Guthrie Daryl A, Nourian Saghar, Takahashi Cyrus G, Toscano John P
Department of Chemistry, 3400 North Charles Street, Johns Hopkins University , Baltimore, Maryland 21218, United States.
J Org Chem. 2015 Feb 6;80(3):1349-56. doi: 10.1021/jo5023316. Epub 2015 Jan 28.
Due to its inherent reactivity, HNO must be generated in situ through the use of donor compounds. One of the primary strategies for the development of new HNO donors has been modifying hydroxylamines with good leaving groups. A recent example of this strategy is the (hydroxylamino)barbituric acid (HABA) class of HNO donors. In this case, however, an undesired intramolecular rearrangement pathway to the corresponding hydantoin derivative competes with HNO formation, particularly in the absence of chemical traps for HNO. This competitive non-HNO-producing pathway has restricted the development of the HABA class to examples with fast HNO release profiles at physiological pH and temperature (t(1/2) < 1 min). Herein, the factors that favor the rearrangement pathway have been examined and two independent strategies that protect against rearrangement to favor HNO generation have been developed. The timecourse and stoichiometry for the in vitro conversion of these compounds to HNO (trapped as a phosphine aza-ylide) and the corresponding barbituric acid (BA) byproduct have been determined by (1)H NMR spectroscopy under physiologically relevant conditions. These results confirm the successful extension of the HABA class of pure HNO donors with half-lives at pH 7.4, 37 °C ranging from 19 to 107 min.
由于HNO具有固有的反应活性，必须通过使用供体化合物原位生成。开发新型HNO供体的主要策略之一是用具有良好离去基团的羟胺进行修饰。该策略的一个最新例子是HNO供体的（羟氨基）巴比妥酸（HABA）类。然而，在这种情况下，生成相应乙内酰脲衍生物的不期望的分子内重排途径与HNO的形成相互竞争，特别是在没有HNO化学捕获剂的情况下。这种竞争性的非HNO生成途径限制了HABA类的发展，使其仅限于在生理pH和温度下具有快速HNO释放曲线（t(1/2) < 1分钟）的例子。在此，研究了有利于重排途径的因素，并开发了两种独立的防止重排以利于HNO生成的策略。在生理相关条件下，通过¹H NMR光谱法确定了这些化合物在体外转化为HNO（捕获为膦氮叶立德）和相应巴比妥酸（BA）副产物的时间进程和化学计量。这些结果证实了纯HNO供体的HABA类成功扩展，其在pH 7.4、37°C下的半衰期为19至107分钟。
