Flash photolysis and pulse radiolysis studies of some semiquinones in relation to cancer induction and therapy

Abstract

Improved knowledge of the mechanism of melanin formation, of agents which interrupt melanogenesis and of the photochemistries of melanin precursors could ultimately provide an improved chemotherapeutic approach towards malignant melanoma. One-electron oxidation of dopa, through N^˙₃ or photoionization, leads to the melanin precursor dopachrome via dopasemiquinone and dopaquinone. The latter reacts with cysteine to form cysteinyldopa, a marker for malignant melanoma metastasis. N^˙_3– initiated oxidation of 5-S-cysteinyldopa proceeds via a different mechanism involving the corresponding semiquinone, quinone and a quinone-imine, which rearranges to a more stable benzothiazine. Photolysis of 5-S-cysteinyldopa leads to initial transient species whose absorption spectra are markedly different from the semiquinone spectra, in this case the primary process involving S—C bond photohomolysis. Dopamine semiquinone cannot be generated by reaction of dopamine with one-electron oxidised N-methyl-4-phenyltetrahydropyridine, which can induce the symptoms of Parkinson's disease. The semireduced form of the anti-tumour agent adriamycin is implicated in cardiotoxic side effects. Adriamycin semiquinone, prepared by reduction with e^–_aq and CO₂^˙–₂, has pK values of 2.9 and 9.2. In the pH range 6–11, adriamycin semiquinone is relatively stable, existing in equilibrium with adrimycin and its hydroquinone, the latter subsequently losing the sugar within ca. 100 ms. The E¹₇ of adriamycin is –328 mV, so at equilibrium the reaction: O₂^˙–₂+ adriamycin ⇌ O₂+ adriamycin semiquinone lies well over to the left.