Department of Science and Drug Technology, University of Torino, Via Pietro Giuria 9, 10125, Torino, Italy.
Laboratory of Photochemistry, Department of Drug Sciences, University of Catania, 95125, Catania, Italy.
ChemMedChem. 2018 Jun 20;13(12):1238-1245. doi: 10.1002/cmdc.201800088. Epub 2018 May 8.
A few compounds in which the nitric oxide (NO) photodonor N-[4-nitro-3-(trifluoromethyl)phenyl]propane-1,3-diamine is joined to the mitochondria-targeting alkyltriphenylphosphonium moiety via flexible spacers of variable length were synthesized. The lipophilicity of the products was evaluated by measuring their partition coefficients in n-octanol/water. The obtained values, markedly lower than those calculated, are consistent with the likely collapsed conformation assumed by the compounds in solution, as suggested by molecular dynamics simulations. The capacity of the compounds to release NO under visible light irradiation was evaluated by measuring nitrite production by means of the Griess reaction. The accumulation of compounds in the mitochondria of human lung adenocarcinoma A549 cells was assessed by UPLC-MS. Interestingly, compound 13 [(9-((3-((4-nitro-3-(trifluoromethyl)phenyl)amino)propyl)amino)-9-oxononyl) triphenylphosphonium bromide] displayed both the highest accumulation value and high toxicity toward A549 cells upon irradiation-mediated NO release in mitochondria.
合成了几种将一氧化氮（NO）光供体 N-[4-硝基-3-（三氟甲基）苯基]丙烷-1,3-二胺通过可变长度的柔性间隔物连接到靶向线粒体的烷基三苯基膦部分的化合物。通过测量它们在正辛醇/水中的分配系数来评估产物的亲脂性。得到的值明显低于计算值，这与分子动力学模拟所表明的化合物在溶液中可能采取的折叠构象一致。通过格里斯反应测量亚硝酸盐的产生来评估化合物在可见光照射下释放 NO 的能力。通过 UPLC-MS 评估化合物在人肺腺癌细胞 A549 线粒体中的积累。有趣的是，化合物 13 [（9-（（3-（（4-硝基-3-（三氟甲基）苯基）氨基）丙基）氨基）-9-氧代壬基）三苯基膦溴化物]在介导线粒体中 NO 释放时，显示出最高的积累值和对 A549 细胞的高毒性。
