Microwave-assisted stereoselective approach to novel steroidal ring D-fused 2-pyrazolines and an evaluation of their cell-growth inhibitory effects in vitro

Mótyán, Gergő; Kovács, Ferenc; Wölfling, János; Gyovai, András; Zupkó, István; Frank, Éva

doi:10.1016/j.steroids.2016.04.014

Cited by 15 publications

(15 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, two additional cyclic tautomers (2d and 2e) can contribute to the equilibrium besides the three open forms (2a-c) [29]. According to 1 H and 13 C NMR (J-MOD) measurements, only one of the possible tautomers (2d) is present in dimethyl sulfoxide (DMSO) solution in good agreement with previous studies, where the same form was evidenced by IR and XRD in the solid-state [23]. Treatment of 2 with KOH in MeOH at room temperature or below resulted in a β-ketonitrile (3) as a mixture of two epimers in excellent yield via base-induced elimination of a water molecule (Scheme 1).…”

Section: Synthetic Studiesmentioning

confidence: 99%

“…In the 1 H NMR spectra the multiplicities of the signals are reported as a singlet (s), a broad singlet (bs), a doublet (d), a double doublet (dd), or a multiplet (m). 1 H-decoupled 13 C NMR spectra were recorded. For the determination of multiplicities, the J-MOD pulse sequence was applied.…”

Section: Generalmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Synthetic Studiesmentioning

confidence: 99%

Section: Generalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

Synthesis, biological evaluation, and in silico study of pyrazoline‐conjugated 2,4‐dimethyl‐1H‐pyrrole‐3‐carboxylic acid derivatives

Rasal

Sonawane

Jagtap

2020

Archiv der Pharmazie

View full text Add to dashboard Cite

A potential molecular hybridization strategy was used to develop 24 novel pyrazoline‐conjugated 2,4‐dimethyl‐1H‐pyrrole‐3‐carboxylic acid and amide derivatives. The preliminary in vitro antimicrobial assay delivered four potential derivatives with growth inhibition in the range of 50.87–56.60% at the concentration of 32 µg/ml. In the search of an anticancer candidate, all derivatives were screened by NCI‐60 at 10 µM concentration, revealing that 12 derivatives were potential agents against the various types of cancer cell lines, with growth inhibition in the range of 50.21–108.37%. The in vitro cytotoxicity assay against the cell line HEK293 (human embryonic kidney cells) and the hemolysis assay of the representative potent compounds propose their potential for a good therapeutic index. In silico studies of the most potent derivatives qualified their significant pharmacokinetic properties with good predicted oral bioavailability and their adherence to Lipinski's rule of five for druglikeness. A molecular docking study against VEGFR‐2 with the best‐scored conformations reinforced their anticancer potency. The docking study of the most potent compound against VEGFR‐2 with the best‐scored conformations displayed a binding affinity (−9.5 kcal/mol) comparable with the drug sunitinib (−9.9 kcal/mol) and exhibited that tighter interactions at the active adenosine triphosphate site might be responsible for anticancer potency.

show abstract

Microwave-induced synthesis of steroids and their chemical manipulations

Borah

Banik

2020

Green Approaches in Medicinal Chemistry for Sustainable Drug Design

View full text Add to dashboard Cite

Microwave-assisted stereoselective approach to novel steroidal ring D-fused 2-pyrazolines and an evaluation of their cell-growth inhibitory effects in vitro

Cited by 15 publications

References 28 publications

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

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

Synthesis, biological evaluation, and in silico study of pyrazoline‐conjugated 2,4‐dimethyl‐1H‐pyrrole‐3‐carboxylic acid derivatives

Microwave-induced synthesis of steroids and their chemical manipulations

Contact Info

Product

Resources

About