group of SA was observed.…”

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confidence: 99%

Microbial conversion of saframycin A to 25-dihydrosaframycin A and 21-decyano-25-dihydrosaframycin A (25-dihydrosaframycin B) and their biological activities.

Takahashi¹,

Yazawa²,

Kishi³

et al. 1982

J. Antibiot.

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25-Dihydrosaframycin A(AR1) and 21-decyano-25-dihydrosaframycinA(AR3) were produced by the microbial conversion of saframycin A(SA). Efficient conversion of SA to AR, and AR3 was observed with Rhodococcus amidophifus IFM 144. Though the antimicrobial activity of AR, was one tenth that of SA, the in vitro antitumor activity of AR1 was found to be equivalent to that of SA. In contrast, AR, was biologically less active.Microlial conversion has been studied extensively1~3) for many classes of organic compounds, namely alkaloids, antibiotics and steroids.For antitumor antibiotics, considerable attention has been given to the microbial reduction of carbonyl groups in relation to antitumor activities .4-8)The antitumor activity of a novel antibiotic, saframycin A, with a unique structure consisting of a dimer of 6-methyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline-5,8-dione, as the basic skeleton, has been reported .9-12)In our studies on the microbial conversion of SA into antibiotics possessing antitumor spectra different from those of the parent compound (SA), reduction of the side chain carbonyl group of SA was observed.In this paper, we report our studies on the microbial conversion of SA to AR, and AR, and their biological properties. Materials and MethodsMicroorganisms and Cultivation Rhodococcus amidophih{s IFM 144 was maintained on slants of I % glycerol nutrient medium until used. The strain was grown in 500-ml Erlenmeyer flasks, each containing 100 ml of a medium consisting of: meat extract 1 %, peptone 1 %, yeast extract 1 %, NaCl 0.3 % (pH 7.2). After 48 hours incubation at 27°C on a rotary shaker at 250 rpm, the culture was centrifuged, washed and suspended in a small volume (23 ml) of 0.1 M phosphate buffer (pH 7.5).Microbial Conversion of Saframyicn A(SA) Two ml of the suspension was mixed with 2 ml of the 10% aqueous methanol solution of SA (0.5 mg/ ml) in a test tube and the mixture incubated at 37°C for 18 hours. The reaction mixture was centrifuged at 500 rpm, and the supernatant extracted with ethyl acetate. The ethyl acetate layer was concentrated in vacuo, and the residue extracted with 1 N HCl solution. After adjustment to pH 7.5 with conc.

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“…These three variants account for > 97% of the 16S rRNA gene sequencing reads (Figure 3). None of these three strains form a close phylogenetic relationship with S. lavendulae , M. xanthus , or P. fluorescens, pure culture producers of the three tetrahydroisoquinoline antibiotics whose pathways have been previously characterized (11, 12, 13). …”

Section: Resultsmentioning

confidence: 99%

Meta-omic Characterization of the Marine Invertebrate Microbial Consortium That Produces the Chemotherapeutic Natural Product ET-743

Rath¹,

et al. 2011

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In many macroorganisms, the ultimate source of potent biologically active natural products has remained elusive due to an inability to identify and culture the producing symbiotic microorganisms. As a model system for developing a meta-omic approach to identify and characterize natural product pathways from invertebrate-derived microbial consortia we chose to investigate the ET-743 (Yondelis®) biosynthetic pathway. This molecule is an approved anti-cancer agent obtained in low abundance (10−4–10−5% w/w) from the tunicate Ecteinascidia turbinata, and is generated in suitable quantities for clinical use by a lengthy semi-synthetic process. Based on structural similarities to three bacterial secondary metabolites, we hypothesized that ET-743 is the product of a marine bacterial symbiont. Using metagenomic sequencing of total DNA from the tunicate/microbial consortium we targeted and assembled a 35 kb contig containing 25 genes that comprise the core of the NRPS biosynthetic pathway for this valuable anti-cancer agent. Rigorous sequence analysis based on codon usage of two large unlinked contigs suggests that Candidatus Endoecteinascidia frumentensis produces the ET-743 metabolite. Subsequent metaproteomic analysis confirmed expression of three key biosynthetic proteins. Moreover, the predicted activity of an enzyme for assembly of the tetrahydroisoquinoline core of ET-743 was verified in vitro. This work provides a foundation for direct production of the drug and new analogs through metabolic engineering. We expect that the interdisciplinary approach described is applicable to diverse host-symbiont systems that generate valuable natural products for drug discovery and development.

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The structure of a novel antitumor antibiotic, saframycin A

Abstract: A structure is assigned to saframycin A, a novel antitumor antibiotic from Streptomyces lavendulae No. 314, on the basis of 13C NMR-spectral data.

Cited by 68 publications

References 7 publications

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

Microbial conversion of saframycin A to 25-dihydrosaframycin A and 21-decyano-25-dihydrosaframycin A (25-dihydrosaframycin B) and their biological activities.

Meta-omic Characterization of the Marine Invertebrate Microbial Consortium That Produces the Chemotherapeutic Natural Product ET-743

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