Kende A S, Ebetino F H, Drendel W B, Sundaralingam M, Glover E, Poland A
Mol Pharmacol. 1985 Nov;28(5):445-53.
1,4-bis-[2-(3,5-Dichloropyridyloxy)]-benzene (TCPOBOP) was previously shown to be an extremely potent phenobarbital-like inducer of hepatic microsomal monooxygenase activity in the mouse. To examine the structure-activity relationship, 31 congeners of TCPOBOP were synthesized and tested for their potency to induce hepatic aminopyrine N-demethylase activity in B6D2F1/J mice. For biological activity, the minimum requirement is a) a central 1,4-dioxygenated benzene ring, b) lateral pyridine rings linked to the central ring by ether bonds, but with other lateral heteroaromatic rings, e.g., quinoline or pyrimidine, also active, c) 5,5'-substituents of Cl, Br, or NO2 on the pyridine rings. For a series of 5,5'-substituted and 3,3'-dichloro,5,5'-substituted bispyridyloxybenzenes, no correlation was observed for Hansch pi and sigma p values. To account for this lack of correlation and conformational variability produced by the two ether bonds, we performed x-ray structure determinations on three compounds: a) TCPOBOP, b) the 5,5'-dichloro analogue, and c) the biologically inactive, 3,3'-dichloro analogue. In the two biologically active congeners the positioning of the pyridine rings is anti to the plane of the central benzene ring, and the dihedral angle between the central ring and the pyridines is approximately 60 degrees. In the inactive analogue the pyridine rings are syn and the dihedral angle is 84 degrees. The x-ray crystallographic data are consistent with the ether oxygen having an sp2-bonding conjugating with the heterodipolar bond of the pyridine C(2)--N(1), which strongly restricts rotation about the ether bonds. The potency of TCPOBOP and other bispyridyloxybenzene analogues to induce a phenobarbital-like pleiotropic response and the sharply defined structure-activity relationship among these congeners support the hypothesis that they act by binding to a specific recognition site.
1,4-双-[2-(3,5-二氯吡啶氧基)]-苯（TCPOBOP）先前已被证明是一种在小鼠体内极具效力的类似苯巴比妥的肝微粒体单加氧酶活性诱导剂。为了研究构效关系，合成了31种TCPOBOP的同系物，并测试了它们在B6D2F1/J小鼠中诱导肝氨基比林N-脱甲基酶活性的效力。对于生物活性而言，最低要求是：a）一个中心的1,4-二氧代苯环；b）通过醚键与中心环相连的侧吡啶环，但其他侧杂芳环，如喹啉或嘧啶，也具有活性；c）吡啶环上的5,5'-取代基为Cl、Br或NO2。对于一系列5,5'-取代和3,3'-二氯、5,5'-取代的双吡啶氧基苯，未观察到与Hansch π和σp值的相关性。为了解释这种缺乏相关性以及两个醚键产生的构象变异性，我们对三种化合物进行了X射线结构测定：a）TCPOBOP；b）5,5'-二氯类似物；c）无生物活性的3,3'-二氯类似物。在两种具有生物活性的同系物中，吡啶环的位置与中心苯环平面呈反式，中心环与吡啶之间的二面角约为60度。在无活性的类似物中，吡啶环是顺式的，二面角为84度。X射线晶体学数据与醚氧具有与吡啶C(2)--N(1)的异偶极键共轭的sp2键一致，这强烈限制了围绕醚键的旋转。TCPOBOP和其他双吡啶氧基苯类似物诱导类似苯巴比妥的多效性反应的效力以及这些同系物之间明确的构效关系支持了它们通过与特定识别位点结合而起作用的假说。
