STRUCTURE ACTIVITY OF PHOTOCHEMISTRY AND PHOTOTOXICITY OF PHENOTHIAZINE DRUGS

吩噻嗪类化合物具有多种药理活性， 最著名的是它们作为镇静剂的作用。氯丙嗪(CPZ)， 这些药物最重要的代表，实际上是在使用 在美国，每年治疗数以千计的精神病人。 光敏化能力的分子光化学机制 CPZ的光毒性仍然未知，即使光毒性是明显的 在这些药物被引入临床实践后不久 上世纪50年代初的S。 CPZ与双链DNA的基态物理结合 光化学共价结合到单链和双链DNA， CPZ的代谢产物，甚至其短暂的瞬变(至少 阳离子自由基)已被排除参与此事 这些药物的不良副作用。激光的最新研究进展 吩噻嗪类化合物的闪光光解研究表明， 这些化合物的三重态可以被有效地猝灭 溶液中的质子。淬火的效果是非常好的 对药物的结构敏感。 这个项目目标是合成几个不可用的 以及研究它们的短暂的瞬变过程，特别是 阳离子自由基和三联体。对于合成，标准方法是 将会被使用。将使用光学技术来表征这些瞬变 用一台激光装置进行吸收测量。两个波长 实验将使用Nd-YAG/准分子激光组合进行。 对于这些化合物的三重态，消光系数和 量子产额将使用比较法和 三重-三重能量传递原理。这些属性 三胞胎的数量与亲本的光毒性相关 化合物，以找出这种中间体是否直接参与了 该药物家族的光毒活性。MNDO理论计算 将进行检查以检查吩噻嗪氮的质子化 在第一激发三重态下是可能的。

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.