Identification of fredericamycin E from Streptomyces griseus: Insights into fredericamycin A biosynthesis highlighting carbaspirocycle formation.
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.
Chen
Yihua
Y
Division of Pharmaceutical Sciences, University of Wisconsin, Madison, Wisconsin 53705-2222, USA.
Luo
Yinggang
Y
Ju
Jianhua
J
Wendt-Pienkowski
Evelyn
E
Rajski
Scott R
SR
Shen
Ben
B
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D002247:Carbon Isotopes; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D015394:Molecular Structure; D013141:Spiro Compounds / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013305:Streptomyces griseus / Q000737:chemistry* / Q000235:genetics*
D000970:Antineoplastic Agents; D002247:Carbon Isotopes; D007546:Isoquinolines; D013141:Spiro Compounds; C529031:fredericamycin E; C016660:fredericamycin A