Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis
作者:Salvatore Savino、Annamaria Toscano、Rosa Purgatorio、Emanuela Profilo、Antonio Laghezza、Paolo Tortorella、Mariacristina Angelelli、Saverio Cellamare、Rosa Scala、Domenico Tricarico、Carlo Marya Thomas Marobbio、Filippo Perna、Paola Vitale、Mariangela Agamennone、Vincenzo Dimiccoli、Anna Tolomeo、Antonio Scilimati
DOI:10.1016/j.ejmech.2018.08.044
日期:2018.10
ethane-1,1-diyl]bis(phosphonic acid) (10) was effective in reducing PC3 and RAW 264.7 cell number in crystal-violet and cell-dehydrogenase activity assays at 100 μM concentration. 10 reduced differentiated osteoclasts number similarly with zoledronic acid in osteoclastogenesis assay. At nanomolar concentrations, 10 was more effective than zoledronic acid in inducing mineralization in MC3T3 and murine
双膦酸盐,例如唑来膦酸,阿仑膦酸和利塞膦酸是临床上用于预防骨密度损失和骨质疏松症的一类药物。合成了新的PCP双膦酸酯,用于靶向人甲羟戊酸途径的关键酶人法呢基焦磷酸合酶(h FPPS)和人香叶基Geranylgeranyl焦磷酸合酶(h GGPPS),并且能够在多种细胞系(PC3,MG63, MC3T3,RAW 264.7,J774A.1,骨髓细胞及其与PC3的共配基涉及骨骼的体内稳态,骨骼形成和死亡。在16种化合物中,[1-羟基-2-(嘧啶-2-基氨基)乙烷-1,1-二基]双(膦酸)(10)在100μM浓度的结晶紫和细胞脱氢酶活性测定中可有效减少PC3和RAW 264.7细胞数量。在破骨细胞生成测定中,与唑来膦酸相似地减少了10个分化的破骨细胞数量。在纳摩尔浓度下,10在诱导MC3T3和鼠骨髓细胞中的矿化作用上比唑来膦酸更有效。此外,10显着抑制h FPPS的活性,IC 50为0.31μM