Mamont P S, Claverie N, Gerhart F
Merrell Dow Research Institute, Strasbourg, France.
Adv Exp Med Biol. 1988;250:691-706. doi: 10.1007/978-1-4684-5637-0_61.
Investigations with the fluorinated spermidine analogues show clearly that these compounds have significant potential for studying the metabolism and functions of the polyamines. However, the biochemical and biological properties of these analogues are dissimilar. This is due to the influence of the fluorine substituent(s) on the basicity of the amine function proximal to the fluoromethylene group, this effect being amplified by geminal disubstitution. The monofluorinated spermidine analogues compare well with the natural amine in their ability to regulate the expression of the decarboxylase enzymes, to be substrates of spermine synthase and to support growth of polyamine-deficient cells. It is also likely that 6-monofluorospermine, formed biochemically in situ, shares with spermine similar functions. These findings raise the possibility of using these spermidine analogues to study the metabolism and pharmacology of polyamines in vivo but also to provide more insight into the regulatory role of spermidine in ODC and SAM-DC expression. Another potential application may be the use of these analogues as probes in tumor imaging and therapy control. This indication has been inferred by studies in tumor-bearing animals, using 19F-NMR spectroscopy determination of tissue fluorospermidine and fluorospermine, formed biochemically from the precursors 2-fluoro or 2,2-difluoroputrescine, and which demonstrate preferential accumulation in tumor versus normal tissue. Finally, these monofluorinated spermidine analogues may exert beneficial effects in pathological states associated with polyamine deficiency. These diseases remain however to be identified. Among the difluorinated spermidine analogues, 7,7-difluorospermidine possesses the most interesting properties. This spermidine analogue still possesses ODC and SAM-DC repressing activities although at much higher concentration than spermidine. More importantly it is a potent inhibitor of spermine synthesis both in cultured cells and in vivo due to its efficient competition with spermidine in the spermine synthase reaction. This compound not only depletes tumor cell of its spermine content but, in addition, appears to exert by itself and/or via 6,6-difluorospermine, the product of its metabolism, polyamine antagonist effects. Combined with MAP but also with DFMO, two potent irreversible inhibitors of ODC which block the synthesis of the natural endogenous polyamines, 7,7-difluorospermidine causes an immediate decrease of viability in cultured HTC cells and promotes tumor regression and stabilization in hepatoma-bearing rats.(ABSTRACT TRUNCATED AT 400 WORDS)
对氟化亚精胺类似物的研究清楚地表明，这些化合物在研究多胺的代谢和功能方面具有巨大潜力。然而，这些类似物的生化和生物学特性并不相同。这是由于氟取代基对靠近氟亚甲基的胺官能团碱性的影响，这种影响因偕二取代而放大。单氟化亚精胺类似物在调节脱羧酶表达、作为精胺合酶底物以及支持多胺缺乏细胞生长的能力方面与天然胺相当。6 - 单氟精胺在体内生化形成，也可能与精胺具有相似功能。这些发现增加了利用这些亚精胺类似物研究体内多胺代谢和药理学的可能性，同时也能更深入了解亚精胺在鸟氨酸脱羧酶（ODC）和S - 腺苷甲硫氨酸脱羧酶（SAM - DC）表达中的调节作用。另一个潜在应用可能是将这些类似物用作肿瘤成像和治疗控制的探针。这一迹象是通过对荷瘤动物的研究推断出来的，利用¹⁹F - NMR光谱法测定由前体2 - 氟或2,2 - 二氟腐胺生化形成的组织氟亚精胺和氟精胺，结果表明它们在肿瘤组织中比正常组织有优先积累。最后，这些单氟化亚精胺类似物可能在与多胺缺乏相关的病理状态中发挥有益作用。然而，这些疾病仍有待确定。在二氟化亚精胺类似物中，7,7 - 二氟亚精胺具有最有趣的特性。这种亚精胺类似物仍然具有ODC和SAM - DC抑制活性，尽管其浓度比亚精胺高得多。更重要的是，由于它在精胺合酶反应中与亚精胺有效竞争，它在培养细胞和体内都是精胺合成的有效抑制剂。这种化合物不仅耗尽肿瘤细胞中的精胺含量，此外，它自身和/或通过其代谢产物6,6 - 二氟精胺似乎还发挥多胺拮抗剂的作用。与甲硫氨酸腺苷转移酶（MAP）以及二氟甲基鸟氨酸（DFMO）联合使用时，这两种ODC的有效不可逆抑制剂可阻断天然内源性多胺的合成，7,7 - 二氟亚精胺会使培养的HTC细胞活力立即下降，并促进荷肝癌大鼠的肿瘤消退和稳定。（摘要截选至400字）
