Fredericamycin A, a newly described potent antitumor antibiotic, exhibits unusual spectroscopic and physical properties. The drug shows a striking color change from red to blue on exposure to O2, with the appearance of an optical absorption band at 675 nm; on addition of acid these changes are readily reversed. 1H and 13C NMR spectra of fredericamycin A show that the resonances from the quininoid half of the molecule disappear after exposure to O2 but reappear on acidification in parallel with the observed optical spectral shift. These unusual NMR data are explained by electron spin resonance studies which demonstrate that fredericamycin A spontaneously forms an oxidized free radical with electron transfer to O2. The observed hyperfine structure of this radical is consistent with one-electron oxidation of the quininoid group. After fredericamycin A is exposed to O2, an EPR signal is observed with axial symmetry with temperature and power saturation behavior suggestive of .O2-. Spin-trapping EPR studies demonstrate that the drug reduces O2 to .O2- and H2O2 to .OH. This spontaneous mechanism of O2 reduction with the generation of oxidized drug free radicals and reduced oxygen free radicals is unprecedented among anticancer drugs, suggesting that fredericamycin A could be the forerunner of a new class of anticancer drug.

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Fredericamycin A (FM A), produced by a strain of Streptomyces griseus, represents a new structural class of antitumor antibiotics containing a spiro ring system. Studies on the producer organism showed that glucose in the fermentation medium is not utilized until late in the growth stage, just prior to synthesis of FM A. [14C]Glucose tracer experiments demonstrated that glucose is incorporated into FM A by catabolism to acetate. Biosynthetic enrichment of FM A with single- and double-labeled [13C]acetate showed that the entire carbon skeleton of the spiro ring system is derived from acetate. L-Methionine was shown to provide the only nonskeletal carbon in FM A, the methoxy carbon at position C-6. The direction of the polyketide chain and the position of the carbon lost during biosynthesis were established by using stable isotope experiments. A general model for FM A biosynthesis is proposed, and a possible scheme for the formation of the spiro carbon center is presented.

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