Colabufo Nicola Antonio, Berardi Francesco, Cantore Mariangela, Perrone Maria Grazia, Contino Marialessandra, Inglese Carmela, Niso Mauro, Perrone Roberto, Azzariti Amalia, Simone Grazia Maria, Paradiso Angelo
Dipartimento Farmacochimico, Università degli Studi di Bari, via Orabona, 4, 70125 Bari, Italy.
Bioorg Med Chem. 2008 Apr 1;16(7):3732-43. doi: 10.1016/j.bmc.2008.01.055. Epub 2008 Feb 2.
Starting from lead compound 1 (EC(50)=1.64 microM), its non-basic nucleus has been conformationally restricted by 4-biphenyl and 2-naphthyl moieties. In each series we investigated if the presence of H-bond donor or acceptor substituents, the basicity and the lipophilicity (clogP) were correlated with the P-gp inhibiting activity of tested compounds. In the biphenyl series, derivative 4d displayed the best results (EC(50)=0.05 microM). The corresponding amide 3d was found less active (EC(50)=3.5 microM) ascertaining the importance of basicity in this series whilst the presence of hydroxy or methoxy substituents seems to be negligible. In the naphthyl series, both the basicity and the presence of H-bond donor or acceptor groups seem to be negligible. Moreover, the lipophilicity did not influence the P-gp inhibition activity of each series. Specific biological assays have been carried out to establish the P-gp interacting mechanism of tested compounds discriminating between substrates and inhibitors. Moreover, compound 4d displayed a potent P-gp inhibition activity with good selectivity towards BCRP pump.
从先导化合物1（EC(50)=1.64微摩尔）开始，其非碱性核心已被4-联苯基和2-萘基部分进行了构象限制。在每个系列中，我们研究了氢键供体或受体取代基的存在、碱性和亲脂性（clogP）是否与测试化合物的P-糖蛋白抑制活性相关。在联苯系列中，衍生物4d表现出最佳结果（EC(50)=0.05微摩尔）。发现相应的酰胺3d活性较低（EC(50)=3.5微摩尔），这确定了该系列中碱性的重要性，而羟基或甲氧基取代基的存在似乎可以忽略不计。在萘基系列中，碱性以及氢键供体或受体基团的存在似乎都可以忽略不计。此外，亲脂性并未影响每个系列的P-糖蛋白抑制活性。已经进行了特定的生物学试验，以确定测试化合物区分底物和抑制剂的P-糖蛋白相互作用机制。此外，化合物4d表现出强大的P-糖蛋白抑制活性，对BCRP转运蛋白具有良好的选择性。
