[Fredericamycin and analogs as novel anticancer agents (really early)]
>>J Am Chem Soc. 2005 Nov 30;127(47):16442-16452.
Cloning, Sequencing, Analysis, and Heterologous Expression of the Fredericamycin Biosynthetic Gene Cluster from Streptomyces griseus.
Wendt-Pienkowski E, Huang Y, Zhang J, Li B, Jiang H, Kwon H, Hutchinson CR, Shen B.
Contribution from the Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705, and Kosan Biosciences Inc., 3832 Bay Center Place, Hayward, California 94545.
Fredericamycin (FDM) A, a pentadecaketide featuring two sets of peri-hydroxy tricyclic aromatic moieties connected through a unique chiral spiro carbon center, exhibits potent cytotoxicity and has been studied as a new type of anticancer drug lead because of its novel molecular architecture. The fdm gene cluster was localized to 33-kb DNA segment of Streptomyces griseus ATCC 49344, and its involvement in FDM A biosynthesis was proven by gene inactivation, complementation, and heterologous expression experiments. The fdm cluster consists of 28 open reading frames (ORFs), encoding a type II polyketide synthase (PKS) and tailoring enzymes as well as several regulatory and resistance proteins. The FDM PKS features a KS(alpha) subunit with heretofore unseen tandem cysteines at its active site, a KS(beta) subunit that is distinct phylogenetically from KS(beta) of hexa-, octa-, or decaketide PKSs, and a dedicated phosphopantetheinyl transferase. Further study of the FDM PKS could provide new insight into how a type II PKS controls chain length in aromatic polyketide biosynthesis. The availability of the fdm genes, in vivo characterization of the fdm cluster in S. griseus, and heterologous expression of the fdm cluster in Streptomyces albus set the stage to investigate FDM A biosynthesis and engineer the FDM biosynthetic machinery for the production of novel FDM A analogues.<<
This compound was apparently discovered over 20 years ago. The papers describing its antitumor activity don't appear to be available online (at least not for free). The synthetic steps required then probably doomed any efforts at commercializing or developing it. Now, with Kosan's expertise in this area . . . I guess we'll see.
>> J Antibiot (Tokyo). 1981 Nov;34(11):1402-7.
Fredericamycin A, a new antitumor antibiotic. II. Biological properties.
Warnick-Pickle DJ, Byrne KM, Pandey RC, White RJ.
Fredericamycin A is a novel antibiotic produced by a soil isolate of Streptomyces griseus (FCRC-48). In vitro, fredericamycin A exhibits antibacterial, antifungal, and cytotoxic activities. In vivo, fredericamycin A exhibits very good antitumor activity against P388 mouse leukemia as well as the CD8F mammary tumor and marginal activity against B16 melanoma. Fredericamycin A failed to demonstrate any interaction with DNA and inhibited protein and RNA synthesis preferentially to DNA synthesis in Bacillus subtilis and P388 cells.<<
>>Biosci Biotechnol Biochem. 2005;69(11):2213-2218.
Fredericamycin A Affects Mitochondrial Inheritance and Morphology in Saccharomyces cerevisiae.
Imamura Y, Yukawa M, Kimura KI, Takahashi H, Suzuki Y, Ojika M, Sakagami Y, Tsuchiya E.
Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University.
Fredericamycin A (FMA) is an antibiotic product of Streptomyces griseus that exhibits modest antitumor activity in vivo and in vitro, but, its functions in vivo are poorly understood. We identified this compound as an inducer of G1 arrest in the yeast, Saccharomyces cerevisiae. FMA exhibits an IC50 of 24 nM towards the growth of a disruptant of multi-drug resistance genes, W303-MLC30, and its cytotoxicity is a function of the time of exposure as well as drug dose. Addition of 0.8 muM of FMA caused aggregation of mitochondria within 10 min of incubation and the drug induced petites at high frequency after 4 h of incubation. rho(-) cells were about 20 times more resistant to FMA than isogenic rho(+) cells. Overexpression of topoisomerase I, a previously suggested target of the drug, did not alleviate the sensitivity of the cells to FMA or the aggregation of mitochondria. Our results suggest that mitochondria are the primary target site of FMA.<<
Nobody else seems to be interested in (perhaps unable to?) making analogs. And nobody seems to know what the mechanism of action is.
Cheers, Tuck |
