Reddy V K, Valasinas A, Sarkar A, Basu H S, Marton L J, Frydman B
SLIL Biomedical Corp., 535 Science Drive, Suite C, Madison, Wisconsin 53711, USA.
J Med Chem. 1998 Nov 19;41(24):4723-32. doi: 10.1021/jm980172v.
Eight analogues of 1N,12N-bisethylspermine (BES) with restricted conformations were synthesized in the search for new spermine mimetics with cytotoxic activities. By replacing the central butane segment of BES with a 1,2-disubstituted cyclopropane ring, a pair of cis/trans-isomers was obtained that introduced a spatial constraint in the otherwise freely mobile butane chain. An analogous pair of isomers was obtained when the butane segment was replaced with a 1, 2-disubstituted cyclobutane ring or with a 2-butene residue. The six new BES analogues thus obtained (three pairs of cis/trans-isomers) were growth inhibitory at low-micromolar concentrations against four human tumor cell lines (A549, HT-29, U251MG, and DU145) but were less growth inhibitory against two other human tumor cell lines (PC-3 and MCF7). 1N,12N-Bisethylspermyne, where the central butane segment of BES was replaced by the rigid 2-butyne segment, was devoid of growth inhibitory activity against five of the six human cell lines studied (DU145 being the only exception), a clear indication of the importance of conformational mobility at the 4N, 9N-butane segment of BES for its biological activity. When the butane segment was replaced by a benzene-1,2-dimethyl residue, the resulting BES analogue was devoid of growth inhibitory activity despite its cisoid conformation. The cytotoxicity of the analogues does not seem to be directly related to their uptake by the cells or to their effects on cellular polyamine levels. BES analogues with restricted conformations but which contained the equivalent of a two-carbon unit, rather than the natural four-carbon unit, at the central segment, such as 1,2-diaminocyclopropyl or 1, 2-diaminocyclobutyl derivatives, were devoid of growth inhibitory effects at the concentrations studied. The development of conformationally restricted polyamine analogues appears to show promise in the further quest for polyamine-related therapeutic agents with specificity of action.
为了寻找具有细胞毒性活性的新型精胺模拟物，合成了8种具有受限构象的1N,12N-双乙基精胺（BES）类似物。通过用1,2-二取代环丙烷环取代BES的中心丁烷片段，得到了一对顺式/反式异构体，这在原本可自由移动的丁烷链中引入了空间限制。当丁烷片段被1,2-二取代环丁烷环或2-丁烯残基取代时，也得到了类似的一对异构体。由此得到的6种新的BES类似物（三对顺式/反式异构体）在低微摩尔浓度下对四种人类肿瘤细胞系（A549、HT-29、U251MG和DU145）具有生长抑制作用，但对另外两种人类肿瘤细胞系（PC-3和MCF7）的生长抑制作用较小。1N,12N-双乙基精胺（其中BES的中心丁烷片段被刚性的2-丁炔片段取代）对所研究的六种人类细胞系中的五种没有生长抑制活性（DU145是唯一的例外），这清楚地表明BES的4N,9N-丁烷片段的构象流动性对其生物活性很重要。当丁烷片段被苯-1,2-二甲基残基取代时，所得的BES类似物尽管具有顺式构象，但没有生长抑制活性。这些类似物的细胞毒性似乎与其被细胞摄取或对细胞多胺水平的影响没有直接关系。具有受限构象但在中心片段含有相当于两个碳单元而非天然四个碳单元的BES类似物，如1,2-二氨基环丙基或1,2-二氨基环丁基衍生物，在所研究的浓度下没有生长抑制作用。构象受限的多胺类似物的开发似乎在进一步寻找具有作用特异性的多胺相关治疗剂方面显示出前景。
