Hrabie Joseph A, Citro Michael L, Chmurny Gwendolyn N, Keefer Larry K
Basic Research Program, SAIC-Frederick, Incorporated, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
J Org Chem. 2005 Sep 16;70(19):7647-53. doi: 10.1021/jo050921y.
[reaction: see text] The enediamine tautomer of a variety of substituted amidine free bases reacts with nitric oxide (NO) to produce compounds containing a carbon-bound diazeniumdiolate [R1R2R3C-N(O)=NO-] functional group (previously called "nitrosohydroxylamines"). The new reaction has been shown to be quite general, although the nature of the products does vary. Amidines containing more than one replaceable hydrogen produce polydiazeniumdiolates as intermolecular salts, while those in which only one diazeniumdiolation can occur provide zwitterionic salts. These diazeniumdiolated amidines are shown to be useful NO donor compounds which undergo very slow spontaneous dissociation on dissolution in pH 7.4 phosphate buffer to produce mixtures of NO and nitrous oxide containing mostly NO. The most advantageous manifestation of the new discovery is the preparation of the monodiazeniumdiolated amidine zwitterions. Reaction of the medically relevant alpha-adrenergic agonists tetrahydrozoline and idazoxan produced monodiazeniumdiolated amidine zwitterions from which NO release was observed for up to 28 days and showed little sign of ending. The reaction should be applicable to a variety of pharmaceutical agents, including NO synthase inhibitors, antitumor agents, and antibacterials.
[反应：见正文] 多种取代脒游离碱的烯二胺互变异构体与一氧化氮（NO）反应，生成含有碳键连的重氮二醇盐[R1R2R3C-N(O)=NO-]官能团的化合物（以前称为“亚硝基羟胺”）。已证明该新反应具有相当的普遍性，尽管产物的性质确实有所不同。含有多个可取代氢的脒会生成聚重氮二醇盐作为分子间盐，而那些只能发生一次重氮二醇化的脒则会生成两性离子盐。这些重氮二醇化的脒被证明是有用的NO供体化合物，它们在pH 7.4的磷酸盐缓冲液中溶解时会非常缓慢地自发解离，生成主要含NO的NO和一氧化二氮混合物。这一新发现最有利的表现是单重氮二醇化脒两性离子的制备。医学上相关的α-肾上腺素能激动剂四氢唑啉和伊达唑胺反应生成单重氮二醇化脒两性离子，观察到从其中释放NO长达28天，且几乎没有结束的迹象。该反应应适用于多种药物制剂，包括NO合酶抑制剂、抗肿瘤剂和抗菌剂。
