STRUCTURE ACTIVITY OF PHOTOCHEMISTRY AND PHOTOTOXICITY OF PHENOTHIAZINE DRUGS

吩噻嗪类药物的光化学结构活性及光毒性

• 批准号: 6271666
• 负责人: CARMELO GARCIA-RUIZ
• 金额: $ 9.28万
• 依托单位: UNIVERSITY OF PUERTO RICO AT HUMACAO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6271666
• 关键词: atomic absorption spectrometry; cations; chemical structure function; chlorpromazine; drug design /synthesis /production; emission spectrometry; flash photolysis; lasers; mathematical model; phenothiazines; photochemistry; triplet state

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.

吩噻嗪衍生物具有许多药理活性， 最著名的是它们的镇静作用。 氯丙嗪（CPZ）， 这些药物中最重要的代表， 在美国，每年治疗数千名精神病患者。 光敏化能力的分子光化学机制 的CPZ仍然是未知的，即使通过光毒性是明显的 在这些药物被引入临床实践后不久， 50年代初。 CPZ与双链DNA的基态物理结合， 光化学共价结合单链和双链DNA， 代谢产物的CPZ，甚至其短暂的瞬变（至少 阳离子自由基）已被排除参与此 这些药物的不良副作用。 激光的最新研究 一些吩噻嗪衍生物的闪光光解表明， 这些化合物的三重态可以被 溶液中的质子。 淬火的有效性是非常 对药物的结构敏感。 该项目的目标是综合几个不可用的 吩噻嗪，并研究其短暂的瞬变，特别是 阳离子自由基和三重态。 对于合成，标准方法 将用于 瞬态特性将采用光学 使用Nd-YAG激光装置进行吸收测量。 两个波长 实验将用Nd-YAG /准分子激光器组合进行。 对于这些化合物的三重态， 量子产率将使用比较方法来确定， 三重态-三重态能量转移原理。 性能 三联体的光毒性与母体的光毒性相关 化合物，以找出这种中间体是否可能直接参与 光毒性活性的药物家族。 MNDO理论计算 检查吩噻嗪氮的质子化 在第一激发三重态是可能的。