Synthesis of Anti-Inflammatory Spirostene-Pyrazole Conjugates by a Consecutive Multicomponent Reaction of Diosgenin with Oxalyl Chloride, Arylalkynes and Hydrazines or Hydrazones.

Maksim E Mironov,Sergey A Borisov,Tatyana V Rybalova,Tatyana G Tolstikova,Elvira E Shults,Dmitry S Baev

doi:10.3390/molecules27010162

Abstract

Steroid sapogenin diosgenin is of significant interest due to its biological activity and synthetic application. A consecutive one-pot reaction of diosgenin, oxalyl chloride, arylacetylenes, and phenylhydrazine give rise to steroidal 1,3,5-trisubstituted pyrazoles (isolated yield 46–60%) when the Stephens–Castro reaction and heterocyclization steps were carried out by heating in benzene. When the cyclization step of alkyndione with phenylhydrazine was performed in 2-methoxyethanol at room temperature, steroidal α,β-alkynyl (E)- and (Z)-hydrazones were isolated along with 1,3,5-trisubstituted pyrazole and the isomeric 2,3,5-trisubstituted pyrazole. The consecutive reaction of diosgenin, oxalyl chloride, phenylacetylene and benzoic acid hydrazides efficiently forms steroidal 1-benzoyl-5-hydroxy-3-phenylpyrazolines. The structure of new compounds was unambiguously corroborated by comprehensive NMR spectroscopy, mass-spectrometry, and X-ray structure analyses. Performing the heterocyclization step of ynedione with hydrazine monohydrate in 2-methoxyethanol allowed the synthesis of 5-phenyl substituted steroidal pyrazole, which was found to exhibit high anti-inflammatory activity, comparable to that of diclofenac sodium, a commercial pain reliever. It was shown by molecular docking that the new derivatives are incorporated into the binding site of the protein Keap1 Kelch-domain by their alkynylhydrazone or pyrazole substituent with the formation of more non-covalent bonds and have higher affinity than the initial spirostene core.

Highlights

Introduction published maps and institutional affilDiosgenin, (25R)-spirost-5-en-3β-ol 1, is a steroid sapogenin part of the saponin dioscin which can be found in several plant species, including dioscorea, yams and smilax [1,2].Preclinical studies have implicated the potential use of diosgenin in several ailments, such as cancer, diabetes, hypercholesterolemia, gastrointestinal disorders, and inflammatory conditions
Described atom- and step-economic synthesis of these heterocycles included the sequence of glyoxylation-alkynylation of aryl(hetaryl) substrates [38,44] or activation-alkynylation ofarylglyoxylic acids and the heterocyclization reaction of the resulting alkynyl diketones [39,40]
Synthesis of these heterocycles the sequence ofdiketones glyoxylation-alkynylation o the heterocyclization reaction included of the resulting alkynyl

Summary

Introduction

Diosgenin, (25R)-spirost-5-en-3β-ol 1, is a steroid sapogenin part of the saponin dioscin which can be found in several plant species, including dioscorea, yams and smilax [1,2]. Preclinical studies have implicated the potential use of diosgenin in several ailments, such as cancer, diabetes, hypercholesterolemia, gastrointestinal disorders, and inflammatory conditions. Antioxidant and anti-inflammatory properties [3,4] of diosgenin prevailed in most of the studies which can be attributed to its therapeutic properties on diabetes, cerebral ailments, obesity, skin ageing, cardiovascular diseases, allergic and menopausal syndrome, and cancer [5,6,7]. The versatile anticancer and anti-inflammatory activity exhibited by diosgenin indicates that this molecule could be a starting point for developing a new medicine, as an alternative drug of natural origin capable of diminishing the sideeffects caused by allopathic drugs. Diosgenin is poorly soluble in physiological media and has low absorption and a high percentage of the absorbed drug is metabolized iations.

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