L. E. Golubovskaya

Antitumor steroids. 3. Synthesis and biological activity of 11β-hydroxyestra-1,3,5(10)-triene derivatives with bis-(2-chloroethyl)amino-containing substituents in the 3-position

A series of antitumor compounds combining cytotoxic and estrogen action have been synthesized on the basis of 11β-acyloxyestra-1,3,5(10)-trienes. The corresponding synthons, 11β-hydroxy derivatives of estrone, estradiol, and ethynylestradiol, were obtained by oxidative nitration of 3-mono-and 3,17-diesters of these estrogens with ceric ammonium nitrate into the corresponding 9α-hydroxy-and 11β-nitroxy analogs with subsequent hydrogenolysis of the 9-hydroxy groups and removal of the nitrate protecting groups.

Search for new drugs

Analogs of 11β-hydroxyestrone and 17α-ethynylestradiol with a cytotoxic bis-(2-chloroethyl)amino-containing substituent were synthesized in two principal steps from the corresponding 11-hydroxysteroids. Introduction of this bulky fragment influences negatively the estrogenic and antitumor activities of the synthesized compounds.

Steroidal nitrates. Part III. Synthesis and antiestrogen activity of the 11α-nitroxy analog of ethynylestradiol

An 11α-nitroxy group was introduced into 17α-ethynylestradiol-3,17-diacetate using a synthetic scheme involving oxidative nitration by cerium ammonium nitrate and configuration inversion at C11 by sodium-borohydride reduction of the 11-nitrate 9α,11β-dihydroxy derivative of the starting steroid. The 11α-nitroxy-containing ethynylestradiol exhibits antiestrogen activity.

Steroid nitrates. II. Synthesis and hormonal activity of 9α,11β-dihydroxyestra-1,3,5(10)-triene 11-nitrates

Abstract11-Nitrates of 9α,11β-dihydroxy derivatives of estrone, estradiol, and ethinylestradiol were synthesized by oxidative nitration of the corresponding estratriene 3-acetates with cerium ammonium nitrate. Three methods are given for this reaction. Compounds had high antifertility and estrogen activity. Antifertility actions were much greater than their estrogen activities, as compared with the similar levels seen with ethinylestradiol.

Steroidal Nitrates: Synthesis and Antitumor Activity of 9α,11β-Dihydroxyestra-1,3,5(10)-triene 11-Nitrates

Steroidal nitrates, in contrast to other inorganic acid esters such as sulfates, are not encountered in nature. Nitration was used only as a means of protecting hydroxy groups [1]. The biological properties of steroidal nitrates are still insufficiently studied, although the spectrum of action can be rather wide. This was demonstrated by the experimental results for 11-nitrates of 11 -hydroxyand 9 ,11 -dihydroxy derivatives of estrone and estradiol, which first showed a high estrogen activity and then revealed the contraceptive properties of these compounds [2, 3]. In continuation of the study of the biological activity spectrum of 11-nitrates of 9 ,11 -dihydroxyestratrienes, we turned to evaluation of their antitumor properties. This interest was inspired by the fact that steroidal nitrates can generate nitric oxide, an agent known to produce a cytotoxic action, besides others [4]. Below we describe the synthesis of 11-nitrates of 9 ,11 -dihydroxyestratrienes containing various substituents in positions 3 and 17 and present data on the antitumor activity of these compounds. The synthesized compounds include the derivatives of estrone (III), estrone acetate (IV), 17-oxime (VI), and oxime diacetate (VII); ethinylestradiol derivatives were represented by 3,17-diacetate (V). The target nitrates were synthesized using the well-known process of nitration with cerium ammonium nitrate [5]. However, estrone acetate and ethinylestradiol 3,17-diacetate were nitrated in a heterogeneous regime, rather than in acetic acid under usual conditions requiring large volumes of solvent (see experimental chemical part below). Note that the oximation of nitrate IV is of interest both as a pathway to potential antitumor drugs and as a means of protecting 17-keto group, opening a simple way to 11 and 11 -hydroxyestrones [6].

A Simple Method of Obtaining 11-Keto-9β-estra-1,3,5(10)-trienes: Potential Reactants for the Synthesis of Steroidal Antigestagens

In recent years there have been extensive investigations into the chemistry and biology of 11-aryl-norsteroids known to possess a broad spectrum of physiological properties, in particular, antigestagen activity [1]. These compounds are capable of competing with natural gestagens for binding to receptors of the reproductive organs of females, thus violating normal development of the fetus. In contrast to traditional oral contraceptives, antigestagen preparations can not only prevent but, owing to their abortive action, terminate gestation. Among the abortive contraceptives, most widely used is the drug mifepristone (RU-486) reproduced in Russia as pencroftone. RU-486 and its analogs are obtained by partial syntheses from estrone. All variants of the synthesis, while differing in the number of stages and or the way of protecting the 3-keto group, employ only estra-5,9-diene-3,17-dione as the initial compound [2 – 4]. At the same tine, the synthesis of related 11-alkyl-19-norsteroids was frequently performed using 11-ketoestrogens, representing steroids with aromatic ring A [5]. These compounds, albeit considered among possible reactants in the synthesis of 11-aryl-19-norsteroids [6], were never used in practice – apparently because of the lack of sufficiently economic and technologically simple methods for their production. The known syntheses, for example, of 11-keto-9 -estrone (compounds with the 9 configuration are most stable in the series of 11-ketoestratrienes [7]), include three principal stages: (i) dehydration with 2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDB), (ii) epoxidation with superacid, and (iii) epoxide conversion into ketone under the action of Lewis acid (BF3, Et2O, LiClO4) [7]. All these schemes possess drawbacks related to the difficulties in reproducing the first stage even for simple 17-analogs of estrone; attempts at using relatively cheap and accessible chloranil instead of DDB were unsuccessful [8 – 10].

Silylsteroids. IV. Hormonal activity and physicochemical properties of C-trimethylsilylestrogens

This communication is a continuation of our investigations [I]. The high hormonal activity observed in many silyl ethers of hydroxysteroids [2-5] has drawn attention to siliconcontaining steroids as a potential source of new hormonal drugs [6]. The activity of silyl ethers of hydroxysteroids by oral administration, and the increased duration of their effect, is due to the lipophilicity of these compounds and their hydrolytic conversion in the body into active steroids. The properties of silicon-containing steroids of a nonether type have scarcely been investigated [7, 8]. In view of the lability of the bond between silicon and the aromatic ring in arylsilanes [9], silylestrogens would be expected to regenerate the parent estrogen in the body, and there should be a connection between the ability to undergo such regeneration and the magnitude of the estrogenic effect.

Synthesis and gestagen activity of 17?-hydroxyprogesterone trimethylsilyl ether

Ethers and esters of 17a-hydroxyprogesterone possess marked gestagen activity while the activity of the nonetherified steroid is insignificant [i]. There are data on the enhanced hormonal activity of the trimethylsilyl (TMS) ethers of estrogens [2], androgens [3], and certain hydroxypregnanes [4] compared with the corresponding alcohols and phenols. It seemed of interest to evaluate the possibility of applying silyl ethers for increasing the hormonal activity of 17u-hydroxyprogesterone since we are unaware of literature data on this problem.