Neptune. McCreery
362 Journal of Medicinal Chemistry, 1978, Vol. 21, N o . 4
Chemical and Electrochemical Oxidation of 7-Hydroxychlorpromazine M a r i l y n N e p t u n e and R i c h a r d L. McCreery* Department of Chemistry, T h e Ohio State University, Columbus, Ohio 43210. Received October 5 , 1977
The oxidation of 7-hydroxychlorpromazine, a process associated with several side effects of chlorpromazine therapy, was examined in vitro by electrochemistry and rapid-scanning spectrophotometry. At pH 2, the oxidation results in a quantitative yield of 7,8-dioxochlorpromazine, but several intermediates are observable during the course of the reaction. These include a quinone imine with a half-life of 0.1 s, a monosubstituted benzoquinone with a half-life of -50 s, and a disubstituted benzoquinone with a half-life of - 5 min. The concentrations of each intermediate were determined quantitatively as a function of time, and a complete oxidation mechanism is proposed. At pH 7 . the yield of 7,8-dioxochlorpromazine is less than at pH 2, and an additional reaction pathway icvolving direct hydroxylation of the quinone imine is observed. The relationship of these reactions to the pharmacology of the hydroxylated chlorpromazine metabolites is discussed
The chemistry a n d pharmacology of the hydroxylated derivatives of chlorpromazine h a v e b e e n examined in several different laboratories for at least three reasons. First, t h e formation of 7-hydroxychlorpromazine (1) a n d 7,8-dihydroxychlorpromazine (2) c o m p r i s e s a m a j o r metabolic route of chlorpromazine b o t h in animals a n d in humans.'-4 S e c o n d , t h e 7-hydroxy derivative is c o m p a -
T h e viability of t h e s e theories, a n d their relationship t o d r u g activity and side effects, could b e b e t t e r assessed if a detailed knowledge of t h e oxidation mechanisms of 1 a n d 2 were available. Accordingly, t h e p r e s e n t work was directed t o w a r d elucidating t h e p r o d u c t s and m e c h a n i s m s of t h e electrochemical and chemical oxidation of 7 hydroxy- and 7,8-dihydroxychlorpromazine. The chemical oxidation of 2 t o 3 has been reported," b u t t h e reaction was used synthetically and n o t s t u d i e d in detail. P r e liminary electrochemical investigation i n o u r laboratory indicated that t h e oxidation of 2 is a reversible two-electron process t o form 3 b u t that the oxidation of 1 is m u c h more complex.'8 Thus t h i s r e p o r t emphasizes t h e results of a m o r e i n - d e p t h examination of the oxidation of 1.
Experimental Section
rable t o chlorpromazine i n pharmacological activity as m e a s u r e d b y several a n i m a l tests, s u c h as b a r b i t u r a t e ~ , ~also has similar sleeping t i m e and m o t o r a c t i ~ i t y ,and effects o n biochemical processes, s u c h as s e r u m prolactin levels a n d mitochondrial calcium a c c ~ m u l a t i o n . ~In ,~ addition, blood levels of 7-hydroxychlorpromazine have been correlated with improvement of psychotic symptoms in m e n t a l patients, a correlation which was n o t as evident for chlorpromazine sulfoxide or chlorpromazine i t ~ e l f . ~ J O T h i r d , b o t h hydroxy derivatives have been associated with several of t h e side effects of long-term chlorpromazine therapy, such as skin pigmentation and corneal opacity.l1-l3 T h e m e c h a n i s m of this toxicity and its relationship to oxidation-reduction reactions of the hydroxylated d e rivatives h a v e been investigated i n several i n d e p e n d e n t studies. In o n e investigation, i t was f o u n d that 1 was hydroxylated t o 2 and then oxidized t o 7,8-dioxochlorpromazine (3) b y m u s h r o o m tyrosinase, a model e n z y m e for m a m m a l i a n tyrosine h y d r o x y 1 a ~ e . l It ~ was suggested that oxidation of 1 m a y eventually lead to melanin-like pigments via t h e formation of 3. T h e authors of a related investigation hypothesized that light-induced oxidation of 1 led to quinoid derivatives of phenothiazine, which in t u r n f o r m e d a "pseudo melanin".'l In a n o t h e r s t u d y , i t was f o u n d that 2 reacts w i t h oxygen t o generate cytotoxic hydrogen peroxide a n d hydroxyl radicals, and i t was proposed that this reaction m a y be responsible for the side effects caused b y hydroxylated chlorpromazine m e t a b o lite~.'~,'~ W h i l e t h e s e pharmacological hypotheses a r e largely u n p r o v e n , t h e y d o indicate t h e p o t e n t i a l i m p o r t a n c e of oxidation of 1 and 2 t o the chemistry of t h e s e chlorp r o m a z i n e metabolites in t h e physiological environment. 0022-26231T8/ 1821-03fi2$01.00/0
The electrochemical techniques used here are well established and are explained in detail e l s e ~ h e r e . ' ~Electrochemical experiments were performed using potentiostats of conventional designs based on operational amplifiers. Experiments requiring fast voltammetric scan rates (>0.5 V/s) or short electrolysis times (
