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Special Issue "Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 31 October 2021.

Special Issue Editor

Prof. Dr. Hidayat Hussain
E-Mail Website
Guest Editor
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Salle), Germany
Interests: natural product chemistry; medicinal chemistry; cancer biology; bioorganic chemistry; pharmacology; diabetes; synthetic chemistry; biology-oriented synthesis
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

In 2021, Prof. Dr. Ludger Wessjohann, Professor and Director of Department Bioorganic Chemistry at Leibniz Institute of Plant Biochemistry, Halle, Germany has his 60th birthday. In recognition of his outstanding lifetime scientific contribution, we have arranged a Special Issue to which you are invited to submit a manuscript.

Prof. Dr Ludger A. Wessjohann

Director Dept. Bioorganic Chemistry

& Full Professor of Chemistry

Leibniz Institute of Plant Biochemistry (IPB)

Address: Weinberg 3, 06120 Halle (Saale), Germany

E-mail: [email protected]

http://www.ipb-halle.de/en/research/bioorganic-chemistry/

Orcid: 0000-0003-2060-8235

Professor Wessjohann studied chemistry in Hamburg (Germany), Southampton (UK), and Oslo (Norway, Prof. Skattebøl). He earned his doctorate in 1990 with Prof. de Meijere in Hamburg. After a short period as lecturer in Brazil, he became a postdoctoral Feodor-Lynen fellow of the Alexander von Humboldt-foundation with Prof. Paul Wender at Stanford University (USA) working on the total synthesis of Taxol®. After an assistant professorship in Munich (LMU, 1992-1998), he was appointed to the Chair of Bioorganic Chemistry at the Vrije Universiteit Amsterdam (NL), working on organometallic chemistry and biocatalysis. Since 2001, he is director of the dept. of bioorganic chemistry at the Leibniz Institute of Plant Biochemistry (IPB) in Halle (Germany), and in parallel holds the chair of natural product chemistry of the Martin Luther-University Halle-Wittenberg. From 2010-2017 he served as the Managing Director of the IPB (www.ipb-halle.de).

Prof. Wessjohann focuses on the discovery, synthesis and application of natural products and bioactive derivatives thereof. He has over 400 publications, 30 patent applications, and is co-founder of six companies. He is member of many boards and commissions, including recently the “mision de sabios” of the Colombian government. He received numerous scholarships, prizes and honors, e.g. Microsoft IT Founders Award, and is a foreign member of the Brazilian Academy of Science.

Natural products (NPs) and their derivatives have historically made a major contribution to pharmacotherapy, in particular for cancer and infectious diseases. NPs are characterized by intriguing scaffold diversity along with structural complexity and because of this NPs continue to be an crucial source of leads for new medicines. Cancer is a world health issue and affects all communities around the globe regardless of religion, race or age. It is noteworthy that cancer is the second leading cause of death globally and is responsible for around 9.6 million deaths in 2018. Natural products (NPs) represent a tremendous resource for anticancer drug development along with treatment of other human diseases. Notably, about 80% of cancer therapy drugs approved by the United States Food and Drug Administration (FDA) during the last three decades are either NPs, NP derivatives, or mimicked NPs. Moreover 41% (646/1562) of all new drug approvals between 1981 and 2014 are NPs or derived from NPs. This illustrates that there is still an urgent need for the development of novel anti-cancer drugs with a unique mechanism of action. 

This Special Issue welcomes original articles, communications and reviews dealing with the isolation and/or the investigation of mechanisms of action of natural products and their synthetic analogs with potential anti-cancer effects. In addition, this Special Issue also welcomes articles about the role of natural products and their derivatives to treat infectious diseases, microbial diseases, cardiovascular diseases and other human diseases. Finding target-identification (with biological assays together with computational studies), in vivo studies and the design of novel natural product derivatives with improved biological effects are also welcome.


text

Prof. Dr. Hidayat Hussain
Guest Editor

Manuscript Submission Information

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Keywords

  • Drug Discovery
  • Natural products
  • Natural product derivatives
  • Cancer
  • Infectious diseases
  • Microbial diseases
  • Diabetes
  • Cardiovascular diseases
  • Human health
  • Human diseases
  • Computational methods
  • In vitro studies
  • In vivo studies
  • Mechanism of action

Published Papers (8 papers)

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Research

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Article
MUG Mel3 Cell Lines Reflect Heterogeneity in Melanoma and Represent a Robust Model for Melanoma in Pregnancy
by , , , , , , , , , , , , , , , , , and
Int. J. Mol. Sci. 2021, 22(21), 11318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111318 - 20 Oct 2021
Viewed by 182
Abstract
Melanomas are aggressive tumors with a high metastatic potential and an increasing incidence rate. They are known for their heterogeneity and propensity to easily develop therapy-resistance. Nowadays they are one of the most common cancers diagnosed during pregnancy. Due to the difficulty in [...] Read more.
Melanomas are aggressive tumors with a high metastatic potential and an increasing incidence rate. They are known for their heterogeneity and propensity to easily develop therapy-resistance. Nowadays they are one of the most common cancers diagnosed during pregnancy. Due to the difficulty in balancing maternal needs and foetal safety, melanoma is challenging to treat. The aim of this study was to provide a potential model system for the study of melanoma in pregnancy and to illustrate melanoma heterogeneity. For this purpose, a pigmented and a non-pigmented section of a lymph node metastasis from a pregnant patient were cultured under different conditions and characterized in detail. All four culture conditions exhibited different phenotypic, genotypic as well as tumorigenic properties, and resulted in four newly established melanoma cell lines. To address treatment issues, especially in pregnant patients, the effect of synthetic human lactoferricin-derived peptides was tested successfully. These new BRAF-mutated MUG Mel3 cell lines represent a valuable model in melanoma heterogeneity and melanoma pregnancy research. Furthermore, treatment with anti-tumor peptides offers an alternative to conventionally used therapeutic options—especially during pregnancy. Full article
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Communication
Polygodial and Ophiobolin A Analogues for Covalent Crosslinking of Anticancer Targets
Int. J. Mol. Sci. 2021, 22(20), 11256; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011256 - 19 Oct 2021
Viewed by 240
Abstract
In a search of small molecules active against apoptosis-resistant cancer cells, including glioma, melanoma, and non-small cell lung cancer, we previously prepared α,β- and γ,δ-unsaturated ester analogues of polygodial and ophiobolin A, compounds capable of pyrrolylation of primary amines and demonstrating double-digit micromolar [...] Read more.
In a search of small molecules active against apoptosis-resistant cancer cells, including glioma, melanoma, and non-small cell lung cancer, we previously prepared α,β- and γ,δ-unsaturated ester analogues of polygodial and ophiobolin A, compounds capable of pyrrolylation of primary amines and demonstrating double-digit micromolar antiproliferative potencies in cancer cells. In the current work, we synthesized dimeric and trimeric variants of such compounds in an effort to discover compounds that could crosslink biological primary amine containing targets. We showed that such compounds retain the pyrrolylation ability and possess enhanced single-digit micromolar potencies toward apoptosis-resistant cancer cells. Target identification studies of these interesting compounds are underway. Full article
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Article
Synthesis of Demissidine Analogues from Tigogenin via Imine Intermediates
Int. J. Mol. Sci. 2021, 22(19), 10879; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910879 - 08 Oct 2021
Viewed by 248
Abstract
A five-step transformation of a spiroketal side chain of tigogenin into an indolizidine system present in solanidane alkaloids such as demissidine and solanidine was elaborated. The key intermediate in the synthesis was spiroimine 3 readily obtained from tigogenin by its RuO4 oxidation [...] Read more.
A five-step transformation of a spiroketal side chain of tigogenin into an indolizidine system present in solanidane alkaloids such as demissidine and solanidine was elaborated. The key intermediate in the synthesis was spiroimine 3 readily obtained from tigogenin by its RuO4 oxidation to 5,6-dihydrokryptogenin followed by amination with aluminum amide generated in situ from DIBAlH and ammonium chloride. The mild reduction of spiroimine to a 26-hydroxy-dihydropyrrole derivative and subsequent mesylation resulted in the formation of 25-epidemissidinium salt or 23-sulfone depending on reaction conditions. Full article
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Article
The Natural Pigment Violacein Potentially Suppresses the Proliferation and Stemness of Hepatocellular Carcinoma Cells In Vitro
Int. J. Mol. Sci. 2021, 22(19), 10731; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910731 - 03 Oct 2021
Viewed by 587
Abstract
Hepatocellular carcinoma (HCC) is a malignant type of primary liver cancer with high incidence and mortality, worldwide. A major challenge in the treatment of HCC is chemotherapeutic resistance. It is therefore necessary to develop novel anticancer drugs for suppressing the growth of HCC [...] Read more.
Hepatocellular carcinoma (HCC) is a malignant type of primary liver cancer with high incidence and mortality, worldwide. A major challenge in the treatment of HCC is chemotherapeutic resistance. It is therefore necessary to develop novel anticancer drugs for suppressing the growth of HCC cells and overcoming drug resistance for improving the treatment of HCC. Violacein is a deep violet-colored indole derivative that is produced by several bacterial strains, including Chromobacterium violaceum, and it possesses numerous pharmacological properties, including antitumor activity. However, the therapeutic effects of violacein and the mechanism underlying its antitumor effect against HCC remain to be elucidated. This study is the first to demonstrate that violacein inhibits the proliferation and stemness of Huh7 and Hep3B HCC cells. The antiproliferative effect of violacein was attributed to cell cycle arrest at the sub-G1 phase and the induction of apoptotic cell death. Violacein induced nuclear condensation, dissipated mitochondrial membrane potential (MMP), increased generation of reactive oxygen species (ROS), activated the caspase cascade, and upregulated p53 and p21. The anticancer effect of violacein on HCC cells was also associated with the downregulation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2 signaling. Violacein not only suppressed the proliferation and formation of tumorspheres of Huh7 and Hep3B cancer stem-like cells but also reduced the expression of key markers of cancer stemness, including CD133, Sox2, Oct4, and Nanog, by inhibiting the signal transducer and activator of transcription 3 (STAT3)/AKT/ERK pathways. These results suggest the therapeutic potential of violacein in effectively suppressing HCC by targeting the proliferation and stemness of HCC cells. Full article
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Article
Incomptine A Induces Apoptosis, ROS Production and a Differential Protein Expression on Non-Hodgkin’s Lymphoma Cells
Int. J. Mol. Sci. 2021, 22(19), 10516; https://doi.org/10.3390/ijms221910516 - 29 Sep 2021
Viewed by 392
Abstract
Sesquiterpene lactones are of pharmaceutical interest due their cytotoxic and antitumor properties, which are commonly found within plants of several genera from the Asteraceae family such as the Decachaeta genus. From Decachaeta incompta four heliangolide, namely incomptines A-D have been isolated. In this [...] Read more.
Sesquiterpene lactones are of pharmaceutical interest due their cytotoxic and antitumor properties, which are commonly found within plants of several genera from the Asteraceae family such as the Decachaeta genus. From Decachaeta incompta four heliangolide, namely incomptines A-D have been isolated. In this study, cytotoxic properties of incomptine A (IA) were evaluated on four lymphoma cancer cell lines: U-937, Farage, SU-DHL-2, and REC-1. The type of cell death induced by IA and its effects on U-937 cells were analyzed based on its capability to induce apoptosis and produce reactive oxygen species (ROS) through flow cytometry with 4′,6-diamidino-2-phenylindole staining, dual annexin V/DAPI staining, and dichlorofluorescein 2′,7′-diacetate, respectively. A differential protein expression analysis study was carried out by isobaric tags for relative and absolute quantitation (iTRAQ) through UPLC-MS/MS. Results reveal that IA exhibited cytotoxic activity against the cell line U-937 (CC50 of 0.12 ± 0.02 μM) and the incubation of these cells in presence of IA significantly increased apoptotic population and intracellular ROS levels. In the proteomic approach 1548 proteins were differentially expressed, out of which 587 exhibited a fold-change ≥ 1.5 and 961 a fold-change ≤ 0.67. Most of these differentially regulated proteins are involved in apoptosis, oxidative stress, glycolytic metabolism, or cytoskeleton structuration. Full article
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Article
Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions
Int. J. Mol. Sci. 2021, 22(13), 7125; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137125 - 01 Jul 2021
Cited by 1 | Viewed by 1007
Abstract
Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using [...] Read more.
Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue 6 possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC50 7.4 ± 0.7 μM) and colon cancer HT29 (IC50 9.0 ± 0.4 μM). Notably, spin-labelled fusidic acid derivative 8 acts strongly against these two cancer cell lines (PC3: IC50 6.0 ± 1.1 μM; HT29: IC50 7.4 ± 0.6 μM). Additionally, another fusidic acid analogue 9 was also found to be active towards HT29 with IC50 7.0 ± 0.3 μM (CV). Studies on the mode of action revealed that compound 8 increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound 18 was successfully achieved, since mitochondria are the major source of ROS generation. Full article
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Review

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Review
Promising Antiviral Activities of Natural Flavonoids against SARS-CoV-2 Targets: Systematic Review
Int. J. Mol. Sci. 2021, 22(20), 11069; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011069 - 14 Oct 2021
Viewed by 404
Abstract
The ongoing COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a globally leading public health concern over the past two years. Despite the development and administration of multiple vaccines, the mutation of newer strains and challenges to universal [...] Read more.
The ongoing COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a globally leading public health concern over the past two years. Despite the development and administration of multiple vaccines, the mutation of newer strains and challenges to universal immunity has shifted the focus to the lack of efficacious drugs for therapeutic intervention for the disease. As with SARS-CoV, MERS-CoV, and other non-respiratory viruses, flavonoids present themselves as a promising therapeutic intervention given their success in silico, in vitro, in vivo, and more recently, in clinical studies. This review focuses on data from in vitro studies analyzing the effects of flavonoids on various key SARS-CoV-2 targets and presents an analysis of the structure-activity relationships for the same. From 27 primary papers, over 69 flavonoids were investigated for their activities against various SARS-CoV-2 targets, ranging from the promising 3C-like protease (3CLpro) to the less explored nucleocapsid (N) protein; the most promising were quercetin and myricetin derivatives, baicalein, baicalin, EGCG, and tannic acid. We further review promising in silico studies featuring activities of flavonoids against SARS-CoV-2 and list ongoing clinical studies involving the therapeutic potential of flavonoid-rich extracts in combination with synthetic drugs or other polyphenols and suggest prospects for the future of flavonoids against SARS-CoV-2. Full article
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Review
Natural Products with Activity against Lung Cancer: A Review Focusing on the Tumor Microenvironment
Int. J. Mol. Sci. 2021, 22(19), 10827; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910827 - 07 Oct 2021
Viewed by 347
Abstract
Lung cancer is one of the most prevalent malignancies worldwide. Despite the undeniable progress in lung cancer research made over the past decade, it is still the leading cause of cancer-related deaths and continues to challenge scientists and researchers engaged in searching for [...] Read more.
Lung cancer is one of the most prevalent malignancies worldwide. Despite the undeniable progress in lung cancer research made over the past decade, it is still the leading cause of cancer-related deaths and continues to challenge scientists and researchers engaged in searching for therapeutics and drugs. The tumor microenvironment (TME) is recognized as one of the major hallmarks of epithelial cancers, including the majority of lung cancers, and is associated with tumorigenesis, progression, invasion, and metastasis. Targeting of the TME has received increasing attention in recent years. Natural products have historically made substantial contributions to pharmacotherapy, especially for cancer. In this review, we emphasize the role of the TME and summarize the experimental proof demonstrating the antitumor effects and underlying mechanisms of natural products that target the TME. We also review the effects of natural products used in combination with anticancer agents. Moreover, we highlight nanotechnology and other materials used to enhance the effects of natural products. Overall, our hope is that this review of these natural products will encourage more thoughts and ideas on therapeutic development to benefit lung cancer patients. Full article
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