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Investigation of Structure-Function Relationships of Cytotoxic Quinones of Natural and Synthetic Origin¹

Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710 [S.M.T., D.G.G., F.S.V.], and Gross Chemical Laboratory, Department of Chemistry, Duke University, Durham, North Carolina 27706 [M.W.C., P.W.J.]

A sulfhydryl-arylating quinone from the mushroom Agaricus bisporus, with an absorption maximum at 490 nm, was demonstrated to inhibit DNA polymerase purified from calf thymus. The "490 quinone" could be generated through tyrosinase-mediated oxidation of -L-glutaminyl-4-hydroxybenzene or -L-glutaminyl-3,4-dihydroxybenzene. However, when -L-glutaminyl-3,4-dihydroxybenzene was oxidized to -L-glutaminyl-3,4-benzoquinone (GBQ) with sodium periodate, the product had an absorption maximum (_max) at 440 nm rather than at 490 nm and demonstrated notably less sulfhydryl reactivity than did the 490 quinone. These properties defined that the 490 quinone is not GBQ, as had been suggested previously, but a product of the oxidation of GBQ by tyrosinase. Additional quinones with an _max at 440 nm, produced from the oxidation of the acetyl and benzoyl analogs of -L-glutaminyl-4-hydroxybenzene and -L-glutaminyl-3,4-dihydroxybenzene, demonstrated the necessity of the amino acid side chain in the genesis of a quinone with an _max at 490 nm. Quinones with an _max near 490 nm were obtained after oxidation of 2,4,5-trihydroxyphenylalanine and 2,4,5-trihydroxyphenylethylamine, but these were exceedingly weak sulfhydryl reagents. Thus, while the precise structure of the 490 quinone remains unknown, these studies distinguish it from GBQ and demonstrate that the sulfhydryl reactivity of the 490 quinone is much greater than that of model quinones with similar spectral properties.

¹ This investigation was supported by Grant CA-19013 awarded by the National Cancer Institute, Department of Health, Education and Welfare, and by a North Carolina United Community Services grant.

² To whom requests for reprints should be addressed.

Received 3/ 6/78. Accepted 7/10/78.