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Synthesis and Bioanalysis of Steroids and Steroid Biosynthesis Inhibitors
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Synthesis and Bioanalysis of Steroids and Steroid Biosynthesis Inhibitors

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 12748

Special Issue Editors

Prof. Dr. Franz Bracher

E-Mail Website
Guest Editor
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University Munich, Butenandtstraße 5-13, 81377 Munich, Germany
Interests: medicinal chemistry; steroids; natural products; antifungals; epigenetic targets; cation channels
Dr. Christoph Müller

E-Mail Website
Guest Editor
Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians University Munich, Butenandtstraße 5-13, 81377 Munich, Germany
Interests: analytical chemistry; cholesterol/ergosterol biosynthesis; antifungal resistance; GC-MS

Special Issue Information

Dear Colleagues,

Steroids are a versatile and structurally diverse class of molecules widespread in nature. They are known as cell-building material and as signaling molecules. In recent years, our understanding of the role of steroids and steroid biosynthesis enzymes has significantly evolved. Recent studies have shown that steroids have diverse and hitherto unknown physiological functions. They are involved in the pathomechanisms of diseases or play a role in the inflammatory process in humans. Furthermore, the main target of antifungal therapy is the ergosterol biosynthesis or directly ergosterol, and related mechanisms have been found in other pathogenic organisms such as protozoa. Thus, the function of the steroids, the enzymes involved in their biosynthesis, as well as inhibitors of these enzymes as drug candidates are of great interest. Hence, the demand for authentic steroid standards for their use in bioassays and for analytical approaches cannot be met by simply extraction of steroids from natural sources. Consequently, new methods for isolation and total and partial synthesis of steroids are highly demanded.

This Special Issue is devoted to recent developments in biochemistry, chemistry, and qualitative and quantitative analysis of steroids from different origins to get a better insight into the molecular mechanisms of physiological functions and metabolism of steroids.

This also includes the development of steroid biosynthesis inhibitors as molecular tools for studying pathomechanisms, as novel drugs fighting against upcoming antifungal drug resistance, or as first-in-class drug candidates targeting distinct enzymes in cholesterol biosynthesis, whose enormous therapeutic potential has been highlighted in the past few years.

Prof. Dr. Franz Bracher
Dr. Christoph Müller
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Enzyme inhibitors (chemistry and pharmacology)
  • Steroid analysis in diverse samples (tissues, plant material, screening systems)
  • Biological activities and metabolism
  • Steroid biosynthesis
  • Synthesis of steroids and analogues
  • Steroid isolation from diverse sources (mammals, plants, microorganisms)

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Published Papers (4 papers)

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Research

24 pages, 1822 KiB  
Article
Synthesis, Biological Evaluation, and Structure–Activity Relationships of 4-Aminopiperidines as Novel Antifungal Agents Targeting Ergosterol Biosynthesis
by Jürgen Krauß, Christoph Müller, Monika Klimt, Leandro Jorquera Valero, José Francisco Martínez, Martin Müller, Karin Bartel, Ulrike Binder and Franz Bracher
Molecules 2021, 26(23), 7208; https://doi.org/10.3390/molecules26237208 - 28 Nov 2021
Cited by 6 | Viewed by 2344
Abstract
The aliphatic heterocycles piperidine and morpholine are core structures of well-known antifungals such as fenpropidin and fenpropimorph, commonly used as agrofungicides, and the related morpholine amorolfine is approved for the treatment of dermal mycoses in humans. Inspired by these lead structures, we describe [...] Read more.
The aliphatic heterocycles piperidine and morpholine are core structures of well-known antifungals such as fenpropidin and fenpropimorph, commonly used as agrofungicides, and the related morpholine amorolfine is approved for the treatment of dermal mycoses in humans. Inspired by these lead structures, we describe here the synthesis and biological evaluation of 4-aminopiperidines as a novel chemotype of antifungals with remarkable antifungal activity. A library of more than 30 4-aminopiperidines was synthesized, starting from N-substituted 4-piperidone derivatives by reductive amination with appropriate amines using sodium triacetoxyborohydride. Antifungal activity was determined on the model strain Yarrowia lipolytica, and some compounds showed interesting growth-inhibiting activity. These compounds were tested on 20 clinically relevant fungal isolates (Aspergillus spp., Candida spp., Mucormycetes) by standardized microbroth dilution assays. Two of the six compounds, 1-benzyl-N-dodecylpiperidin-4-amine and N-dodecyl-1-phenethylpiperidin-4-amine, were identified as promising candidates for further development based on their in vitro antifungal activity against Candida spp. and Aspergillus spp. Antifungal activity was determined for 18 Aspergillus spp. and 19 Candida spp., and their impact on ergosterol and cholesterol biosynthesis was determined. Toxicity was determined on HL-60, HUVEC, and MCF10A cells, and in the alternative in vivo model Galleria mellonella. Analysis of sterol patterns after incubation gave valuable insights into the putative molecular mechanism of action, indicating inhibition of the enzymes sterol C14-reductase and sterol C8-isomerase in fungal ergosterol biosynthesis. Full article
(This article belongs to the Special Issue Synthesis and Bioanalysis of Steroids and Steroid Biosynthesis Inhibitors)
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16 pages, 1345 KiB  
Article
Spirostanol Sapogenins and Saponins from Convallaria majalis L. Structural Characterization by 2D NMR, Theoretical GIAO DFT Calculations and Molecular Modeling
by Karolina Dąbrowska-Balcerzak, Jadwiga Nartowska, Iwona Wawer, Paweł Siudem and Katarzyna Paradowska
Molecules 2021, 26(10), 2999; https://doi.org/10.3390/molecules26102999 - 18 May 2021
Cited by 5 | Viewed by 2794
Abstract
Two new spirostanol sapogenins (5β-spirost-25(27)-en-1β,2β,3β,5β-tetrol 3 and its 25,27-dihydro derivative, (25S)-spirostan-1β,2β,3β,5β-tetrol 4) and four new saponins were isolated from the roots and rhizomes of Convallaria majalis L. together with known sapogenins (isolated from Liliaceae): 5β-spirost-25(27)-en-1β,3β-diol 1, (25S)-spirostan-1β,3β-diol 2, 5β-spirost-25(27)-en-1β,3β,4β,5β-tetrol [...] Read more.
Two new spirostanol sapogenins (5β-spirost-25(27)-en-1β,2β,3β,5β-tetrol 3 and its 25,27-dihydro derivative, (25S)-spirostan-1β,2β,3β,5β-tetrol 4) and four new saponins were isolated from the roots and rhizomes of Convallaria majalis L. together with known sapogenins (isolated from Liliaceae): 5β-spirost-25(27)-en-1β,3β-diol 1, (25S)-spirostan-1β,3β-diol 2, 5β-spirost-25(27)-en-1β,3β,4β,5β-tetrol 5, (25S)-spirostan-1β,3β,4β,5β-tetrol 6, 5β-spirost-25(27)-en-1β,2β,3β,4β,5β-pentol 7 and (25S)-spirostan-1β,2β,3β,4β,5β-pentol 8. New steroidal saponins were found to be pentahydroxy 5-O-glycosides; 5β-spirost-25(27)-en-1β,2β,3β,4β,5β-pentol 5-O-β-galactopyranoside 9, 5β-spirost-25(27)-en-1β,2β,3β,4β,5β-pentol 5-O-β-arabinonoside 11, 5β-(25S)-spirostan-1β,2β,3β,4β,5β-pentol 5-O-galactoside 10 and 5β-(25S)-spirostan-1β,2β,3β,4β,5β-pentol 5-O-arabinoside 12 were isolated for the first time. The structures of those compounds were determined by NMR spectroscopy, including 2D COSY, HMBC, HSQC, NOESY, ROESY experiments, theoretical calculations of shielding constants by GIAO DFT, and mass spectrometry (FAB/LSI HR MS). An attempt was made to test biological activity, particularly as potential chemotherapeutic agents, using in silico methods. A set of 12 compounds was docked to the PDB structures of HER2 receptor and tubulin. The results indicated that diols have a higher affinity to the analyzed targets than tetrols and pentols. Two compounds (25S)-spirosten-1β,3β-diol 1 and 5β-spirost-25(27)-en-1β,2β,3β,4β,5β-pentol 5-O-galactoside 9 were selected for further evaluation of biological activity. Full article
(This article belongs to the Special Issue Synthesis and Bioanalysis of Steroids and Steroid Biosynthesis Inhibitors)
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18 pages, 2366 KiB  
Article
New Insights into the Metabolism of Methyltestosterone and Metandienone: Detection of Novel A-Ring Reduced Metabolites
by Steffen Loke, Lingyu Liu, Maxi Wenzel, Heike Scheffler, Michele Iannone, Xavier de la Torre, Nils Schlörer, Francesco Botrè, Annekathrin Martina Keiler, Matthias Bureik and Maria Kristina Parr
Molecules 2021, 26(5), 1354; https://doi.org/10.3390/molecules26051354 - 3 Mar 2021
Cited by 13 | Viewed by 4090
Abstract
Metandienone and methyltestosterone are orally active anabolic-androgenic steroids with a 17α-methyl structure that are prohibited in sports but are frequently detected in anti-doping analysis. Following the previously reported detection of long-term metabolites with a 17ξ-hydroxymethyl-17ξ-methyl-18-nor-5ξ-androst-13-en-3ξ-ol structure in the chlorinated metandienone analog dehydrochloromethyltestosterone (“oral [...] Read more.
Metandienone and methyltestosterone are orally active anabolic-androgenic steroids with a 17α-methyl structure that are prohibited in sports but are frequently detected in anti-doping analysis. Following the previously reported detection of long-term metabolites with a 17ξ-hydroxymethyl-17ξ-methyl-18-nor-5ξ-androst-13-en-3ξ-ol structure in the chlorinated metandienone analog dehydrochloromethyltestosterone (“oral turinabol”), in this study we investigated the formation of similar metabolites of metandienone and 17α-methyltestosterone with a rearranged D-ring and a fully reduced A-ring. Using a semi-targeted approach including the synthesis of reference compounds, two diastereomeric substances, viz. 17α-hydroxymethyl-17β-methyl-18-nor-5β-androst-13-en-3α-ol and its 5α-analog, were identified following an administration of methyltestosterone. In post-administration urines of metandienone, only the 5β-metabolite was detected. Additionally, 3α,5β-tetrahydro-epi-methyltestosterone was identified in the urines of both administrations besides the classical metabolites included in the screening procedures. Besides their applicability for anti-doping analysis, the results provide new insights into the metabolism of 17α-methyl steroids with respect to the order of reductions in the A-ring, the participation of different enzymes, and alterations to the D-ring. Full article
(This article belongs to the Special Issue Synthesis and Bioanalysis of Steroids and Steroid Biosynthesis Inhibitors)
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18 pages, 2136 KiB  
Article
Synthesis of New Brassinosteroid 24-Norcholane Type Analogs Conjugated in C-3 with Benzoate Groups
by Karoll Ferrer, Katy Díaz, Miroslav Kvasnica, Andrés F. Olea, Mauricio Cuellar and Luis Espinoza
Molecules 2021, 26(4), 1173; https://doi.org/10.3390/molecules26041173 - 22 Feb 2021
Cited by 6 | Viewed by 2629
Abstract
The metabolism of brassinosteroid leads to structural modifications in the ring skeleton or the side alkyl chain. The esterification and glycosylation at C-3 are the most common metabolic pathways, and it has been suggested that conjugate brassinosteroids are less active or inactive. In [...] Read more.
The metabolism of brassinosteroid leads to structural modifications in the ring skeleton or the side alkyl chain. The esterification and glycosylation at C-3 are the most common metabolic pathways, and it has been suggested that conjugate brassinosteroids are less active or inactive. In this way, plants regulate the content of active brassinosteroids. In this work, the synthesis of brassinosteroid 24-norcholane type analogs conjugated at C-3 with benzoate groups, carrying electron donor and electron attractant substituents on the aromatic ring, is described. Additionally, their growth-promoting activities were evaluated using the Rice Lamina Inclination Test (RLIT) and compared with that exhibited by brassinolide (used as positive control) and non-conjugated analogs. The results indicate that at the lowest tested concentrations (10−8–10−7 M), all analogs conjugated at C-3 exhibit similar or higher activities than brassinolide, and the diasteroisomers with S configuration at C-22 are the more active ones. Increasing concentration (10−6 M) reduces the biological activities of analogs as compared to brassinolide. Full article
(This article belongs to the Special Issue Synthesis and Bioanalysis of Steroids and Steroid Biosynthesis Inhibitors)
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