Department of Biosciences, University of Eastern Finland, Kuopio, Finland.
J Med Chem. 2010 Aug 12;53(15):5738-48. doi: 10.1021/jm100439p.
Biogenic polyamines, spermidine and spermine, are positively charged at physiological pH. They are present in all cells and essential for their growth and viability. Here we synthesized three novel derivatives of the isosteric charge-deficient spermine analogue 1,12-diamino-3,6,9-triazadodecane (SpmTrien, 5a) that are N(1)-Ac-SpmTrien (5c), N(12)-Ac-SpmTrien (5b), and N(1),N(12)-diethyl-1,12-diamino-3,6,9-triazadodecane (N(1),N(12)-Et(2)-SpmTrien, 5d). 5a and 5d readily accumulated in DU145 cells at the same concentration range as natural polyamines and moderately competed for the uptake with putrescine (1) but not with spermine (4a) or spermidine (2). 5a efficiently down-regulated ornithine decarboxylase and decreased polyamine levels, while 5d proved to be inefficient, compared with N(1),N(11)-diethylnorspermine (6). None of the tested analogues were substrates for human recombinant spermine oxidase, but those having free aminoterminus, including 1,8-diamino-3,6-diazaoctane (Trien, 3a), were acetylated by mouse recombinant spermidine/spermine N(1)-acetyltransferase. 5a was acetylated to 5c and 5b, and the latter was further metabolized by acetylpolyamine oxidase to 3a, a drug used to treat Wilson's disease. Thus, 5a is a bioactive precursor of 3a with enhanced bioavailability.
生物源多胺，如亚精胺和精胺，在生理 pH 值下带正电荷。它们存在于所有细胞中，对细胞的生长和活力至关重要。在这里，我们合成了三种新型的同系物电荷缺乏的精胺类似物 1,12-二氨基-3,6,9-三氮杂十二烷（SpmTrien，5a）的衍生物，即 N(1)-乙酰基-SpmTrien（5c）、N(12)-乙酰基-SpmTrien（5b）和 N(1),N(12)-二乙基-1,12-二氨基-3,6,9-三氮杂十二烷（N(1),N(12)-Et(2)-SpmTrien，5d）。5a 和 5d 以与天然多胺相同的浓度范围在 DU145 细胞中易积累，并适度与腐胺（1）竞争摄取，但不与精胺（4a）或精脒（2）竞争。5a 能有效下调鸟氨酸脱羧酶并降低多胺水平，而 5d 与 N(1),N(11)-二乙基-norspermine（6）相比效率较低。测试的类似物都不是人重组精脒氧化酶的底物，但那些具有游离氨基末端的类似物，包括 1,8-二氨基-3,6-二氮杂辛烷（Trien，3a），被小鼠重组精脒/精胺 N(1)-乙酰转移酶乙酰化。5a 被乙酰化为 5c 和 5b，后者进一步被乙酰多胺氧化酶代谢为 3a，3a 是一种用于治疗威尔逊病的药物。因此，5a 是 3a 的生物活性前体，具有增强的生物利用度。
