Oxidative coupling of mithramycin and hydroquinone catalyzed by copper oxidases and benzoquinone. Implications for the mechanism of action of aureolic acid antibiotics
✍ Scribed by Innocent O. Anyanwutaku; Richard J. Petroski; John P.N. Rosazza
- Book ID
- 103992055
- Publisher
- Elsevier Science
- Year
- 1994
- Tongue
- English
- Weight
- 972 KB
- Volume
- 2
- Category
- Article
- ISSN
- 0968-0896
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✦ Synopsis
copper oxidases human ceruloplasmin and Polyporous anceps lactase catalyze the oxidative coupling of mithramycin (1) and its aglycone chromomycinone (2) with p-hydroquinone to form new mithramycin-hydroquinone
(3) and chromomycinone-hydroquinone adducts (4), respectively. Similar adducts could be formed by the nonenzymatic mimic of this reaction using benzoquinone and these aureolic acids in buffer solutions. FAEMS of 3 indicated that the hydroquinone moiety was attached to the aureolic acid aglycone. Acid hydrolysis of 3 yielded a compound with the same chromatographic and spectroscopic characteristics as 4. Structure elucidation of 4 by NMR and MS revealed that the hydroquinone was attached to the C-S position of the aglycone. NMR evidence indicated that 4 consisted of a mixture of o&o-substituted biphenyl rotamers. The mechanism of the copper oxidase catalyzed adduct formation reaction is presumed to involve radical formation through hydrogen removal at the 8phenolic position, radical isomerization, and coupling with semiquinone radical also formed during enzymatic and nonenzymatic incubations. Identification of the covalent-hydroquinone adduct provides evidence that aureolic acid antibiotics can be metabolically converted to reactive radical intermediates, and it establishes the C-5 position of aureolic acid as an enzymatically reactive site. Unlike mithramycin, the mithramycin-hydroquinone adduct was inactive in the in vivo P388 leukemic antitumor test svstem.