QUANTITATIVE STUDIES ON THE STRUCTURE-ACTIVITY RELATIONSHIPS OF 1, 3, 5 (10) ESTRA-TRIENE DERIVATIVES

Quantitative relationships between the structure and estrogenic activity of 28 derivatives of 1,3,5(10) estratriene series have been examined by multiple variable regression analysis. The results indicate that the estrogenic activity of a derivative may be regarded as the total sum of the activity contributed by the unsubstituented parent structure 1,3,5(10)estra-triene on the one hand and that by the substituents on the other. Since the correlation coefficient is equal to 0.98, the additivity model can be accepted. The effective value of a given substituent is a constant. The contributions elicited by hydroxy, methoxy, cyclopetoxy and other oxygen containing groups at C-3 and C-17β positions are unanimously positive i.e. to enhance the biological activity. On the contrary, contributions elicited by groups at C-2, C-6, C-13, C-16 and C-17α positions, except the 17α ethynyl group, are negative. Since the group contribution of a substituent varies with different positions attached, it seems reasonable to infer that the steric effects may play an important role inestrogenic activity.