Synthesis of methoxycarbonylpyrazolylandrostene derivatives, and their potential inhibitory effect on androgen biosynthesis and cell proliferation

Nikoletta Szabó; Zoltán Iványi; Mihály Szécsi; János Julesz; Erzsébet Mernyák; Judit Huber; János Wölfling; Renáta Minorics; István Zupkó; Gyula Schneider

doi:10.1016/j.steroids.2015.03.008

Synthesis of methoxycarbonylpyrazolylandrostene derivatives, and their potential inhibitory effect on androgen biosynthesis and cell proliferation

Steroids. 2015 Jun:98:143-52. doi: 10.1016/j.steroids.2015.03.008. Epub 2015 Mar 21.

Authors

Affiliations

¹ 1st Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720 Szeged, Hungary.
² Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.
³ 1st Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720 Szeged, Hungary. Electronic address: szecsi.mihaly@med.u-szeged.hu.
⁴ Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6., H-6720 Szeged, Hungary.
⁵ Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. Electronic address: schneider@chem.u-szeged.hu.

PMID: 25804762
DOI: 10.1016/j.steroids.2015.03.008

Abstract

The Claisen condensations of 3β-acetoxypregn-5-en-20-one (1) and 3β-acetoxypregna-5,16-diene (7) with dimethyl oxalate are known to lead to 3β-hydroxy-21-methoxalylpregn-5-en-20-one (2) and 3β-hydroxy-21-methoxalylpregna-5,16-dien-20-one (8), respectively. The reactions of 2 with p-substituted phenylhydrazines afford pyrazol-5-yl derivatives (5) as main, and 3-yl regioisomers (4) as minor products. The corresponding reactions of 16-ene analogue 8 afford only pyrazol-5-yl regioisomer 9. Oppenauer oxidation of the pyrazolyl compounds yields the corresponding Δ(4)-3-ketosteroids. We investigated the antiandrogenic effects of new methoxycarbonylpyrazolyl compounds through determination of their in vitro inhibition of the activities of rat testicular C17,20-lyase, Δ(5)-3β-hydroxysteroid dehydrogenase (Δ(5)-3β-HSD) and 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). A Δ(5)-3β-hydroxy compound in the D-ring-saturated androst-5-ene series bearing an unsubstituted phenyl group on the pyrazolyl heterocycle (5a) proved to be a potent inhibitor of Δ(5)-3β-HSD. The 4-methoxyphenyl derivative (5e) and the 3-oxo counterpart (6a) of 5a also displayed substantial inhibition. The other tested compounds exerted only weak inhibitory action against the enzymes investigated. The newly synthetized compounds were evaluated in vitro by means of MTT assays for antiproliferative activity against Hela (cervical carcinoma), A431 (skin epidermoid carcinoma) and MCF7 (breast adenocarcinoma) cells. In all four groups (3β-hydroxy- and 3-ketosteroids with saturated or unsaturated ring D), the most potent analogs contain a 4-tolyl or 4-methoxyphenyl group. Compound 5d exhibited substantial antiproliferative action against the three cell lines investigated, whereas 9d inhibited the growth of Hela cells markedly. The most noteworthy inhibition was exerted by 6a against A431 cells.

Keywords: Antiandrogen effect; Antiproliferative action; Methoxycarbonylpyrazolone; Pregnadienolone; Pregnenolone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androstenes* / chemical synthesis
Androstenes* / chemistry
Androstenes* / pharmacology
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Proliferation*
Drug Screening Assays, Antitumor
HeLa Cells
Humans
MCF-7 Cells

Substances

Androstenes
Antineoplastic Agents