Synthesis of steroidal derivatives containing substituted, fused and spiro pyrazolines

doi:10.1016/j.steroids.2014.05.013

Steroids

Volume 87, September 2014, Pages 86-92

https://doi.org/10.1016/j.steroids.2014.05.013 Get rights and content

Highlights

•
The synthesis of novel pyrazoline steroids is described.
•
We report the synthesis of the first spiro-steroidal pyrazoline at C-22.
•
The cycloaddition of hydrazine to α,β-unsaturated ketones was the key step.
•
The mechanism of reaction was established by the isolation of an intermediate.
•
The structures of new compounds were confirmed by NMR studies.

Abstract

An efficient and facile synthesis of fused, substituted and spiro pyrazoline steroid derivatives through a cycloaddition reaction of different α,β-unsaturated ketones with hydrazine acetate in acetic acid is reported. Depending on the starting material, the ring closure reaction provided a mixture of two steroidal pyrazoline epimers that were separated and studied by NMR techniques. In one case it was possible to isolate and characterize the hydrazone derivative as the reaction intermediate, which confirms the mechanism proposed in the literature [11,25,26].

Graphical abstract

Introduction

Several types of steroids fused to heterocycles have been carefully studied since the 1960s and their chemistry has been progressing subsequently; based on these results, it was possible to establish the structure–activity relationship between the steroidal structure and their physiological properties [1], [2]. In recent years, the efforts have been undertaken towards the rational modification of steroid molecules involving the incorporation of a heteroatom, such as N or O. This kind of compounds has shown many different biological activities including anti-microbial, anti-inflammatory, hypotensive, hypocholesterolemic and diuretic activities [3], [4], [5], [6]. Pyrazoline derivatives are electron rich nitrogen heterocycles which show interesting pharmacological properties such as analgesic, antipyretic, antirheumatic [7], [8], anti-inflammatory [9], antidiabetic [10], anticancer [11], [12], [13], [14] and antimicrobial activities [15].

Herein we report a very facile and high yielding synthesis of steroidal pyrazolines located on D and E rings, starting from 20-keto pregnane, trans-androsterone and diosgenin through a condensation reaction between α,β-unsaturated carbonyl compounds and 1,2-binucleophilic compounds such as hydrazine (Scheme 1) [16].

Section snippets

General methods

NMR spectra 1D and 2D ¹H and ¹³C (DEPT, COSY, NOESY, HSQC, HMBC) were recorded on a VARIAN Mercury spectrometer (400 MHz for ¹H, 100 MHz for ¹³C). Chemical shifts are stated in ppm (δ), and are referred to the ¹H signal (δ = 7.24) or to the central ¹³C triplet signal (δ = 77.0) for CDCl₃. Coupling constants (J) are quoted in Hz. IR spectra were acquired on a Nicolet FT-IR 380 spectrophotometer (ν_max, cm⁻¹). FAB-MS, EI-MS and high resolution mass (HRMS) spectra were recorded on a Jeol-JMS-700 MS

Results and discussion

The importance of different steroidal heterocycles is well known. In our attempt to increase the biological activity we decided to build up pyrazoline rings from steroidal α,β-unsaturated ketones and hydrazine. Three different types of compounds were synthesized as precursors of steroidal pyrazoline derivatives.

The first α,β-unsaturated ketone was synthesized through the aldolic condensation of pregnanolone acetate 1 with benzaldehyde under basic conditions to give the corresponding benzylidene

Acknowledgments

The authors thank CONACYT – Mexico for scholarships to ARL and the Retention grant 190909 to PMM. Also we thank VIEP-BUAP for financial support (grant to SMS). We are also grateful to the anonymous reviewer for their comments and to Dr. Francisco J. Meléndez-Bustamante (Lab. de Química Teórica, BUAP) for theoretical studies.

References (30)

J.H. Ahn et al.
Synthesis and DP-IV inhibition of cyano-pyrazoline derivatives as potent anti-diabetic agents
Bioorg Med Chem Lett
(2004)
Z. Iványi et al.
Synthesis of D-ring-substituted (5′R)-and (5′S)-17b-pyrazolinylandrostene epimers and comparison of their potential anticancer activities
Steroids
(2012)
A.G. Hammam et al.
Synthesis of novel tricyclicheterocyclic compounds as potential anticancer agents using chromanone and thiochromanoneas synthons
Ind J Chem
(2003)
A.H. Banday et al.
Studies on novel D-ring substituted steroidal pyrazolines as potential anticancer agents
Steroids
(2010)
A.E. Amr
Synthesis of some heterocyclic compounds as potential antimicrobial agents using 2,6-diacetylpyridine as synthon
Ind J Heterocycl Chem
(2000)
A. Lévai
Synthesis of 2-pyrazolines by the reactions of α, β-unsaturated aldehydes, ketones, and esters with diazoalkanes, nitrile imines, and hydrazines
J Heterocyclic Chem
(2002)
O. Viñas-Bravo et al.
¹H and ¹³C NMR of synthetic steroid sapogenins. Part II. C-23 Substituted derivatives of (25S)-spirostanes
Arkivoc
(2003)
F. Zeelen
Medicinal chemistry of steroids
(1990)
A.A. Akhrem et al.
Derivatives of steroids with condensed heterocycles
Russ Chem Rev
(1967)
I.V. Zavarzin et al.
Steroids fused to heterocycles at positions 16,17 of the D-ring
Russ Chem Rev
(2011)
T. Luigio et al.
Chemoselective construction of novel steroid derivatives
Steroids
(2002)

R.M. Mohared et al.

Synthesis of modification as a novel class of non-ulcerogenic, anti-inflammatory and anti-nociceptive agent

Steroid

(2011)

M. Natalija et al.

New androst-4-en-17-spiro-1,3,2-oxathiaphospholanes. Synthesis, assignment of absolute configuration and in vitro cytotoxic and antimicrobial activities

Steroids

(2012)

R.M. Mohared et al.

Reaction of pregnenolone with cyanoacetylhydrazine: novel synthesis of hydrazide–hydrazone, pyrazole, pyridine, thiazole, thiophene derivatives and their cytotoxicity evaluations

Steroids

(2012)

J. Hukki et al.

Preparation and pharmacological activity of pyrazole derivatives with potential antihistaminic properties. II. An attempted synthesis of 1-phenyland 1-benzyl-3-methyl-5-pyrazolones aminoalkylated at position 2

Pharm Acta Helv

(1968)

J.C. Jung et al.

Synthesis and cyclization reaction of pyrazolin-5-one derivatives

Heterocycles

(2005)

Cited by (22)

Synthesis, characterization, molecular docking studies, and in vitro elucidation of protein aggregation inhibition potential of 3β-acetoxy steroidal pyrazolines
2023, Journal of Molecular Structure
Protein misfolding and amyloid fibril deposition may lead to several neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's, and similar amyloid polyneuropathies. Inhibition of fibril formation and disaggregation of mature fibrils by some chemical compounds could be a therapeutic approach toward such chronic diseases. In this study, we synthesized a series of novel steroidal pyrazolines and tested the effects of the series on the in vitro inhibition of human lysozyme aggregation. The effect of synthesized steroidal compounds on the kinetics of protein aggregation inhibition was elucidated by Tryptophan (Trp), 8-anilino-1-naphthalenesulfonic acid (ANS), and Congo red (CR) spectral analysis. Further, we examined that the ring closure reaction in the later step produced a mixture of two steroidal pyrazoline epimers that could only be separated in their acetylated form. The (5’S)-3β-acetoxy steroidal pyrazolines (5a-i) were found as the major product and their structures were examined using NMR techniques. The efficacy of various acid catalysts to catalyze the condensation reaction was also evaluated to obtain better yield in lesser time. In addition, molecular docking studies were also performed to understand the receptor-ligand binding interactions.
Recent advances on synthesis and biological activities of C-17 aza-heterocycle derived steroids
2022, Bioorganic and Medicinal Chemistry
Citation Excerpt :
Similar products were also reported by A. Romero-López et al. in 2014. Using the different steroids as the starting material, some new steroidal pyrazolines 16 were obtained (Scheme 2).28 Subjecting progesterone to the Knoevenagel reaction with malononitrile or ethyl cyanoacetate in the presence of NH4OAc furnished the condensed products, which reacted with hydrazine derivatives to give different pyrazole derivatives 19 and 20 in moderate to high yields.
Steroids modification for improving their biological activities is one of the most efficient and fruitful methods to develop novel medicines. Steroids with aza-heterocycles attaching to the C-17 owing various biological activities have received great attentions and some of the compounds are developed successfully as drugs. In this review, the research of the syntheses and biological activities of steroids bearing various aza-heterocycles published in the last 8 years is assembled, and some important structure–activity relationships (SARs) of active compounds are presented. According to the analysis of the literatures and our experiences in this field, the potential of aza-heterocyclic steroids as medicinal drugs is proposed.
Green chemistry approaches to the synthesis of pyrazoline steroid derivatives and their theoretical DFT characterization
2021, Green Chemistry and Computational Chemistry: Shared Lessons in Sustainability
Pyrazoline steroids are electron-rich nitrogen-containing heterocyclic structures that exhibit several desirable pharmacological features. Conventional synthetic techniques to obtain these compounds provide high yields in short times (3–5 h). However, the search for alternative procedures to decrease the time required for the reaction, obtain higher yields, avoid by-product generation, and reduce the purification processes remains a significant challenge. The synthesis of pyrazoline steroid derivatives assisted by microwave radiation has emerged as an interesting alternative approach since it not only speeds up the reaction rate (to 20–35 min) and increases the yields but also prevents the use of organic acids as solvents or catalysts. Thus, this approach satisfies green chemistry principles by maximizing the efficiency of the reaction while minimizing toxic effects on human health and on the environment. Yet, even though the microwave irradiation has been identified as an efficient method for the synthesis of pyrazoline steroids, the identification of the best reaction conditions is still an ongoing challenging process (and usually on a case-by-case basis).
Aiding in the selection of appropriate reaction conditions, as well as providing specific details about the reaction mechanism, is a well-suited task for theoretical chemistry research. Methodologies based on DFT calculations are used to provide reliable insights about the cis/trans and Z/E isomerization and the stereochemical configuration of the substituted, fused, and spiro pyrazoline steroids derivatives by the theoretical prediction of chemical shifts and coupling constants of ¹H and ¹³C NMR. This is particularly useful because of the formation of new stereogenic centres in the synthesized products. The present work provides evidence of a suitable methodology for studying the structural and spectroscopic properties of substituted, fused, and spiro pyrazoline steroid derivatives and simultaneously highlights the relevance of the synergy between green chemistry and computational chemistry.
Microwave-induced synthesis of steroids and their chemical manipulations
2020, Green Approaches in Medicinal Chemistry for Sustainable Drug Design
The medicinal chemistry has a great potential challenge in the chemical manipulations of steroids on account of their enhanced and varied biological properties. In recent times, the development of soft corticosteroids applying retro-metabolic drug concept has gained considerable importance in the steroid drug industry to minimize the severe side effects associated with corticosteroids including percutaneous absorption and cutaneous atrophy. Besides these, synthetic works toward the development of the modified steroid molecules and a number of molecular hybrids as combinations of parts of different steroid molecules with other building blocks are also an area of interest because of their diverse biological properties. Microwave (MW)-assisted chemical reactions are currently gaining considerable importance in steroid synthesis to contribute to green technology. Hybrid systems in recent times are drawing considerable attention in the area of drug development as many of such systems are now becoming drug targets in diverse therapeutical applications.
Diverse synthesis of medicinally active steroids
2020, Green Approaches in Medicinal Chemistry for Sustainable Drug Design
16,17-N′-(alky/arylsulfonyl)pyrazoline substituted neuroprotective heterosteroids: Synthesis, molecular docking and preclinical efficacy/toxicity studies in rodents
2019, Steroids
Citation Excerpt :
The A- or D- ring substituted steroidal analogues have gained much attention as molecules having diversified medicinal properties during the last decades [7–9] and more recently as novel neuroprotective agents [10–13]. Pyrazoline nucleus is a privileged scaffold endowed with abundant varied pharmacological activities such as anti-inflammatory, analgesic, antidepressant, antimicrobial and anticancer actions [14–16]. The N′-(arylsulfonyl)-pyrazoline derivatives (I) act as potent antagonists of 5-HT6 receptors and could be of use for the therapeutic management of AD [17].
The synthesis and neuroprotective efficacy and toxicity studies of a new series of 16,17-N′-(alkyl/arylsulfonyl)pyrazolinyl steroids is presented. Significant suppression of the overexpressed acetylcholinesterase and lipid peroxidation, marked reduction of nitrite, oxidative stress and TNF-α levels and noticeable improvement in cognitive and locomotor functions were observed after treatment with the newly synthesized steroids 2-4a-d in the LPS-treated animal models. Higher neuroprotective effects were produced by some of the pyrazolinyl steroids in comparison to the reference drugs celecoxib and dexamethasone. N′-(4-fluorobenzenesulfonyl) derivative 4c showed the most promising effects on all the analyzed parameters and is the most potent molecule among all compounds of this series. Acute toxicity studies on the most active steroids 2-4c at 50 mg/kg did not reveal any toxic effects on animals, however hepatitis and chronic nephritis were observed in histological examination of liver and kidney of mice after 28 days of treatment. The pyrazolinyl steroids 2-4a-d could be considered as promising candidates for the designing of novel multitarget-directed neuroprotectives for an effective therapy of AD and PD.

View all citing articles on Scopus

View full text

Synthesis of steroidal derivatives containing substituted, fused and spiro pyrazolines

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

General methods

Results and discussion

Acknowledgments

Bioorg Med Chem Lett

Steroids

Ind J Chem

Steroids

Ind J Heterocycl Chem

J Heterocyclic Chem

Arkivoc

Medicinal chemistry of steroids

Derivatives of steroids with condensed heterocycles

Russ Chem Rev

Steroids fused to heterocycles at positions 16,17 of the D-ring

Russ Chem Rev

Chemoselective construction of novel steroid derivatives

Steroids

Synthesis of modification as a novel class of non-ulcerogenic, anti-inflammatory and anti-nociceptive agent

Steroid

New androst-4-en-17-spiro-1,3,2-oxathiaphospholanes. Synthesis, assignment of absolute configuration and in vitro cytotoxic and antimicrobial activities

Steroids

Reaction of pregnenolone with cyanoacetylhydrazine: novel synthesis of hydrazide–hydrazone, pyrazole, pyridine, thiazole, thiophene derivatives and their cytotoxicity evaluations

Steroids

Preparation and pharmacological activity of pyrazole derivatives with potential antihistaminic properties. II. An attempted synthesis of 1-phenyland 1-benzyl-3-methyl-5-pyrazolones aminoalkylated at position 2

Pharm Acta Helv

Synthesis and cyclization reaction of pyrazolin-5-one derivatives

Heterocycles