THE ROLE OF CHARGE IN POLYAMINE ANALOG RECOGNITION
THE ROLE OF CHARGE IN POLYAMINE ANALOG RECOGNITION
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DOI：
10.1021/jm00013a003
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发表时间：
1995-06-23
影响因子：
7.3
通讯作者：
VINSON, JRT
中科院分区：
文献类型：
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作者：
BERGERON, RJ;MCMANIS, JS;VINSON, JRT
合成了N-1，N-12-二乙基精胺(DESPM)的一系列类似物和同系物，并对其生物学性质进行了评价。这些四胺包括DESPM，N-1，N-12-双(2，2，2-三氟乙基)精胺(FDESPM)的简单线性类似物，DESPM，N，N‘-二(4-哌啶甲基)-1，4-二氨基丁烷[PIP(4，4，4)]和N，N’-bis[2-(4-piperidinyl)ethyl]-1，4-diaminobutane[PIP(5，4，5)]的环类似物，以及它们的芳香族化合物N，N‘-双(4-吡啶甲基)-1，4-二氨基丁烷[PYR(4，4，4)]和N，N’-双(4-吡啶甲基)-1，4-二氨基丁烷[PYR(4，4，4)]和N，N‘-双(4-吡啶甲基)-1，4-二氨基丁烷[PYR(4，4，4)]和N，N‘-双[2-(4-吡啶)乙基]-1，4-二氨基丁烷[PYR(5，4，5)]。类似物FDESPM、PIP(4，4，4)和PYR(4，4，4)的氮原子间距几乎与DESPM相同。较长的类似物PIP(5，4，5)和PYR(5，4，5)的氨基间距非常相似。然而，基团中氮的pK(A)不同，因此质子化的程度和基团成员之间的电荷特征也不同。对这些化合物的生物学特性的比较清楚地表明，毒胺必须带电才能被细胞识别。与低氮类似物PK(A)S认为，这样的氮素在生理pH下质子化较差，不能很好地与亚精胺竞争摄取，如预期的那样，具有较高的96hIC50值，对S-腺苷甲硫氨酸脱羧酶、鸟氨酸脱羧酶、亚精胺/精胺N-1-乙酰转移酶活性和细胞内多胺库几乎没有影响。
A series of analogues and homologues of N-1,N-12-diethylspermine (DESPM) was synthesized, and their biological properties were evaluated. These tetraamines include a simple linear analogue of DESPM, N-1,N-12-bis(2,2,2-trifluoroethyl)spermine (FDESPM), the cyclic analogues of DESPM, N,N'-bis(4-piperidinylmethyl)-1,4-diaminobutane [PIP(4,4,4)] and N,N'-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane [PIP(5,4,5)], and their aromatic counterparts, N,N'-bis(4-pyridylmethyl)-1,4-diaminobutane [PYR(4,4,4)] and N,N'-bis[2-(4-pyridyl)ethyl]-1,4-diaminobutane [PYR(5,4,5)]. The analogues FDESPM, PIP(4,4,4), and PYR(4,4,4) have distances between their nitrogen atoms almost identical to those of DESPM. The longer analogues PIP(5,4,5) and PYR(5,4,5) are very similar in the spacing of their amino groups. However, the pK(a) of the nitrogens in the groups differ; thus, the extent of protonation and the charge characteristics among the members of the groups differ. A comparison of the biological properties of these compounds clearly demonstrates that the tetraamines must be charged to be ''recognized'' by the cell. Analogues with low nitrogen pK(a)'s such that the nitrogens are poorly protonated at physiological pH do not compete well with spermidine for uptake and, as expected, have high 96 h IC50 values and have little effect on S-adenosylmethionine decarboxylase, ornithine decarboxylase, and spermidine/spermine N-1-acetyltransferase activities and on intracellular polyamine pools.