The œstrogenic activity of some condensed-ring compounds in relation to their other biological activities

Abstract

Two probable formulae are given for estrone (ketohydroxyestratriene). The results of an attempt to establish essential molecular conditions of estrogenesis by using pure synthetic compounds of known molecular structure indicate that a number of substances of rather widely differing structure have estrogenic power. A certain degree of unsaturation, ethylenic or aromatic, is apparently necessary, but varies widely. O-containing groups (carbonyl, hydroxyl) are not essential but optimum conditions for potency are attained only when such polar groups are present. Estrogenic activity of certain diols derived from the carcinogenic hydrocarbon 1:2:5:6-dibenzanthracene is comparable with that of estriol. Substituents at position 9, also changing the position of the O-group, inactivated l-keto-l:2:3:4-tetrahydrophenanthrene. Correlation observed between estrogenic and carcinogenic potency of l:2-benzpyrene and 5:6-cyclopenteno-l:2-benzanthracene have led to investigations of carcinogenic properties of natural estrogenic hormones. Of sterols, bile acids, and their derivatives, the more highly saturated compounds were negative, the less saturated (ergosterol, neo-ergosterol, crystallized vitamin D) showed marked activity. The apparently most active compound, the di-n-propyl of the group of 9:10-dihydroxy-9:10-dialkyl-9:10-dihydro-l:2:5:6-dibenzanthracene, has activity approaching 20,000 rat units estrone per gm. Uterine as well as vaginal changes of estrus were present. As judged by vaginal smear, the induced estrus is indistinguishable from the normal and from that induced by estrone in ovariectomized animals. 9:10-dihydroxy-9:10-di-w-butyl-9:10-dihydro-l:2:5:6-dibenzanthracene (1 mgm. twice daily for 3 days) induced premature puberty in infantile female rats. Members of the series 9:10-dihydroxy-9:10-dialkyl-9:10-dihydro-1: 2:5:6-dibenzanthracene were active when given orally or by injection; ketotetra-hydrophananthrene was inactivated by oral administration. The most active estrogenic substances are: the dimethyl, diethyl, di-n-propyl, di-n-butyl, di-n-amyl, and di-n-hexyl members of the series 9:10-dihydroxy-9:10-dialkyl-9:10-dihydro-1:2:5:6-dibenzanthracene; 1-keto-1:2:3:4-tetrahydrophenanthrene; 5:6-cycZopenteno-1:2-benzanthracene-1:2-benzpyrene, neo-ergosterol, calciferol, ergosterol, 1:9-dimethyl-phenanthrene, clupanodonic acid (after treatment with bromine) . 34 refs.