Oxidation of Amino Acids by Chlorpromazine Cation Radical and Co-Catalysis by Chlorpromazine

Abstract

The long-tem use of chlorpromazine (CPZ) may cause severe side effects. This property of CPZ might be related to pro-oxidant effects of the chlorpromazine cation radical (CPZ<sup>·+</sup>), which can be easily generated by catalytic action of peroxidases, including the neutrophil myeloperoxidase (MPO) and by methemoglobin. Aiming the comprehension of a putative physiological effect of CPZ<sup>·+</sup> upon biomolecules, in this work we studied the reactivity of CPZ<sup>·+</sup> with amino acids and the co-catalytic effect of CPZ during the oxidation of amino acids by horseradish peroxidase (HRP)/H<sub>2</sub>O<sub>2</sub> system. We also studied whether natural blood plasma components as ascorbic acid, uric acid and nitrite could inhibit the oxidative effect of CPZ<sup>·+</sup>. We found that tryptophan, tyrosine and cysteine were easily oxidized by pure CPZ<sup>·+</sup>. Other amino acids as methionine, glycine, phenylalanine, aspartic acid and lysine were unreactive. The decomposition of CPZ<sup>·+</sup> was exacerbated by uric acid, ascorbic acid and nitrite, provoking inhibition in the amino acids oxidation. In experiments with HRP/H<sub>2</sub>O<sub>2</sub>, and using CPZ as a co-catalyst, a strong effect upon oxidation of tryptophan, tyrosine and cysteine was obtained. It was also found that tryptophan was more reactive than tyrosine with CPZ<sup>·+</sup>, a feature that could be related to the recently described favorable interaction between tryptophan and CPZ. The use of CPZ as a co-catalyst is discussed regarding its role in the efficient oxidation of tryptophan

Spectrophotometric Kinetic and Mechanistic Investigation of Chlorpromazine Radical Cation with Hexachloroiridate (IV) in Catalyzed Aqueous Acid Medium

“…Activities of these compounds in chemical oxidation are well known. [6,[15][16][17] In aqueous medium, different absorbance bands at 270, 310, 440, 530, 610 nm [4,[18][19][20] have already been reported for reaction of CPZ.…”

“…[1][2][3] Their applications are continuously increasing with several properties as antioxidants and antipsychotic drugs. In late years, there has been significant interest in these drugs due to the reactivity of phenothiazine as neutral as well as radical cationic [4][5][6] form, and some interesting mechanistic approaches of these radical with nucleophiles have been investigated. [7][8][9][10][11][12] The mainly used Phenothiazine based drugs are substituted at the position 2 and 10, [13] and the types of substituent have chemical and reactivity properties of these compounds governing their uses.…”

Electrochemically Induced Mesomorphism Switching in a Chlorpromazine Hydrochloride Lyotropic Liquid Crystal

“…The tranquilizing drug, chlorpromazine (Figure a), and its derivatives are often used as one-electron mediators in electrochemistry, as well as in the treatment of schizophrenia; its biological activity is thought to derive from its facile oxidation and photo-oxidation to a stable cation radical − and its flexibility: − in the solid state and in solution, the neutral molecule folds about the N–S axis with the central six-ring in a boat confirmation (“butterfly”-shaped, dihedral angle of 139–153°, Figure a), with rapid molecular motions that include those associated with the side chain, pyramidal inversion at nitrogen and ring inversion, even at low temperatures . Oxidation to the cation radical flattens the ring system through relaxing steric repulsions and readjusting the side chain, so that the dihedral angle opens up to 170–180°. − In contrast, further oxidation to the dication followed by hydrolysis with water yields the corresponding sulfoxide, which is thought to exist with the central six-ring in the boat conformation, at least in the solid state .…”