Doré J C, Gilbert J, Bignon E, Crastes de Paulet A, Ojasoo T, Pons M, Raynaud J P, Miquel J F
CNRS URA 401, Muséum National d'Histoire Naturelle, Paris, France.
J Med Chem. 1992 Feb 7;35(3):573-83. doi: 10.1021/jm00081a021.
The response profiles of 36 para-substituted diphenylethylenes (DPEs) and triphenylacrylonitriles (TPEs) have been compared by multivariate analysis. The responses measured were (a) relative binding affinity (RBA) for the cytosol estrogen receptor (ER), (b) ability to promote the growth of the human MCF7 breast cancer cell-line, (c) cytotoxicity in MCF7 cells, and (d) ability to stimulate or inhibit protein kinase C (PKC) III activity under three different conditions of enzyme activation. The prime object of the analysis was to observe the simultaneous influence of diverse combinations of substituents on all these in vitro responses. To do this, the minimum spanning tree (MST) method was used to organize the molecules into a network in which proximate molecules are closely related with regard to their responses whereas remote molecules are distinct. The MST of this population of molecules had four main branches. E2 and its TPE mime were located in a central position within the trunk whereas the tips of the branches tended toward molecules of different specificity, i.e., cytotoxic molecules that bind to ER and interfere with PKC, noncytotoxic molecules that also bind to ER and interfere with PKC but promote cell growth, molecules only active on PKC, and molecules active on all parameters except PKC stimulation. A parallel MST analysis of the relationships among the response parameters themselves confirmed previous conclusions: For this population of molecules, RBAs for ER are fairly closely related to ability to promote MCF7 cell growth and only little to cytotoxicity (Bignon et al. J. Med. Chem. 1989, 32, 2092). Cytotoxicity is much more clearly correlated with inhibition of diacylglycerol-stimulated PKC activity than with RBAs for ER. PKC inhibition differs substantially depending upon whether the substrate is H1 histone or protamine sulfate.
通过多变量分析比较了36种对位取代的二苯乙烯（DPEs）和三苯丙烯腈（TPEs）的反应谱。所测量的反应包括：（a）对胞质雌激素受体（ER）的相对结合亲和力（RBA）；（b）促进人MCF7乳腺癌细胞系生长的能力；（c）对MCF7细胞的细胞毒性；以及（d）在三种不同酶激活条件下刺激或抑制蛋白激酶C（PKC）III活性的能力。分析的主要目的是观察取代基的不同组合对所有这些体外反应的同时影响。为此，使用最小生成树（MST）方法将分子组织成一个网络，其中相邻分子在反应方面密切相关，而相距较远的分子则不同。这群分子的MST有四个主要分支。E2及其TPE模拟物位于主干的中心位置，而分支的末端趋向于不同特异性的分子，即与ER结合并干扰PKC的细胞毒性分子、也与ER结合并干扰PKC但促进细胞生长的非细胞毒性分子、仅对PKC有活性的分子以及除PKC刺激外对所有参数有活性的分子。对反应参数之间关系的平行MST分析证实了先前的结论：对于这群分子，ER的RBA与促进MCF7细胞生长的能力相当密切相关，而与细胞毒性关系不大（Bignon等人，《药物化学杂志》，1989年，32卷，2092页）。细胞毒性与二酰基甘油刺激的PKC活性抑制的相关性比与ER的RBA更明显。PKC抑制根据底物是H1组蛋白还是硫酸鱼精蛋白而有很大差异。
