Gardner Richard Andrew, Delcros Jean-Guy, Konate Fanta, Breitbeil Fred, Martin Bénédicte, Sigman Michael, Huang Min, Phanstiel Otto
Department of Chemistry, P.O. Box 162366, University of Central Florida, Orlando, FL 32816-2366, USA.
J Med Chem. 2004 Nov 18;47(24):6055-69. doi: 10.1021/jm0497040.
Several N(1)-arylalkylpolyamines containing various aromatic ring systems were synthesized as their respective HCl salts. The N(1)-substituents evaluated ranged in size from N(1)-benzyl, N(1)-naphthalen-1-ylmethyl, N(1)-2-(naphthalen-1-yl)ethyl, N(1)-3-(naphthalen-1-yl)propyl, N(1)-anthracen-9-ylmethyl, N(1)-2-(anthracen-9-yl)ethyl, N(1)-3-(anthracen-9-yl)propyl, and pyren-1-ylmethyl. The polyamine architecture was also altered and ranged from diamine to triamine and tetraamine systems. Biological activities in L1210 (murine leukemia), Chinese hamster ovary (CHO), and CHO's polyamine transport-deficient mutant (CHO-MG) cell lines were investigated via IC(50) cytotoxicity determinations. K(i) values for spermidine uptake were also determined in L1210 cells. The size of the N(1)-arylalkyl substituent as well as the polyamine sequence used had direct bearing on the observed cytotoxicity profiles. N(1)-Tethers longer than ethylene showed dramatic loss of selectivity for the polyamine transporter (PAT) as shown in a CHO/CHO-MG cytotoxicity screen. In summary, there are clear limits to the size of N(1)-substituents, which can be accommodated by the polyamine transporter. A direct correlation was observed between polyamine-conjugate uptake and cytotoxicity. In this regard, a cytotoxicity model was proposed, which describes a hydrophobic pocket of set dimensions adjacent to the putative PAT polyamine-binding site.
合成了几种含有不同芳环系统的N(1)-芳基烷基多胺，并制成了它们各自的盐酸盐。所评估的N(1)-取代基大小各异，包括N(1)-苄基、N(1)-萘-1-基甲基、N(1)-2-(萘-1-基)乙基、N(1)-3-(萘-1-基)丙基、N(1)-蒽-9-基甲基、N(1)-2-(蒽-9-基)乙基、N(1)-3-(蒽-9-基)丙基和芘-1-基甲基。多胺结构也有所改变，范围从二胺到三胺和四胺系统。通过IC(50)细胞毒性测定研究了这些化合物在L1210（小鼠白血病）、中国仓鼠卵巢（CHO）以及CHO的多胺转运缺陷突变体（CHO-MG）细胞系中的生物活性。还测定了L1210细胞中精胺摄取的K(i)值。N(1)-芳基烷基取代基的大小以及所使用的多胺序列对观察到的细胞毒性谱有直接影响。如在CHO/CHO-MG细胞毒性筛选中所示，比乙烯长的N(1)-连接链对多胺转运体（PAT）的选择性显著降低。总之，多胺转运体能够容纳的N(1)-取代基大小存在明确限制。观察到多胺缀合物摄取与细胞毒性之间存在直接相关性。在这方面，提出了一个细胞毒性模型，该模型描述了与假定的PAT多胺结合位点相邻的特定尺寸的疏水口袋。
