Potential antitumor agents. 62. Structure-activity relationships for tricyclic compounds related to the colon tumor active drug 9-oxo-9H-xanthene-4-acetic acid.
Potential antitumor agents. 62. Structure-activity relationships for tricyclic compounds related to the colon tumor active drug 9-oxo-9H-xanthene-4-acetic acid.
复制标题
潜在的抗肿瘤剂。
DOI：
10.1021/jm00106a003
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发表时间：
1991
影响因子：
7.3
通讯作者：
W. Denny
中科院分区：
文献类型：
--
作者：
G. Rewcastle;G. Atwell;B. Palmer;P. Boyd;B. Baguley;W. Denny
制备了一系列9-氧- 9h -杂蒽-4-乙酸的三环类似物，并对其在小鼠皮下植入结肠肿瘤中引起出血性坏死的能力进行了评估，以扩展该系列的构效关系。正如之前发现的黄酮-8-乙酸（FAA）类似物（Atwell等）。抗癌药物Des. 1989, 4,161)，所有XAA核的电子修饰导致活性严重降低或完全消除，表明结构-活性关系狭窄。计算了许多化合物的偶极矩，发现分子的偶极矩在这些分子的芳族部分的平面上的分布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。偶极矩的大小和活动之间似乎没有任何一般的关系。然而，对于含有9-羰基官能团的化合物，偶极子向量的取向可能是有意义的。在所有在乙酸侧链附近具有醚基团的化合物中，它与侧链OH之间的距离很近（约2.4 a）。
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.