Quadri L, Cerri A, Ferrari P, Folpini E, Mabilia M, Melloni P
Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau, Settimo Milanese (MI), Italy.
J Med Chem. 1996 Aug 16;39(17):3385-93. doi: 10.1021/jm950806n.
A series of 17 beta-(hydrazonomethyl)-5 beta-androstane-3, beta,14 beta-diol derivatives was synthesized and evaluated in the displacement of [3H]ouabain binding from Na+,K(+)-ATPase. The data were explored with multiple linear regression and partial least-squares to find possible quantitatives structure-activity relationships. Good correlations were found between binding to the receptor and van der Waals volumes or molar refractivities of the 17 beta-hydrazonomethyl substituents and pKa values of the compounds. Equivalent results were obtained using the proton affinity (calculated using MOPAC) of the hydrazone residues instead of experimental pKa. As basicity or related electronic factors of the substituents explain a significant portion of the observed changes in the activity, an ion-pair interaction between a carboxylate residue of the enzyme and the protonated 17 beta-hydrazonomethyl group, as postulated by Thomas, plays an important role in the interaction of the ligand to the Na+,K(+)-ATPase receptor.
合成了一系列17β-(腙甲基)-5β-雄甾烷-3β,14β-二醇衍生物，并对其从Na⁺,K⁺-ATP酶置换[³H]哇巴因结合的能力进行了评估。用多元线性回归和偏最小二乘法对数据进行探究，以寻找可能的定量构效关系。发现与受体的结合与17β-腙甲基取代基的范德华体积或摩尔折射率以及化合物的pKa值之间存在良好的相关性。使用腙残基的质子亲和力（使用MOPAC计算）代替实验pKa也得到了等效结果。由于取代基的碱性或相关电子因素解释了观察到的活性变化的很大一部分，如Thomas所假设的，酶的羧酸盐残基与质子化的17β-腙甲基基团之间的离子对相互作用在配体与Na⁺,K⁺-ATP酶受体的相互作用中起重要作用。
