Rewcastle G W, Atwell G J, Palmer B D, Boyd P D, Baguley B C, Denny W A
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
J Med Chem. 1991 Feb;34(2):491-6. doi: 10.1021/jm00106a003.
A series of tricyclic analogues of 9-oxo-9H-xanthene-4-acetic acid have been prepared and evaluated for their ability to cause hemorrhagic necrosis in subcutaneously implanted colon 38 tumors in mice, in an effort to extend the structure-activity relationships for this series. As was found previously with analogues of flavone-8-acetic acid (FAA) (Atwell et al. Anti-Cancer Drug Des. 1989, 4, 161), all electronic modifications of the XAA nucleus led to severe decreases or complete abolition of activity, suggesting narrow structure-activity relationships. Dipole moments for many of the compounds were computed, and the degree to which the molecular dipole moment lay out of the plane of the aromatic part of these molecules was found to be determined largely by the contributions from the acetic acid moiety relative to that from the tricyclic ring system. There did not appear to be any general relationship between the magnitude of the dipole moment and activity. However, for compounds containing the 9-carbonyl functionality, the orientation of the dipole vector may be of significance. In all compounds possessing an ether group peri to the acetic acid side chain, there was a close approach (ca. 2.4 A) between this and the side chain OH.
已制备了一系列9-氧代-9H-呫吨-4-乙酸的三环类似物，并评估了它们在小鼠皮下植入的结肠38肿瘤中引起出血性坏死的能力，以扩展该系列的构效关系。正如之前在黄酮-8-乙酸（FAA）类似物中发现的那样（阿特韦尔等人，《抗癌药物设计》，1989年，第4卷，第161页），XAA核的所有电子修饰都会导致活性严重降低或完全丧失，这表明构效关系较为狭窄。计算了许多化合物的偶极矩，发现这些分子的分子偶极矩偏离芳环部分平面的程度在很大程度上取决于乙酸部分相对于三环系统的贡献。偶极矩的大小与活性之间似乎没有任何普遍关系。然而，对于含有9-羰基官能团的化合物，偶极矢量的方向可能具有重要意义。在所有乙酸侧链邻位含有醚基的化合物中，该醚基与侧链OH之间存在紧密接近（约2.4 Å）。
