INTERACTION OF TRACE METALS WITH PHENOTHIAZINE DRU DERIVATIVES, III. THEORETICAL PART

Abstract

Data concerning the chromophoric semiquinone radical ions produced from phenothiazine derivatives by certain metal ions and by other univalent oxidants were discussed, and hypotheses were advanced concerning their significance. The sequence of electron transfer interactions involved in the full oxidation of such thiazine congeners was formulated, taking note of several complicating reactions previously encountered. It was proposed that the many common characteristics of all substituted phenothiazines derive from the reactive properties strongly dependent on the thioether sites of their thiazine rings. The demonstrated specific reactions with trace metals under mild conditions raised the further possibility that these properties may imply interaction with metals in vivo. In any case, the hypothesis demands that the chemical pharmacology of all thiazine derivatives be similar, regardless of the site of biological action. However, the localization of drug molecules, at both the gross and subcellular levels, should depend strongly on the prosthetic radicals, which thus provide each congener with its distinctive pharmacological character within the broader pattern of phenothiazine group behavior. Possible modes of biological reactivity associated with the formation of the semiquinone radical were advanced: The chemical lability of the free radical might shunt normal electron transfer or phosphorylation pathways, or the availability of biologically essential trace metal ions might be altered at critical intracellular sites. The well-delineated metal-phenothiazine reaction system also was proposed as a useful model for the more general study of free radical-metal interactions that may often be related to the biochemistry of metal ions in the respiratory chain of biological electron transport or to their role as cofactors in enzymic reactions. It is also possible that formation of the highly colored phenothiazine semiquinone ions might serve as a test of [metal] oxidation states in chemistry or of the presence of other interacting free radical reactions.