PMID:18232659
| Citation |
Chen, Y, Luo, Y, Ju, J, Wendt-Pienkowski, E, Rajski, SR and Shen, B (2008) Identification of fredericamycin E from Streptomyces griseus: Insights into fredericamycin A biosynthesis highlighting carbaspirocycle formation. J. Nat. Prod. 71:431-7 |
|---|---|
| Abstract |
Fredericamycin (FDM) A ( 1), a pentadecaketide featuring two sets of peri-hydroxy tricyclic aromatic moieties connected through a unique asymmetric carbaspiro center, exhibits potent cytotoxicity and represents a novel anticancer drug lead. We have localized previously the fdm gene cluster to a 33 kb DNA segment of Streptomyces griseus ATCC49344, the involvement of which in the biosynthesis of 1 was confirmed by gene inactivation, complementation, and heterologous expression experiments. We now report the isolation and characterization of FDM E ( 5), a heretofore undetected intermediate for 1 biosynthesis from S. griseus, shedding new insight into the mechanism of carbaspirocycle formation. The structure of 5 was elucidated through the combination of spectroscopic methods and isotope-labeling experiments. The core spiro[4.5]decane scaffold of 5 is characterized by a unique cyclohexa-1,2,4-triketone moiety. Transformation of the spiro[4.5]decane 5 into the spiro[4.4]nonane 1 can be rationalized by a biosynthetic benzilic acid-like rearrangement. This unusual rearrangement can be mimicked in vitro by proceeding under aerobic conditions in the absence of enzyme. FDM E displays cytotoxic activity on par with 1 against a selected set of cancer cells, a finding that further supports the unique molecular topology, resulting from the unprecedented carbaspirocycle as exemplified by 1 and 5, as a novel pharmacophore for this family of anticancer agents. |
| Links |
PubMed Online version:10.1021/np070664n |
| Keywords |
Animals; Antineoplastic Agents/chemistry; Antineoplastic Agents/isolation & purification; Antineoplastic Agents/pharmacology; Carbon Isotopes; Drug Screening Assays, Antitumor; Humans; Isoquinolines/chemistry; Isoquinolines/isolation & purification; Isoquinolines/pharmacology; Molecular Structure; Spiro Compounds/chemistry; Spiro Compounds/isolation & purification; Spiro Compounds/pharmacology; Streptomyces griseus/chemistry; Streptomyces griseus/genetics |
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