双膦酸盐前药：在HuH7肝癌细胞中的合成及生物学评价
Bisphosphonate prodrugs: synthesis and biological evaluation in HuH7 hepatocarcinoma cells.
作者信息
Monteil Maelle, Migianu-Griffoni Evelyne, Sainte-Catherine Odile, Di Benedetto Mélanie, Lecouvey Marc
机构信息
Université Paris 13, Sorbonne Paris Cité, Laboratoire de Chimie, Structure, Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), CNRS UMR 7244, 74, Rue Marcel Cachin, F-93017 Bobigny, France.
Université Paris 13, Sorbonne Paris Cité, Laboratoire de Chimie, Structure, Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), CNRS UMR 7244, 74, Rue Marcel Cachin, F-93017 Bobigny, France.
出版信息
Eur J Med Chem. 2014 Apr 22;77:56-64. doi: 10.1016/j.ejmech.2014.02.054. Epub 2014 Feb 23.
We investigated the biological effects of new synthesized bisphosphonates (BPs) on HuH7 hepatocarcinoma cells. BPs containing p-bromophenyl (R1 = p-Br, Ph, 2) in their side chain were the more potent to inhibit HuH7 cell viability. In addition, phenyl diesterified analogues (R2 = R3 = Ph, 2a) were more potent than methyl (R2 = R3 = Me, 2b) or non-esterified BPs (2) inducing more necrosis suggesting that they better entered into cells. Phosphodiesterase inhibitor (IBMX) reversed the effect of the esterified BPs and not that of non-esterified ones suggesting role of cell phosphodiesterases to release active BPs. BP analogues inhibited HuH7 cell migration but esterified ones had no effect on invasion due to the hiding of phosphonic groups. All together, these results indicated the therapeutic interest of these new BP prodrugs.
我们研究了新合成的双膦酸盐（BPs）对HuH7肝癌细胞的生物学效应。侧链含有对溴苯基（R1 = 对溴，苯基，2）的双膦酸盐对抑制HuH7细胞活力更有效。此外，苯基二酯化类似物（R2 = R3 = 苯基，2a）比甲基（R2 = R3 = 甲基，2b）或非酯化双膦酸盐（2）更有效，诱导更多坏死，表明它们能更好地进入细胞。磷酸二酯酶抑制剂（IBMX）逆转了酯化双膦酸盐的作用，而非酯化双膦酸盐则无此作用，这表明细胞磷酸二酯酶在释放活性双膦酸盐中起作用。双膦酸盐类似物抑制HuH7细胞迁移，但酯化双膦酸盐由于膦酸基团被掩盖而对侵袭无影响。总之，这些结果表明了这些新型双膦酸盐前药的治疗意义。
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