Journal of the American Chemical Society
COMMUNICATION
efficient and novel methodology for the construction of the
tetramic acid scaffold should thus contribute to the development
of versatile chemical libraries with promising biological activities.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and spec-
b
troscopic data. This material is available free of charge via the
’ AUTHOR INFORMATION
Corresponding Author
Figure 3. Active-site structure of BAS. The diketide intermediate and
the tetramic acid product 6 from (A) L-tryptophanoyl-CoA and (B) D-
tryptophanoyl-CoA are shown as green stick models.
’ ACKNOWLEDGMENT
We thank Prof. K. Sekimizu and Dr. H. Hamamoto (Graduate
School of Pharmaceutical Sciences, The University of Tokyo) for
kindly providing bacterial strains. We also thank Dr. S. Fukuzawa
(Department of Chemistry, School of Science, The University of
Tokyo) for murine leukemia P388 cells. This work was finan-
cially supported by the Nagase Science and Technology Founda-
tion and by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science, and Technology
(MEXT), Japan.
Furthermore, the cytotoxic and antibacterial activities of tetramic
acid-containing natural products have also been reported. There-
fore, the above-obtained tetramic acid derivatives were tested for
their antibacterial activity against Staphylococcus aureus, Escher-
ichia coli, and Bacillus cereus and for their cytotoxic activity
against murine leukemia P388 cells. None of the products was
active against any of the bacteria, but the tetramic acid dimer D-5
derived from D-phenylalanine showed moderate cytotoxicity
(IC50 = 1 μg/mL) against murine leukemia P388 cells. It is quite
remarkable that the differences in the stereochemistry and
aromatic ring substituent significantly affected the cytotoxic
activity. Further investigations to elucidate the detailed mechan-
ism of the cytotoxicity are now in progress.
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In conclusion, we have demonstrated for the first time that
the structurally simple type-III PKS catalyzes the formation of a
series of unnatural, novel tetramic acid derivatives. Remarkably,
the novel tetramic acid dimer D-5 from D-phenylalanoyl-CoA
showed moderate cytotoxicity against a tumor cell line. This
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