Tmej C, Chiba P, Huber M, Richter E, Hitzler M, Schaper K J, Ecker G
Institute of Pharmaceutical Chemistry, University of Vienna, Wien.
Arch Pharm (Weinheim). 1998 Jul-Aug;331(7-8):233-40. doi: 10.1002/(sici)1521-4184(199807)331:7/8<233::aid-ardp233>3.0.co;2-2.
A series of 48 propafenone-type modulators of multidrug resistance was synthesized and their P-glycoprotein inhibitory activity was measured using the daunomycin efflux assay. Both a Free-Wilson and a combined Hansch/Free-Wilson analysis were performed using log P, partial log P and molar refraction values as Hansch descriptors. The results of the Free-Wilson analysis show that modifications on the central aromatic ring generally influence pharmacological activity, whereby in almost all cases a decrease in MDR-modulating potency is observed (Q2cv = 0.66). The combined approach results in equations with remarkably higher predictive power (Q2cv = 0.83), specifically molar refractivity shows high significance in all equations derived. This indicates that polar interactions also contribute to protein binding.
合成了一系列48种多药耐药性的普罗帕酮型调节剂，并使用柔红霉素外排试验测定了它们对P-糖蛋白的抑制活性。使用log P、部分log P和摩尔折射值作为汉施描述符，进行了自由威尔逊分析和汉施/自由威尔逊联合分析。自由威尔逊分析的结果表明，中心芳环上的修饰通常会影响药理活性，几乎在所有情况下，都会观察到多药耐药性调节效力的降低（交叉验证的Q2 = 0.66）。联合方法得出的方程具有显著更高的预测能力（交叉验证的Q2 = 0.83），具体而言，摩尔折射率在所有推导方程中都显示出高度显著性。这表明极性相互作用也有助于蛋白质结合。
