Synthesis and Biological Activity of New 16,17-Secoestrone Derivatives

Abstract

Starting from estrone 3-benzyloxy-17β-hydroxyestra-1,3,5(10)-trien-16-one oxime (3b) was synthesized, which underwent Beckmann fragmentation giving the 3-benzyloxy-17-oxo- 16,17-secoestra-1,3,5(10)-triene-16-nitrile (4b). Sodium borohydride reduction of this compound afforded 3-benzyloxy-17-hydroxy-16,17-secoestra-1,3,5(10)-triene-16-nitrile (5b). The deprotection of the 3-hydroxy group was achieved by action of hydrogen upon derivatives 4b and 5b in presence of Pd/C as a catalyst, yielding 3-hydroxy-17-oxo-16,17-secoestra- 1,3,5(10)-triene-16-nitrile (4a) and 3,17-dihydroxy-16,17-secoestra-1,3,5(10)-triene-16-nitrile (5a). In biological tests on experimental animals, compounds 4a, 4b, 5a and 5b showed virtually a complete loss of estrogenic activity, whereas compounds 4a, 5a and 5b exhibited moderate antiestrogenic effect.

Antihormonal potential of selected D-homo and D-seco estratriene derivatives

“…Binding energies of ligands present in the X-ray crystal structure were calculated following re-docking. obtained before, for parent compounds, 1 and 1a [11]. The differences of uteri weights of treated and control animals served for the calculation of the agonistic and antagonistic effects [31], presented in Table 4.…”

“…The starting compound, 3-benzyloxy-17-hydroxy-16,17-secoestra-1,3,5(10)-trien-16-nitrile (1) was synthesised from estrone in several synthetic steps [11]. The syntheses of new compounds were performed according to Scheme 1.…”

“…The estrogenic and antiestrogenic effects of compounds 2-5 and tamoxifen were tested on experimental animals, using the uterotrophic and antiuterotrophic methods [30,11].…”

“…Specifically, this compound showed practically complete loss of estrogenic activity, while displaying satisfactory antihormonal properties. On the other hand, its 3-hydroxy equivalent showed less antiestrogenic activity, with complete loss of estrogenic potency [11]. These facts prompted us to further pursue chemical transformations of this secocyanoalcohol, in order to study the influence of different modifications of the D-ring on the biological potential of new compounds.…”

“…A broader project, directed towards preparation of potential antihormones and steroidogenesis enzymes inhibitors resulted in the synthesis of many D-modified steroidal compounds possessing promising antihormonal properties [11][12][13][14][15][16][17][18] Among others, 3-benzyloxy-17-hydroxy-16,17-secoestra-1,3,5(10)-trien-16-nitrile, was of special interest, as well as its corresponding 3-hydroxy derivative. Specifically, this compound showed practically complete loss of estrogenic activity, while displaying satisfactory antihormonal properties.…”