Holt Jason J, Gannon M K, Tombline Gregory, McCarty Taylor A, Page Phillip M, Bright Frank V, Detty Michael R
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260-3000, USA.
Bioorg Med Chem. 2006 Dec 15;14(24):8635-43. doi: 10.1016/j.bmc.2006.08.023. Epub 2006 Aug 30.
Pentacyclic thio- (1) and seleno- (2) analogues of tetramethylrosamine (TMR) were prepared with a julolidyl fragment replacing the 3-dimethylamino substituent in the xanthylium core. The pentacylic structure increases the lipophilicity of 1 and 2 relative to TMR-S and TMR-Se and locks the lone-pair of electrons on the julolidyl N atom into conjugation with the xanthylium core. This conformational rigidization leads to longer wavelengths of absorption, but has little impact on other photophysical properties such as quantum yields for fluorescence and singlet-oxygen generation and fluorescence lifetimes in 1 and 2 relative to TMR-S and TMR-Se. Both 1 and 2 are effective photosensitizers against chemosensitive AUXB1 cells in vitro at 1x10(-7)M and compound 2 is an effective photosensitizer against multidrug-resistant CR1R12 cells in vitro at 1x10(-7)M. While the uptake TMR-S into CR1R12 cells as measured by fluorescence is significantly lower than uptake into chemosensitive AUXB1 cells, there is no significant difference in the uptake of 1 into either AUXB1 or CR1R12 cells. The addition of 2x10(-4)M verapamil to the cells prior to treatment with 1 had no significant effect on the uptake of 1 into either AUXB1 or CR1R12 cells. Treating lipid-activated, purified Pgp with 2 and light gave complete inhibition of Pgp ATPase activity.
制备了四甲基玫瑰胺（TMR）的五环硫代类似物（1）和硒代类似物（2），其中一个 julolidyl 片段取代了呫吨鎓核心中的 3 - 二甲氨基取代基。相对于 TMR - S 和 TMR - Se，五环结构增加了 1 和 2 的亲脂性，并使 julolidyl N 原子上的孤对电子与呫吨鎓核心共轭。这种构象刚性化导致吸收波长变长，但相对于 TMR - S 和 TMR - Se，对 1 和 2 的其他光物理性质影响很小，如荧光量子产率、单线态氧生成以及荧光寿命。1 和 2 在体外对化学敏感的 AUXB1 细胞均为有效的光敏剂，浓度为 1×10⁻⁷M，化合物 2 在体外对多药耐药的 CR1R12 细胞为有效的光敏剂，浓度为 1×10⁻⁷M。通过荧光测量，TMR - S 进入 CR1R12 细胞的摄取量明显低于进入化学敏感的 AUXB1 细胞的摄取量，但 1 进入 AUXB1 或 CR1R12 细胞的摄取量没有显著差异。在用 1 处理细胞之前，向细胞中添加 2×10⁻⁴M 维拉帕米对 1 进入 AUXB1 或 CR1R12 细胞的摄取量没有显著影响。用 2 和光处理脂质激活的纯化 P - 糖蛋白，可完全抑制 P - 糖蛋白的 ATP 酶活性。
