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Special Issue "Chemical Biology of Sterols, Triterpenoids and Other Natural Products: A Themed Issue in Honor of Professor W. David Nes on the Occasion of His 65th Birthday"

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

Deadline for manuscript submissions: 1 October 2018

Special Issue Editors

Guest Editor
Assoc. Prof. Dr. Wenxu Zhou

Department of Chemistry and Biochemistry, Center for Chemical Biology (CCB), Texas Tech University, Lubbock, TX 79409, USA
Website | E-Mail
Interests: sterol; antifungal; sterol biosynthesis; sterol auxotrophy; metabolomics
Guest Editor
Prof. Dr. De-an Guo

Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
Website | E-Mail
Interests: natural products chemistry; phytochemical analysis; herbal quality control; biotransformation; pharmacokinetics

Special Issue Information

Dear Colleagues,

Dr. W. David Nes is an eminent sterol biochemist who has made seminal contributions to the areas of chemical analysis, biosynthesis, and mechanistic enzymology. His fundamental research has led to the isolation and synthesis of over 300 sterols and triterpenoids, to a greater understanding of sterol diversity and function across kingdoms, and new knowledge for catalytic competence and three-dimensional structures of sterol biosynthesis enzymes. He developed significant collaborations in the US and abroad to advance steroidal inhibitors for the treatment of fungal and protozoan diseases. Dr. W. David Nes is currently a Paul Whitfield Horn Professor of Chemistry & Biochemistry at Texas Tech University, Lubbock, Texas. He received his BA from Gettysburg College (1975), MS from Drexel University (1977), and PhD from the University of Maryland, College Park (1979). He completed post-doctoral studies at the University of California, Berkeley and at the ARS-USDA regional laboratory in Albany CA during years 1979 to 1982. He continued on in the Plant Physiology and Chemistry Research Unit in Albany and then in the Microbial Products Research Unit at the USDA laboratory in Athens, GA until 1993 as Lead Research Chemist. In 1993, he moved to the Department of Chemistry & Biochemistry and was promoted to Horn professor in 2007. From 1999 to 2016, he was Division Chair of Biochemistry, and from 2012 to 2016, Director of the Center for Chemical Biology at Texas Tech University. He took a two-year leave of absence from the university during the period 2003–2005 to be Program Director of Molecular Biochemistry in the Division of Molecular and Cellular Biosciences at the National Science Foundation.

Professor Nes has received several awards for research excellence while at the USDA and at Texas Tech University, including the Barnie E. Rushing Jr. Award for Research Excellence. He has received an Honorable Guest Professorship (Peking University, China, 1995), Advanced Distinguished Lectureship (Kansas State University, 2010), DAAD fellowship from Germany (1982), and was sponsored by several members of the National Academy of Sciences and Royal Society to publish papers in PNAS and Proc. R. Soc. and contributed papers to special issues honoring members of the US National Academy of Sciences. During his career, he has held adjunct professor positions in the chemistry department at Auburn University (1988–1993) and the Natural Product Institute at the University of Georgia (1991–1993). He has held Visiting Professorships at the Institute for Chemical Ecology (Max Planck Institute, Jena, Germany 2007) and Centre for Cytochrome P-450 Biodiversity (College of Medicine, Swansea University, Wales, 2013) and Professorship in the Department of Immunology and Molecular Microbiology (Texas Tech Health Sciences Center School of Medicine, 2013–2017) and has served on the editorial boards of high-impact journals and on a range of federal panels, including the National Institutes of Health and National Science Foundation. He has been funded by USDA, NIH, NSF, Welch Foundation and Industry, including AstraZeneca Pharmaceuticals, Norvatis, Monsanto, and Bayer Crops, and mentored 30 MS and PhD students and 43 Post-doctoral fellows and Visiting Scientists. His high H-index is reflective of his >200 publications and eight books, many of which are among some of the highly cited or considered classics.

Molecules is highly pleased to host a Special Issue, and invites scientists to submit original contributions to “Chemical Biology of Sterols, Triterpenoids and Other Natural Products: A Themed Issue in Honor of Professor W. David Nes on the Occasion of His 65th Birthday”.

Assoc. Prof. Dr. Wenxu Zhou
Prof. Dr. De-an Guo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 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

  • sterol
  • sterol biosynthesis
  • natural products
  • isoprenoids
  • cholesterol
  • phytosterol
  • lipidomics
  • enzymology/enzyme mechanisms
  • ergosterol biosynthesis inhibitors
  • drug therapy
  • CYP51
  • sterol C24-methyltransferase
  • suicide substrate
  • transition state analog
  • antifungal
  • anti-parasite drugs
  • sparking function
  • chemical analysis
  • eukaryotic pathogen
  • sterol evolution
  • sterol auxotroph

Published Papers (7 papers)

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Research

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Open AccessArticle Squalene Cyclases and Cycloartenol Synthases from Polystichum polyblepharum and Six Allied Ferns
Molecules 2018, 23(8), 1843; https://doi.org/10.3390/molecules23081843
Received: 29 June 2018 / Revised: 20 July 2018 / Accepted: 23 July 2018 / Published: 24 July 2018
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Abstract
Ferns are the most primitive of all vascular plants. One of the characteristics distinguishing them from flowering plants is its triterpene metabolism. Most cyclic triterpenes in ferns are hydrocarbons derived from the direct cyclization of squalene by squalene cyclases (SCs). Both ferns and
[...] Read more.
Ferns are the most primitive of all vascular plants. One of the characteristics distinguishing them from flowering plants is its triterpene metabolism. Most cyclic triterpenes in ferns are hydrocarbons derived from the direct cyclization of squalene by squalene cyclases (SCs). Both ferns and more complex plants share sterols and biosynthetic enzymes, such as cycloartenol synthases (CASs). Polystichum belongs to Dryopteridaceae, and is one of the most species-rich of all fern genera. Several Polystichum ferns in Japan are classified as one of three possible chemotypes, based on their triterpene profiles. In this study, we describe the molecular cloning and functional characterization of cDNAs encoding a SC (PPH) and a CAS (PPX) from the type species Polystichum polyblepharum. Heterologous expression in Pichia pastoris revealed that PPH and PPX are hydroxyhopane synthase and CAS, respectively. By using the PPH and PPX sequences, we successfully isolated SC- and CAS-encoding cDNAs from six Polystichum ferns. Phylogenetic analysis, based on SCs and oxidosqualene cyclase sequences, suggested that the Polystichum subclade in the fern SC and CAS clades reflects the chemotype—but not the molecular phylogeny constructed using plastid molecular markers. These results show a possible relation between triterpenes and their biosynthetic enzymes in Polystichum. Full article
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Open AccessArticle Sterol Composition of Clinically Relevant Mucorales and Changes Resulting from Posaconazole Treatment
Molecules 2018, 23(5), 1218; https://doi.org/10.3390/molecules23051218
Received: 3 May 2018 / Revised: 15 May 2018 / Accepted: 17 May 2018 / Published: 19 May 2018
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Abstract
Mucorales are fungi with increasing importance in the clinics. Infections take a rapidly progressive course resulting in high mortality rates. The ergosterol biosynthesis pathway and sterol composition are of interest, since they are targeted by currently applied antifungal drugs. Nevertheless, Mucorales often exhibit
[...] Read more.
Mucorales are fungi with increasing importance in the clinics. Infections take a rapidly progressive course resulting in high mortality rates. The ergosterol biosynthesis pathway and sterol composition are of interest, since they are targeted by currently applied antifungal drugs. Nevertheless, Mucorales often exhibit resistance to these drugs, resulting in therapeutic failure. Here, sterol patterns of six clinically relevant Mucorales (Lichtheimia corymbifera, Lichtheimia ramosa, Mucor circinelloides, Rhizomucor pusillus, Rhizopus arrhizus, and Rhizopus microsporus) were analysed in a targeted metabolomics fashion after derivatization by gas chromatography-mass spectrometry. Additionally, the effect of posaconazole (POS) treatment on the sterol pattern of R. arrhizus was evaluated. Overall, fifteen different sterols were detected with species dependent variations in the total and relative sterol amount. Sterol analysis from R. arrhizus hyphae confronted with sublethal concentrations of posaconazole revealed the accumulation of 14-methylergosta-8,24-diene-3,6-diol, which is a toxic sterol that was previously only detected in yeasts. Sterol content and composition were further compared to the well-characterized pathogenic mold Aspergillus fumigatus. This work contributes to a better understanding of the ergosterol biosynthesis pathway of Mucorales, which is essential to improve antifungal efficacy, the identification of targets for novel drug design, and to investigate the combinatorial effects of drugs targeting this pathway. Full article
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Open AccessArticle Improved Synthesis of N-Methylcadaverine
Molecules 2018, 23(5), 1216; https://doi.org/10.3390/molecules23051216
Received: 25 April 2018 / Revised: 10 May 2018 / Accepted: 15 May 2018 / Published: 19 May 2018
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Abstract
Alkaloids compose a large class of natural products, and mono-methylated polyamines are a common intermediate in their biosynthesis. In order to evaluate the role of selectively methylated natural products, synthetic strategies are needed to prepare them. Here, N-methylcadaverine is prepared in 37.3%
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Alkaloids compose a large class of natural products, and mono-methylated polyamines are a common intermediate in their biosynthesis. In order to evaluate the role of selectively methylated natural products, synthetic strategies are needed to prepare them. Here, N-methylcadaverine is prepared in 37.3% yield in three steps. The alternative literature two-step strategy resulted in reductive deamination to give N-methylpiperidine as determined by the single crystal structure. A straightforward strategy to obtain the mono-alkylated aliphatic diamine, cadaverine, which avoids potential side-reactions, is demonstrated. Full article
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Open AccessArticle Ursolic Acid Attenuates Atherosclerosis in ApoE−/− Mice: Role of LOX-1 Mediated by ROS/NF-κB Pathway
Molecules 2018, 23(5), 1101; https://doi.org/10.3390/molecules23051101
Received: 28 March 2018 / Revised: 19 April 2018 / Accepted: 28 April 2018 / Published: 7 May 2018
Cited by 2 | PDF Full-text (1739 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Atherosclerosis, a chronic inflammatory disease, is a major contributor to cardiovascular diseases. Ursolic acid (UA) is a phytonutrient with widely biological effects including anti-oxidative, anti-inflammatory, and so on. At present, the effect of UA on atherosclerosis and the mechanism of action are still
[...] Read more.
Atherosclerosis, a chronic inflammatory disease, is a major contributor to cardiovascular diseases. Ursolic acid (UA) is a phytonutrient with widely biological effects including anti-oxidative, anti-inflammatory, and so on. At present, the effect of UA on atherosclerosis and the mechanism of action are still obscure. This study focused on investigating the effects of UA on atherosclerosis both in vivo and in vitro. We first selected LOX-1 as our target, which was reckoned as a new promising receptor for treating atherosclerosis. The evaluation in vitro suggested that UA significantly decreased endothelial LOX-1 expression induced by LPS both in mRNA and protein levels. Pre-treatment of UA also inhibited TLR4/MyD88 signaling activated by LPS. Moreover, UA reduced ROS production and suppressed the activation of NF-κB stimulated by LPS. Particularly, the evaluation in vivo further verified the conclusion obtained in vitro. In ApoE−/− mice fed with an atherogenic diet, both UA (100 mg/kg/day) and simvastatin significantly attenuated atherosclerotic plaque formation and shrunk necrotic core areas. The enhanced expression of LOX-1 in atherosclerotic aorta was also dramatically decreased by administration of UA. Taken together, these results suggested that UA, with anti-atherosclerotic activity through inhibition of LOX-1 mediated by ROS/NF-κB signaling pathways, may become a valuable vascular protective candidate for the treatment of atherosclerosis. Full article
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Open AccessArticle The Effects of Plant-Derived Oleanolic Acid on Selected Parameters of Glucose Homeostasis in a Diet-Induced Pre-Diabetic Rat Model
Molecules 2018, 23(4), 794; https://doi.org/10.3390/molecules23040794
Received: 22 February 2018 / Revised: 23 March 2018 / Accepted: 27 March 2018 / Published: 29 March 2018
Cited by 2 | PDF Full-text (1315 KB) | HTML Full-text | XML Full-text
Abstract
Prolonged exposure to high energy diets has been implicated in the development of pre-diabetes, a long-lasting condition that precedes type 2 diabetes mellitus (T2DM). A combination of pharmacological and dietary interventions is used to prevent the progression of pre-diabetes to T2DM. However, poor
[...] Read more.
Prolonged exposure to high energy diets has been implicated in the development of pre-diabetes, a long-lasting condition that precedes type 2 diabetes mellitus (T2DM). A combination of pharmacological and dietary interventions is used to prevent the progression of pre-diabetes to T2DM. However, poor patient compliance leads to negligence of the dietary intervention and thus reduced drug efficiency. Oleanolic acid (OA) has been reported to possess anti-diabetic effects in type 1 diabetic rats. However, the effects of this compound on pre-diabetes have not yet been established. Consequently, this study sought to evaluate the effects OA on a diet-induced pre-diabetes rat model. Pre-diabetic male Sprague Dawley rats were treated with OA in both the presence and absence of dietary intervention for a period of 12 weeks. The administration of OA with and without dietary intervention resulted in significantly improved glucose homeostasis through reduced caloric intake, body weights, plasma ghrelin concentration and glycated haemoglobin by comparison to the pre-diabetic control. These results suggest that OA may be used to manage pre-diabetes as it was able to restore glucose homeostasis and prevented the progression to overt type 2 diabetes. Full article
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Open AccessArticle Nine New Gingerols from the Rhizoma of Zingiber officinale and Their Cytotoxic Activities
Molecules 2018, 23(2), 315; https://doi.org/10.3390/molecules23020315
Received: 9 December 2017 / Revised: 30 January 2018 / Accepted: 31 January 2018 / Published: 2 February 2018
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Abstract
Nine new gingerols, including three 6-oxo-shogaol derivatives [(Z)-6-oxo-[6]-shogaol (1), (Z)-6-oxo-[8]-shogaol (2), (Z)-6-oxo-[10]-shogaol (3)], one 6-oxoparadol derivative [6-oxo-[6]-paradol (4)], one isoshogaol derivative [(E)-[4]-isoshogaol (5)], and four
[...] Read more.
Nine new gingerols, including three 6-oxo-shogaol derivatives [(Z)-6-oxo-[6]-shogaol (1), (Z)-6-oxo-[8]-shogaol (2), (Z)-6-oxo-[10]-shogaol (3)], one 6-oxoparadol derivative [6-oxo-[6]-paradol (4)], one isoshogaol derivative [(E)-[4]-isoshogaol (5)], and four paradoldiene derivatives [(4E,6Z)-[4]-paradoldiene (8), (4E,6E)-[6]-paradoldiene (9), (4E,6E)-[8]-paradoldiene (10), (4E,6Z)-[8]-paradoldiene (11)], together with eight known analogues, were isolated from the rhizoma of Zingiber officinale. Their structures were elucidated on the basis of spectroscopic data. It was noted that the isolation of 6-oxo-shogaol derivatives represents the first report of gingerols containing one 1,4-enedione motif. Their structures were elucidated on the basis of spectroscopic and HRESIMS data. All the new compounds were evaluated for their cytotoxic activities against human cancer cells (MCF-7, HepG-2, KYSE-150). Full article
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Review

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Open AccessReview Synthesis and Biological Activity of Sterol 14α-Demethylase and Sterol C24-Methyltransferase Inhibitors
Molecules 2018, 23(7), 1753; https://doi.org/10.3390/molecules23071753
Received: 20 June 2018 / Revised: 13 July 2018 / Accepted: 15 July 2018 / Published: 17 July 2018
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Abstract
Sterol 14α-demethylase (SDM) is essential for sterol biosynthesis and is the primary molecular target for clinical and agricultural antifungals. SDM has been demonstrated to be a valid drug target for antiprotozoal therapies, and much research has been focused on using SDM inhibitors to
[...] Read more.
Sterol 14α-demethylase (SDM) is essential for sterol biosynthesis and is the primary molecular target for clinical and agricultural antifungals. SDM has been demonstrated to be a valid drug target for antiprotozoal therapies, and much research has been focused on using SDM inhibitors to treat neglected tropical diseases such as human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis. Sterol C24-methyltransferase (24-SMT) introduces the C24-methyl group of ergosterol and is an enzyme found in pathogenic fungi and protozoa but is absent from animals. This difference in sterol metabolism has the potential to be exploited in the development of selective drugs that specifically target 24-SMT of invasive fungi or protozoa without adversely affecting the human or animal host. The synthesis and biological activity of SDM and 24-SMT inhibitors are reviewed herein. Full article
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