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

Abstract

Taking into account the pharmacological relevance of heterocycle-fused natural steroids, the objective of the current study was to develop a multistep reaction sequence for the efficient synthesis of novel D-ring-condensed 5-amino-1-arylpyrazoles from dehydroepiandrosterone (DHEA). A condensation reaction of 16-formyl-DHEA with hydroxylamine afforded the corresponding oxime, which was demonstrated to be stable in one of its cyclic isoxazoline forms due to possible ring-chain tautomerism. The subsequent base-induced dehydration to a diastereomeric β-ketonitrile, followed by microwave-assisted heterocyclization with different arylhydrazines led to the desired pyrazoles. The generally good yields of the products depended slightly on the electronic character of the substituent present on the aromatic ring of the reagent. The proton dissociation processes of the DHEA-derived heterocycles were investigated in aqueous solution by UV-visible spectrophotometric titrations to reveal their actual chemical forms at physiological pH. The determined pKa values attributed to the pyrazole NH+ moiety were low (1.8–4.0) and varied by the different substituents of the benzene ring. The antiproliferative effects of the structurally similar compounds were screened in vitro on human cancer cells (namely on HeLa, U2Os, MCF-7, PC-3, and A549), along with a noncancerous cell line (MRC-5). The IC50 values of the most active derivative were determined on all cell lines.

Guggulsterone – a potent bioactive phytosteroid: synthesis, structural modification, and its improved bioactivities

“…Moreover, they successfully evaluated their anticancer activity against various malignant cell lines, such as HeLa, MCF7, A2780, and A43. Likewise, several approaches have been reported for steroidal-thiazole, 112 imidazolidine, 113,114 isoxazoline, 115 pyrazole, 116 oxazole, 117 tetrazole, 118 pyrazoline, 119 pyridine, 120 and pyrimidine 121 derivative syntheses. In GS chemistry, hetero-functionalized derivatives have so far been limited.…”

Synthesis and Pharmacological Properties of Modified A- and D-Ring in Dehydroepiandrosterone (DHEA): A Review

“…The desired pyrazoles 139a – h were obtained after base-induced dehydration to a diastereomeric steroidal β-ketonitrile 136 , followed by microwave-assisted heterocyclization with various arylhydrazines 138a – h ( Scheme 20 ). 27 However, the 1 H NMR spectra of compound 136 revealed the presence of two diastereomers in a 2:1 ratio, as evidenced by the appearance of duplicated proton peaks (16-H, 18-CH 3 ) at distinct chemical shifts and with different integrals. The peak shapes of the 16-H protons allowed us to distinguish the epimers; for the 16β-CN derivative, a triplet at 3.78 ppm ( J = 9.3 Hz) was allocated, while a doublet at 4.36 ppm ( J = 8.7 Hz) was assigned for the 16α-CN isomer.…”

Recent Advances in the Development of Pyrazole Derivatives as Anticancer Agents

“…Mótyán et al synthesized novel D-ring-condensed 5-amino-1-arylpyrazoles and tested them for in vitro antiproliferative effects on human cancer cell lines including HeLa, U2Os, MCF7, PC3, and A549 [ 132 ]. Among the derivatives, compound 122 displayed significant cytotoxic activity against the tested cell lines with IC 50 values ranging from 3.5 to 7.9 µM.…”