PHOTOCHEMISTRY OF DIAZENIUMDIOLATES--NO RELEASING DRUGS

描述(摘自摘要)：一氧化氮(NO)是一种重要的 一种生物调节剂，参与控制神经传递、血液 凝血和血压。此外，NO已被证明会导致 癌细胞。因此，以前的研究主要集中在开发 能够高效和选择性地向肿瘤细胞输送NO的药物 而不会对其他生物调控过程产生重大影响。 安定是一类有趣的此类药物，目前在 发展。 最近为使重氮二醇酯更有效的药物所做的努力 集中使用此类化合物的衍生品来传递NO 特别是到一个目标地点。拟议研究的一个主要目标是 开发重氮二醇酸盐的光化学前体，可用作 有效的NO释放剂。由于最初在其他地方进行的实验 具有经典光保护基团的实验室提供了意想不到的和 令人失望的结果，反应途径将被澄清，以便更多 可以合理设计高效的光触发NO释放药物。在……里面 此外，如果二氮肼二酯要享受常规医疗用途，其基本 必须了解光化学，这样光毒性问题才可能 预期的和避免的 拟议研究的具体目标涉及上述目标， 简要概述了：(1)光化学中涉及的反应途径 将通过产品分析来阐明O-烷基重氮二醇类化合物的组成 以及时间分辨红外(TRIR)光谱的强大工具。(2) 氧取代硝烯(O-硝烯)，被认为是中间体 通过光解O-烷基重氮二酸盐类高效生产的 特色化的。(3)由于O-硝烯是迄今为止未被研究过的一类 中间体的反应性将由两家公司详细检查 实验和计算方法。(4)最终，新的O-烷基化 用于高效光化学生产的重氮烯二酸衍生物 NO将被设计和测试。

DESCRIPTION (Adapted from abstract): Nitric oxide (NO) is an important bioregulator that is involved in the control of neurotransmission, blood clotting, and blood pressure. In addition, NO has been shown to kill cancerous tumor cells. Thus, previous research has focused on developing drugs that can deliver NO efficiently and selectively, e.g., to tumor cells without dramatically affecting other bioregulatory processes. Diazeniumdiolates are an interesting class of such drugs presently under development. Recent efforts to make diazeniumdiolates more effective pharmaceuticals have concentrated on using derivatives of such compounds to deliver NO specifically to a targeted site. A major goal of the proposed research is to develop photochemical precursors to diazeniumdiolates that can be used as effective NO-releasing agents. Since initial experiments in other laboratories with classic photoprotecting groups gave unexpected and disappointing results, reaction pathways will be clarified so that more efficient phototriggered NO-releasing drugs can be rationally designed. In addition, if diazeniumdiolates are to enjoy routine medical use, their basic photochemistry must be understood so that phototoxicity issues may be anticipated and avoided The specific aims of the proposed research, which address the above goals, are briefly outlined: (1) Reaction pathways involved in the photochemistry of O-alkylated diazeniumdiolates will be elucidated with product analysis and the powerful tool of time-resolved infrared (TRIR) spectroscopy. (2) Oxygen-substituted nitrenes (O-nitrenes), proposed to be intermediates efficiently produced by photolysis of O-alkylated diazeniumdiolates will be characterized. (3) Since O-nitrenes are a heretofore unstudied class of intermediates their reactivity will be examined in detail by both experimental and computational methods. (4) Ultimately, new O-alkylated diazeniumdiolate derivatives for the efficient photochemical production of NO will be designed and tested.