STRUCTURE ACTIVITY OF PHOTOCHEMISTRY AND PHOTOTOXICITY OF PHENOTHIAZINE DRUGS

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Phenothiazine derivatives have numerous pharmacological activities, the best known being their action as tranquilizers. Chloropromazine (CPZ), the most important representant of these drugs, is actually being used in the United States to treat thousands of psychiatric patients annually. The molecular photochemical mechanisms for the photosensitizing ability of CPZ are still unknown, even through the phototoxicity was apparent shortly after these drugs were introduced into clinical practice in the early 1950's. The ground state physical binding of CPZ to double stranded DNA, the photochemical covalent binding to single- and double stranded DNA, the metabolic products of CPZ and even its short-lived transients (at least the cation radical) have been ruled out of participating in this undesirable side-effect of these drugs. Recent studies on the laser flash photolysis of some phenothiazine derivatives showed that the triplet state of these compounds can be efficiently quenched by the protons in the solution. The effectiveness of the quenching is very sensitive to the structure of the drug. The goal of this project is to synthesize several non available phenothiazines and to study their short-lived transients, especially the cation radical and the triplet. For the synthesis, the standard method will be used. The transients will be characterized using optical absorption measurements with a Nd-YAG laser set-up. Two wavelength experiments will be performed with a Nd-YAG / Excimer laser combination. For the triplet state of these compounds, the extinction coefficient and the quantum yield will be determined using a comparative method and the triplet-triplet energy transfer principle, respectively. The properties of the triplet will be correlated with the phototoxicity of the parent compound to find out if this intermediate may be directly involved in the phototoxic activity of this drug family. MNDO theoretical calculations will be performed to check if protonation of the phenothiazine nitrogen is possible in the first excited triplet state.