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  • The introduction of a pyrazole moiety into any

    2024-02-21

    The introduction of a pyrazole moiety into any position of the sterane core by cross-coupling reactions [13] or by Knorr construction from a CCC bis-electrophilic sterane precursor and an N,N binucleophile building block [17], [19] may serve as an example. Very few reports are to be found, however, on the synthesis of steroids functionalized with a 4′-formylpyrazole heteroring prepared by a [4 + 1] reaction from CCNN binucleophilic and C electrophilic synthons [20]. This latter method, involving the cyclization of N-aryl-, N-acyl-, N-alkylhydrazones or semicarbazones of methyl ketones under Vilsmeier-Haack conditions, is a convenient approach to N-substituted or N-unsubstituted pyrazole-4-carboxaldehydes [21] without suffering from the regioselectivity problems often characteristic of [3 + 2] processes. The electrophilic Vilsmeier-Haack adduct, generally prepared from POCl3 and DMF at low temperature, reacts with the hydrazone via cyclization and simultaneous insertion of one carbon from the reagent, leading to the pyrazole intermediate. This ret inhibitor further undergoes 4-formylation by the electrophilic attack of another molecule of Vilsmeier-Haack reagent and subsequent hydrolysis [22]. The analogous reaction of semicarbazones often leads to N-unsubstituted heterocycles by elimination of the aminocarbonyl group in the form of CO2 and NH3[23]. On the basis of the above-mentioned literature background and as a continuation of our research on steroidal 17-exo-heterocycles [16], [24], our present goal was to introduce a 4-formylpyrazole moiety onto C-17 of the sterane core. The syntheses were planned from pregnadienolone acetate containing both a methyl ketone and a 16,17-double bond as important structural elements. The hydrazones of the starting material were assumed to undergo pyrazole formation under Vilsmeier-Haack conditions, and further derivatization of the primary products (with a consideration of pharmacological aspects) was also designed. All compounds were screened in vitro by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay [25] for their antiproliferative activities against a panel of four human breast cancer cell lines (MCF7, T47D, MDA-MB-231 and MDA-MB-361) and the IC50 values were calculated for the most potent derivatives. The inhibitory effects of products meeting the structural requirements for a potent enzyme inhibitor were also determined on rat testicular C17,20-lyase by a radiosubstrate incubation technique.
    Results and discussion
    Conclusions In summary, novel 17-exo-(4′-formyl)pyrazoles in the Δ5,16 androstadiene series were efficiently synthesized under Vilsmeier-Haack conditions via hydrazone and semicarbazone intermediates obtained from the condensation of pregnadienolone acetate with monosubstituted hydrazines and semicarbazide. The subsequent derivatization of the primary products resulted in a large set of structurally diverse compounds suitable for two kinds of in vitro pharmacological studies. The cell growth-inhibition assays of all the synthesized compounds on malignant breast cell lines revealed that several 3β-OH derivatives exerted substantial effects on cell proliferation, while three of the tested steroidal pyrazoles displayed noteworthy inhibition on rat testicular C17,20-lyase, with an IC50 of the same order of magnitude as that for abiraterone. The hydroxymethyl substituent on position 4′ of the heteroring was found to be the most preferable in respect of both effects, while aryl substitution of the pyrazole-N1′ favored the antiproliferative action over the unsubstituted analog with a marked enzyme-inhibitory effect. The results indicate that pyrazoles can be regarded as promising structural motifs of steroids, motivating the design and pharmacological investigation of further derivatives.
    Experimental
    Acknowledgments The financial support by the Hungarian Scientific Research Fund (OTKA K-109107 and K-109293) is gratefully acknowledged. The research by D. Kovács was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP 4.2.4, A/2-11/1-2012-0001 ″National Excellence Program″. The work of N. Szabó was supported by a PhD Fellowship of the Talentum Fund of Richter Gedeon Plc.