Günter Neef

New steroids with antiprogestational and antiglucocorticoid activities

A number of 11-substituted 19-norsteroids with inverse configuration at C-13 were synthesized. 11 beta-Aryl compounds in this series were found to possess antiprogestational and antiglucocorticoid activities.

Progesterone antagonists: Tumor-inhibiting potential and mechanism of action☆

A new approach for the treatment of breast cancer could be the use of progesterone antagonists. These compounds were originally developed for the inhibition of progesterone-dependent processes and have been shown to be effective in inhibition of nidation and interruption of pregnancy. Although the roles of progesterone and the progesterone receptor in control of cell growth remain unclear, it was found in progesterone receptor positive mammary carcinoma cell lines that the antiprogestin, Mifepristone, had an inhibitory effect on cell growth and a growth-inhibiting action on the DMBA-induced mammary carcinoma of the rat. We have shown that the progesterone antagonists, Onapristone and ZK 112993, which possess a reduced antiglucocorticoid activity compared to Mifepristone, exert a strong tumor-inhibiting effect in a panel of hormone-dependent mammary tumor models. The effects of these compounds were in some systems superior to those of tamoxifen or high dose progestins and comparable to ovariectomy. Although prerequisites for their antiproliferative potency are an affinity to the progesterone receptor as well as a sufficient number of available receptors in the tumors, the strong tumor inhibiting potential of the antiprogestins cannot be explained by a classical anti-hormonal mechanism. Surprisingly, the antitumor activity is evident in spite of elevated serum levels of ovarian and pituitary hormones. It was established by morphometric procedures that treatment with Onapristone triggers differentiation of the mitotically active polygonal tumor epithelial cell towards secretory active glandular structures and acini. All our quantitative light and electron microscopic data indicate that the antitumor action of antiprogestins is accompanied by the initiation of terminal differentiation leading to (apoptotic) cell death. Finally, our flow cytometry studies revealed an accumulation of the tumor cells in the G0G1 phase of the cell cycle, which may result from induction of differentiation since a differentiation-specific G1 arrest has already been proposed for other stem cell systems. It can be concluded from these data that the progesterone receptor antagonists differ in their mode of action from compounds used in established endocrine treatment strategies for mammary carcinoma. The ability of progesterone antagonists like Onapristone to reduce the number of cells in S-phase may offer a significant clinical advantage, since it is established that the S-phase fraction is a highly significant predictor of disease-free survival among axillary node-negative patients with diploid mammary tumors.

Synthesis and pharmacological evaluation of 8α-estradiol derivatives

Abstract A number of 2- and 16-alkyl 8α-estradiol derivatives were synthesized and pharmacologically characterized with respect to estrogenic/antiestrogenic activities.

Synthesis of antiprogestational steroids.

The discovery of the first competitive progesterone antagonist RU 38,486 has initiated an intense search for more potent and more selective anti-progestins. Among several hundreds of compounds under preliminary investigation, biological characterization is most advanced for derivatives RU 38,486, ZK 98,734 and ZK 98,299. These compounds do not only differ in relative potency, but are clearly distinguished by their different behaviour in various animal models. Emphasis is laid on the synthetic problems associated with chemical operations in a sterically crowded environment as represented by structures RU 38,486 and ZK 98,299.

Synthetic variations of the progesterone antagonist RU 38 486

Abstract Irradiation of 17-keto-estranes bearing an 11-aryl substituent offers a preparatively useful access to pharmacologically interesting steroids with inverted configuration at C-13.

Stereoselective epoxidation of 5(10),9(11)-estradienes

Abstract 3,3-(2,2-Dimethyltrimethylene-1,3-dioxy)-5(10),9(11)-estradien- 17-one is converted to its 5α,10α-epoxide by iron phthalocyanine/iodosylbenzene in a highly stereoselective manner.

Reaction of unsaturated sulfoxides with alkyllithiums

Abstract Nucleophilic attack of methyllithium on allene sulfoxides offers a stereospecific access to sulfur-free allenes. Reaction of phenylsulfinyl substituted diene 15 leads via a benzilic-type rearrangement to phenyl substituted diene 18 .

Synthesis of ENT-17-(prop-1-ynyl-17β-hydroxy-11β-(4-(N,N-dimethylamino) -phenyl)-4,9-estradien-3-one, the antipode of RU — 38 486

The title compound was synthesized and tested for its biological activities. It showed neither antiprogesterone nor antiglucocorticoid properties.

Influence of bulky 11β-substituents on reactivity of estrene derivatives

Abstract Steric constraint exercised by 11β-aryl substituents prevents transformation of 5(10)-estrene derivatives to their 4-estrene analogues.

A cycloaddition route to 14-hydroxysteroids

Abstract Steroidal 14,16-dienolacetates are stereoselectively converted to either 14β- or 14α-hydroxy steroids by a reaction sequence based on [4+2] cycloaddition with benzyl nitrosoformate.