Structure of fredericamycin A, an antitumor antibiotic of a novel skeletal type. Spectroscopic and mass spectral characterization.

Misra, Renuka; Rc, Pandey; Bd, Hilton; Pp, Roller; Jv, Silverton

doi:10.7164/antibiotics.40.786

Cited by 46 publications

(20 citation statements)

References 23 publications

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“…The UV spectrum of compound 1 displayed λ max at 260, 302, 316, 332, 357, 373 and 392 nm (Additional file 1 : Figure S4), and the chemical formula of compound 1 was determined to be C 30 H 21 NO 9 by HR-ESI-MS (m/z 540.1280 [M + H] + , calcd 540.1295) (Figure 2 B). Both are consistent with those of FDM A [ 12 ]. The 1 H-NMR (Figure 2 C) and 13 C-NMR (Figure 2 D) data of compound 1 were further recorded, and the chemical shifts were summarized in Additional file 1 : Table S2.…”

Section: Resultssupporting

confidence: 90%

“…FDM A, first isolated from terrestrial Streptomyces griseus ATCC49344 in 1981 [ 11 ], is an aromatic pentadecaketide featuring two sets of peri-hydroxy tricyclic aromatic moieties connected through a unique asymmetric carbaspiro center, representing a new chemotype for anticancer drug leads [ 12 ]. The cytotoxicity of FDM A against tumor cell lines resulted from inhibition of DNA topoisomerases I and II as well as the peptidyl-prolyl cis/trans isomerase Pin1, which is involved in the regulation of cell cycle and cell division [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Activation and enhancement of Fredericamycin A production in deepsea-derived Streptomyces somaliensis SCSIO ZH66 by using ribosome engineering and response surface methodology

Zhang

Huang

et al. 2015

Microb Cell Fact

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BackgroundMarine microorganisms are an important source of new drug leads. However, the discovery and sustainable production of these compounds are often hampered due to the unavailable expression of cryptic biosynthetic gene clusters or limited titer. Ribosome engineering and response surface methodology (RSM) integrated strategy was developed in this study to activate cryptic gene cluster in the deepsea-derived Streptomyces somaliensis SCSIO ZH66, and subsequently isolation, structural analysis, and the yield enhancement of the activated compound, anticancer drug lead Fredericamycin A (FDM A), were performed.ResultsIn order to discover novel natural products from marine Streptomyces strains by genome mining strategy, the deepsea-derived S. somaliensis SCSIO ZH66 was subject to ribosome engineering to activate the expression of cryptic gene clusters. A resistant strain ZH66-RIF1 was thereby obtained with 300 μg/mL rifampicin, which accumulated a brown pigment with cytotoxicity on MS plate while absent in the wild type strain. After screening of fermentation conditions, the compound with pigment was purified and identified to be FDM A, indicating that the activation of a cryptic FDM A biosynthetic gene cluster was taken place in strain ZH66-RIF1, and then it was identified to be ascribed to the mutation of R444H in the β subunit of RNA polymerase. To further improve the yield efficiently, nine fermentation medium components were examined for their significance on FDM A production by Plackett–Burman design and Box-Behnken design. The optimum medium composition was achieved by RSM strategy, under which the titer of FDM A reached 679.5 ± 15.8 mg/L after 7 days of fermentation, representing a 3-fold increase compared to the original medium. In terms of short fermentation time and low-cost fermentation medium, strain ZH66-RIF1 would be an ideal alternative source for FDM A production.ConclusionsOur results would hasten the efforts for further development of FDM A as a drug candidate. Moreover, this ribosome engineering and RSM integrated methodology is effective, fast and efficient; it would be applicable to genome mining for novel natural products from other strains.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-015-0244-2) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Activation and enhancement of Fredericamycin A production in deepsea-derived Streptomyces somaliensis SCSIO ZH66 by using ribosome engineering and response surface methodology

Zhang

Huang

et al. 2015

Microb Cell Fact

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“…With more than 30 predicted B scaffold-based natural products reported in the literature, this 26-carbon scaffold, which arises from an acetate starter unit and 12 malonyl CoA extension steps is responsible for most of the structural diversity seen in known PPs (Figure 5 ). The only reported gene clusters predicted to encode the A, C, and D scaffolds are the pradimicins 13 (PP-A), arenimycins 14 (PP-A), benastatins 15 (PP-C), FD-594s 16 (PP-C) and fredericamycins 17 (PP-D).…”

Section: Results and Discussionmentioning

confidence: 99%

Mining Soil Metagenomes to Better Understand the Evolution of Natural Product Structural Diversity: Pentangular Polyphenols as a Case Study

Kang

Brady

2014

J. Am. Chem. Soc.

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Sequence-guided mining of metagenomic libraries provides a means of recovering specific natural product gene clusters of interest from the environment. In this study, we use ketosynthase gene (KS) PCR amplicon sequences (sequence tags) to explore the structural and biosynthetic diversities of pentangular polyphenols (PP). In phylogenetic analyses, eDNA-derived sequence tags often fall between closely related clades that are associated with gene clusters known to encode distinct chemotypes. We show that these common “intermediate” sequence tags are useful for guiding the discovery of not only novel bioactive metabolites but also collections of closely related gene clusters that can provide new insights into the evolution of natural product structural diversity. Gene clusters corresponding to two eDNA-derived KSβ sequence tags that reside between well-defined KSβ clades associated with the biosynthesis of (C24)-pradimicin and (C26)-xantholipin type metabolites were recovered from archived soil eDNA libraries. Heterologous expression of these gene clusters in Streptomyces albus led to the isolation of three new PPs (compounds 1–3). Calixanthomycin A (1) shows potent antiproliferative activity against HCT-116 cells, whereas arenimycins C (2) and D (3) display potent antibacterial activity. By comparing genotypes and chemotypes across all known PP gene clusters, we define four PP subfamilies, and also observe that the horizontal transfer of PP tailoring genes has likely been restricted to gene clusters that encode closely related chemical structures, suggesting that only a fraction of the “natural product-like” chemical space that can theoretically be encoded by these secondary metabolite tailoring genes has likely been sampled naturally.

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“…With this novel and economical protocol, various quaternary carbon-centered spirocyclopentanones could be readily obtained.Carbocyclic spiro motifs are the structural centerpieces of biologically active products, chiral ligands, and new materials ( Figure 1). For example, fredericamycin A [1] , which was isolated from a new strain of Streptomyces griseus, exhibits antitumor activity, and dimethyl gloiosiphone A exhibits an-…”

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confidence: 99%

Phosphine‐Initiated Domino Reaction: A Convenient Method for the Preparation of Spirocyclopentanones

Liang

Xie

et al. 2014

Chemistry An Asian Journal

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Structure of fredericamycin A, an antitumor antibiotic of a novel skeletal type. Spectroscopic and mass spectral characterization.

Cited by 46 publications

References 23 publications

Activation and enhancement of Fredericamycin A production in deepsea-derived Streptomyces somaliensis SCSIO ZH66 by using ribosome engineering and response surface methodology

Activation and enhancement of Fredericamycin A production in deepsea-derived Streptomyces somaliensis SCSIO ZH66 by using ribosome engineering and response surface methodology

Mining Soil Metagenomes to Better Understand the Evolution of Natural Product Structural Diversity: Pentangular Polyphenols as a Case Study

Phosphine‐Initiated Domino Reaction: A Convenient Method for the Preparation of Spirocyclopentanones

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