Lee Younghee, Ling Ke-Qing, Lu Xingliang, Silverman Richard B, Shepard E M, Dooley D M, Sayre Lawrence M
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Am Chem Soc. 2002 Oct 16;124(41):12135-43. doi: 10.1021/ja0205434.
We previously reported that 3-pyrroline and 3-phenyl-3-pyrroline effect a time-dependent inactivation of the copper-containing quinone-dependent amine oxidase from bovine plasma (BPAO) (Lee et al. J. Am. Chem. Soc. 1996, 118, 7241-7242). Quinone cofactor model studies suggested a mechanism involving stoichiometric turnover to a stable pyrrolylated cofactor. Full details of the model studies are now reported along with data on the inhibition of BPAO by a family of 3-aryl-3-pyrrolines (aryl = substituted phenyl, 1-naphthyl, 2-naphthyl), with the 4-methoxy-3-nitrophenyl analogue being the most potent. At the same time, the parent 3-phenyl analogue is a pure substrate for the flavin-dependent mitochondrial monoamine oxidase B from bovine liver. Spectroscopic studies (including resonance Raman) on BPAO inactivated by the 4-methoxy-3-nitrophenyl analogue are consistent with covalent derivatization of the 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor. The distinction of a class of compounds acting as an inactivator of one amine oxidase family and a pure substrate of another amine oxidase family represents a unique lead to the development of selective inhibitors of the mammalian copper-containing amine oxidases.
我们之前报道过，3-吡咯啉和3-苯基-3-吡咯啉会使牛血浆中的含铜醌依赖性胺氧化酶（BPAO）发生时间依赖性失活（Lee等人，《美国化学会志》，1996年，第118卷，7241 - 7242页）。醌辅因子模型研究表明了一种涉及化学计量转化为稳定吡咯化辅因子的机制。现在报告模型研究的全部细节以及关于一类3-芳基-3-吡咯啉（芳基 = 取代苯基、1-萘基、2-萘基）对BPAO抑制作用的数据，其中4-甲氧基-3-硝基苯基类似物的抑制作用最强。同时，母体3-苯基类似物是牛肝中黄素依赖性线粒体单胺氧化酶B的纯底物。对被4-甲氧基-3-硝基苯基类似物失活的BPAO进行的光谱研究（包括共振拉曼光谱）与2,4,5-三羟基苯丙氨酸醌（TPQ）辅因子的共价衍生化一致。一类化合物作为一个胺氧化酶家族的失活剂，同时又是另一个胺氧化酶家族的纯底物，这一区别为开发哺乳动物含铜胺氧化酶的选择性抑制剂提供了独特的线索。
