Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

Abstract

Multistep syntheses of novel 17β-pyrazol-5'-ones in the Δ5-androstane series were efficiently carried out from pregnenolone acetate. A steroidal 17-carboxylic acid was first synthesized as a norpregnene precursor by the bromoform reaction and subsequent acetylation. Its CDI-activated acylimidazole derivative was then converted to a β-ketoester containing a two carbon atom-elongated side chain than that of the starting material. A Knorr cyclization of the bifunctional 1,3-dicarbonyl compound with hydrazine and its monosubstituted derivatives in AcOH under microwave heating conditions led to the regioselective formation of 17-exo-heterocycles in good to excellent yields. The suppression of an acid-catalyzed thermal decarboxylation of the β-ketoester and thus a significant improvement in the yield of the desired heterocyclic products could be achieved by the preliminary liberation of the arylhydrazines from their hydrochloride salts in EtOH in the presence of NaOAc. The reaction rates were found to depend on the electronic character of the substituent present in the phenylhydrazine applied. The antiproliferative activities of the structurally related steroidal pyrazol-5'-ones and their deacetylated analogs were screened on three human adherent breast cancer cell lines (MCF7, T47D and MDA-MB-231): the microculture tetrazolium assay revealed that some of the presented derivatives exerted cell growth inhibitory effects on some of these cell lines comparable to those of the reference compound, cisplatin.

Chemical modification of different compounds with nitrogen-containing heterocycles

“…Наиболее специфичным в отношении линии клеток рака груди человека MDA-MB231 оказалось соединение 34 (IC50 9,17 ± 1,6). Некоторые из синтезированных в работе [48] стероидных N-арилзамещенных пиразолонов 39 a-c проявили высокую, сравнимую с Цисплатином антипрофилеративную активность в отношении трех клеточных линий рака молочной железы человека (схема 16).…”

Recent syntheses of steroidal derivatives containing heterocycles

“…Motyan et al 49 developed a microwave-assisted one-pot method for the facile and efficient synthesis of novel steroidal 17-exo-pyrazol-5'-ones from a β-ketoester precursor with arylhydrazine hydrochlorides. The steroidal β-ketoester precursor 126, suitable for the attempted heterocyclization reaction with hydrazines, was synthesized from commercially available pregnenolone acetate 123 via a multistep sequence (Scheme 26).…”

Microwave-Assisted Synthesis, Proton Dissociation Processes, and Anticancer Evaluation of Novel D-Ring-Fused Steroidal 5-Amino-1-Arylpyrazoles

“…Heteroaromatic five-membered pyrazoles containing two adjacent nitrogen atoms have received considerable attention thanks to their facile synthetic availability and their usefulness as intermediates for the preparation of various biologically active compounds, metal complexes, and functional materials [4,5]. Over the past decades, numerous pyrazoles in the androstane series and their partially saturated pyrazoline analogs have been reported to exhibit a more marked antitumor activity rather than their expected hormonal effect ( Figure 1) [6][7][8][9][10][11][12][13]. Amongst functionalized pyrazoles, 5-aminopyrazoles have been widely investigated as biologically active agents [14] and as useful binucleophilic precursors for fused pyrazoloazines of medicinal interest [15].…”

“…The cytotoxicity of the molecules was screened in vitro on . Some previously synthesized androstane-based pyrazol(in)es with anticancer activity [6][7][8][9][10][11][12][13] and 5-amino-1-arylpyrazoles (framed), which are the subjects of the present study.…”

“…In view of the marked cytotoxic activity of some androstane-based pyrazol(in)es [6][7][8][9][10][11][12][13], and the pharmacological relevance of drugs containing a 5-amino-1-arylpyrazole moiety [16], the aim of the present study was to introduce such heterocyclic subunit fused to ring D of dehydroepiandrosterone (DHEA) to obtain a set of compounds suitable for further investigations. To our knowledge, steroidal 5-aminopyrazoles have not been synthesized and studied so far.…”