Editorial

5 pages, 214 KiB

Open AccessEditorial

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

by Hidayat Hussain

Int. J. Mol. Sci. 2022, 23(10), 5835; https://doi.org/10.3390/ijms23105835 - 23 May 2022

Viewed by 978

Abstract

Nature continuously produces biologically useful molecules and provides mankind with life-saving drugs or therapies [...] Full article

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

6 pages, 696 KiB

Open AccessEditorial

Prof. Ludger Wessjohann: A Lifelong Career Dedicated to a Remarkable Service in “Natural Products Sciences”

by Hidayat Hussain

Int. J. Mol. Sci. 2022, 23(10), 5440; https://doi.org/10.3390/ijms23105440 - 13 May 2022

Viewed by 1926

Abstract

It is a great honor and a pleasure for me to serve as Guest Editor for this Issue of the “International Journal of Molecular Sciences”, dedicated to our mentor and colleague, Professor Dr [...] Full article

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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Research

Jump to: Editorial, Review

18 pages, 5629 KiB

Open AccessArticle

Synthesis of Multiple Bispecific Antibody Formats with Only One Single Enzyme Based on Enhanced Trypsiligase

by Johanna Voigt, Christoph Meyer and Frank Bordusa

Int. J. Mol. Sci. 2022, 23(6), 3144; https://doi.org/10.3390/ijms23063144 - 15 Mar 2022

Cited by 2 | Viewed by 1926

Abstract

Bispecific antibodies (bsAbs) were first developed in the 1960s and are now emerging as a leading class of immunotherapies for cancer treatment with the potential to further improve clinical efficacy and safety. Many different formats of bsAbs have been established in the last [...] Read more.

Bispecific antibodies (bsAbs) were first developed in the 1960s and are now emerging as a leading class of immunotherapies for cancer treatment with the potential to further improve clinical efficacy and safety. Many different formats of bsAbs have been established in the last few years, mainly generated genetically. Here we report on a novel, flexible, and fast chemo–enzymatic, as well as purely enzymatic strategies, for generating bispecific antibody fragments by covalent fusion of two functional antibody Fab fragments (Fabs). For the chemo–enzymatic approach, we first modified the single Fabs site-specifically with click anchors using an enhanced Trypsiligase variant (eTl) and afterward converted the modified Fabs into the final heterodimers via click chemistry. Regarding the latter, we used the strain-promoted alkyne-azide cycloaddition (SPAAC) and inverse electron-demand Diels–Alder reaction (IEDDA) click approaches well known for their fast reaction kinetics and fewer side reactions. For applications where the non-natural linkages or hydrophobic click chemistry products might interfere, we developed two purely enzymatic alternatives enabling C- to C- and C- to N-terminal coupling of the two Fabs via a native peptide bond. This simple system could be expanded into a modular system, eliminating the need for extensive genetic engineering. The bispecific Fab fragments (bsFabs) produced here to bind the growth factors ErbB2 and ErbB3 with similar K_D values, such as the sole Fabs. Tested in breast cancer cell lines, we obtained biologically active bsFabs with improved properties compared to its single Fab counterparts. Full article

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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19 pages, 2626 KiB

Open AccessArticle

Induction of Isochromanones by Co-Cultivation of the Marine Fungus Cosmospora sp. and the Phytopathogen Magnaporthe oryzae

by Ernest Oppong-Danquah, Martina Blümel, Silvia Scarpato, Alfonso Mangoni and Deniz Tasdemir

Int. J. Mol. Sci. 2022, 23(2), 782; https://doi.org/10.3390/ijms23020782 - 11 Jan 2022

Cited by 9 | Viewed by 2305

Abstract

Microbial co-cultivation is a promising approach for the activation of biosynthetic gene clusters (BGCs) that remain transcriptionally silent under artificial culture conditions. As part of our project aiming at the discovery of marine-derived fungal agrochemicals, we previously used four phytopathogens as model competitors [...] Read more.

Microbial co-cultivation is a promising approach for the activation of biosynthetic gene clusters (BGCs) that remain transcriptionally silent under artificial culture conditions. As part of our project aiming at the discovery of marine-derived fungal agrochemicals, we previously used four phytopathogens as model competitors in the co-cultivation of 21 marine fungal strains. Based on comparative untargeted metabolomics analyses and anti-phytopathogenic activities of the co-cultures, we selected the co-culture of marine Cosmospora sp. with the phytopathogen Magnaporthe oryzae for in-depth chemical studies. UPLC-MS/MS-based molecular networking (MN) of the co-culture extract revealed an enhanced diversity of compounds in several molecular families, including isochromanones, specifically induced in the co-culture. Large scale co-cultivation of Cosmospora sp. and M. oryzae resulted in the isolation of five isochromanones from the whole co-culture extract, namely the known soudanones A, E, D (1-3) and their two new derivatives, soudanones H-I (4-5), the known isochromans, pseudoanguillosporins A and B (6, 7), naphtho-γ-pyrones, cephalochromin and ustilaginoidin G (8, 9), and ergosterol (10). Their structures were established by NMR, HR-ESIMS, FT-IR, electronic circular dichroism (ECD) spectroscopy, polarimetry ([α]_D), and Mosher’s ester reaction. Bioactivity assays revealed antimicrobial activity of compounds 2 and 3 against the phytopathogens M. oryzae and Phytophthora infestans, while pseudoanguillosporin A (6) showed the broadest and strongest anti-phytopathogenic activity against Pseudomonas syringae, Xanthomonas campestris, M. oryzae and P. infestans. This is the first study assessing the anti-phytopathogenic activities of soudanones. Full article

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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18 pages, 5210 KiB

Open AccessArticle

Butein and Frondoside-A Combination Exhibits Additive Anti-Cancer Effects on Tumor Cell Viability, Colony Growth, and Invasion and Synergism on Endothelial Cell Migration

by Shahrazad Sulaiman, Kholoud Arafat, Aya Mudhafar Al-Azawi, Noura Abdulraouf AlMarzooqi, Shamsa Nasser Ali Hussain Lootah and Samir Attoub

Int. J. Mol. Sci. 2022, 23(1), 431; https://doi.org/10.3390/ijms23010431 - 31 Dec 2021

Cited by 11 | Viewed by 2127

Abstract

Despite the significant advances in targeted- and immuno-therapies, lung and breast cancer are at the top list of cancer incidence and mortality worldwide as of 2020. Combination therapy consisting of a mixture of different drugs taken at once is currently the main approach [...] Read more.

Despite the significant advances in targeted- and immuno-therapies, lung and breast cancer are at the top list of cancer incidence and mortality worldwide as of 2020. Combination therapy consisting of a mixture of different drugs taken at once is currently the main approach in cancer management. Natural compounds are extensively investigated for their promising anti-cancer potential. This study explored the anti-cancer potential of butein, a biologically active flavonoid, on two major solid tumors, namely, A549 lung and MDA-MB-231 breast cancer cells alone and in combination with another natural anti-cancer compound, frondoside-A. We demonstrated that butein decreases A549 and MDA-MB-231 cancer cell viability and colony growth in vitro in addition to tumor growth on chick embryo chorioallantoic membrane (CAM) in vivo without inducing any noticeable toxicity. Additionally, non-toxic concentrations of butein significantly reduced the migration and invasion of both cell lines, suggesting its potential anti-metastatic effect. We showed that butein anti-cancer effects are due, at least in part, to a potent inhibition of STAT3 phosphorylation, leading to PARP cleavage and consequently cell death. Moreover, we demonstrated that combining butein with frondoside-A leads to additive effects on inhibiting A549 and MDA-MB-231 cellular viability, induction of caspase 3/7 activity, inhibition of colony growth, and inhibition of cellular migration and invasion. This combination reached a synergistic effect on the inhibition of HUVECs migration in vitro. Collectively, this study provides sufficient rationale to further carry out animal studies to confirm the relevance of these compounds’ combination in cancer therapy. Full article

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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13 pages, 4948 KiB

Open AccessArticle

Target Characterization of Kaempferol against Myocardial Infarction Using Novel In Silico Docking and DARTS Prediction Strategy

by Xunxun Wu, Xiaokun Li, Chunxue Yang and Yong Diao

Int. J. Mol. Sci. 2021, 22(23), 12908; https://doi.org/10.3390/ijms222312908 - 29 Nov 2021

Cited by 4 | Viewed by 2029

Abstract

Target identification is a crucial process for advancing natural products and drug leads development, which is often the most challenging and time-consuming step. However, the putative biological targets of natural products obtained from traditional prediction studies are also informatively redundant. Thus, how to [...] Read more.

Target identification is a crucial process for advancing natural products and drug leads development, which is often the most challenging and time-consuming step. However, the putative biological targets of natural products obtained from traditional prediction studies are also informatively redundant. Thus, how to precisely identify the target of natural products is still one of the major challenges. Given the shortcomings of current target identification methodologies, herein, a novel in silico docking and DARTS prediction strategy was proposed. Concretely, the possible molecular weight was detected by DARTS method through examining the protected band in SDS-PAGE. Then, the potential targets were obtained from screening and identification through the PharmMapper Server and TargetHunter method. In addition, the candidate target Src was further validated by surface plasmon resonance assay, and the anti-apoptosis effects of kaempferol against myocardial infarction were further confirmed by in vitro and in vivo assays. Collectively, these results demonstrated that the integrated strategy could efficiently characterize the targets, which may shed a new light on target identification of natural products. Full article

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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21 pages, 4092 KiB

Open AccessArticle

Rare Glutamic Acid Methyl Ester Peptaibols from Sepedonium ampullosporum Damon KSH 534 Exhibit Promising Antifungal and Anticancer Activity

by Yen T. H. Lam, Manuel G. Ricardo, Robert Rennert, Andrej Frolov, Andrea Porzel, Wolfgang Brandt, Pauline Stark, Bernhard Westermann and Norbert Arnold

Int. J. Mol. Sci. 2021, 22(23), 12718; https://doi.org/10.3390/ijms222312718 - 24 Nov 2021

Cited by 7 | Viewed by 2759

Abstract

Fungal species of genus Sepedonium are rich sources of diverse secondary metabolites (e.g., alkaloids, peptaibols), which exhibit variable biological activities. Herein, two new peptaibols, named ampullosporin F (1) and ampullosporin G (2), together with five known compounds, ampullosporin A [...] Read more.

Fungal species of genus Sepedonium are rich sources of diverse secondary metabolites (e.g., alkaloids, peptaibols), which exhibit variable biological activities. Herein, two new peptaibols, named ampullosporin F (1) and ampullosporin G (2), together with five known compounds, ampullosporin A (3), peptaibolin (4), chrysosporide (5), c(Trp-Ser) (6) and c(Trp-Ala) (7), have been isolated from the culture of Sepedonium ampullosporum Damon strain KSH534. The structures of 1 and 2 were elucidated based on ESI-HRMSⁿ experiments and intense 1D and 2D NMR analyses. The sequence of ampullosporin F (1) was determined to be Ac-Trp¹-Ala²-Aib³-Aib⁴-Leu⁵-Aib⁶-Gln⁷-Aib⁸-Aib⁹-Aib¹⁰-GluOMe¹¹-Leu¹²-Aib¹³-Gln¹⁴-Leuol¹⁵, while ampullosporin G (2) differs from 1 by exchanging the position of Gln⁷ with GluOMe¹¹. Furthermore, the total synthesis of 1 and 2 was carried out on solid-phase to confirm the absolute configuration of all chiral amino acids as L. In addition, ampullosporin F (1) and G (2) showed significant antifungal activity against B. cinerea and P. infestans, but were inactive against S. tritici. Cell viability assays using human prostate (PC-3) and colorectal (HT-29) cancer cells confirmed potent anticancer activities of 1 and 2. Furthermore, a molecular docking study was performed in silico as an attempt to explain the structure-activity correlation of the characteristic ampullosporins (1–3). Full article

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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13 pages, 2050 KiB

Open AccessArticle

COX Inhibitory and Cytotoxic Naphthoketal-Bearing Polyketides from Sparticola junci

by Katherine Yasmin M. Garcia, Mark Tristan J. Quimque, Gian Primahana, Andreas Ratzenböck, Mark Joseph B. Cano, Jeremiah Francis A. Llaguno, Hans-Martin Dahse, Chayanard Phukhamsakda, Frank Surup, Marc Stadler and Allan Patrick G. Macabeo

Int. J. Mol. Sci. 2021, 22(22), 12379; https://doi.org/10.3390/ijms222212379 - 17 Nov 2021

Cited by 5 | Viewed by 2106

Abstract

Axenic fermentation on solid rice of the saprobic fungus Sparticola junci afforded two new highly oxidized naphthalenoid polyketide derivatives, sparticatechol A (1) and sparticolin H (2) along with sparticolin A (3). The structures of 1 and 2 [...] Read more.

Axenic fermentation on solid rice of the saprobic fungus Sparticola junci afforded two new highly oxidized naphthalenoid polyketide derivatives, sparticatechol A (1) and sparticolin H (2) along with sparticolin A (3). The structures of 1 and 2 were elucidated on the basis of their NMR and HR-ESIMS spectroscopic data. Assignment of absolute configurations was performed using electronic circular dichroism (ECD) experiments and Time-Dependent Density Functional Theory (TDDFT) calculations. Compounds 1–3 were evaluated for COX inhibitory, antiproliferative, cytotoxic and antimicrobial activities. Compounds 1 and 2 exhibited strong inhibitory activities against COX-1 and COX-2. Molecular docking analysis of 1 conferred favorable binding against COX-2. Sparticolin H (2) and A (3) showed a moderate antiproliferative effect against myelogenous leukemia K-562 cells and weak cytotoxicity against HeLa and mouse fibroblast cells. Full article

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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16 pages, 7291 KiB

Open AccessArticle

ATG 4B Serves a Crucial Role in RCE-4-Induced Inhibition of the Bcl-2–Beclin 1 Complex in Cervical Cancer Ca Ski Cells

by Fang-Fang You, Jing Zhang, Fan Cheng, Kun Zou, Xue-Qing Zhang and Jian-Feng Chen

Int. J. Mol. Sci. 2021, 22(22), 12302; https://doi.org/10.3390/ijms222212302 - 14 Nov 2021

Cited by 5 | Viewed by 1804

Abstract

RCE-4, a steroidal saponin isolated from Reineckia carnea, has been studied previously and has exhibited promising anti-cervical cancer properties by inducing programmed cell death (PCD) of Ca Ski cells. Considering the cancer cells developed various pathways to evade chemotherapy-induced PCD, there is, [...] Read more.

RCE-4, a steroidal saponin isolated from Reineckia carnea, has been studied previously and has exhibited promising anti-cervical cancer properties by inducing programmed cell death (PCD) of Ca Ski cells. Considering the cancer cells developed various pathways to evade chemotherapy-induced PCD, there is, therefore, an urgent need to further explore the potential mechanisms underlying its actions. The present study focused on targeting the Bcl-2–Beclin 1 complex, which is known as the key regulator of PCD, to deeply elucidate the molecular mechanism of RCE-4 against cervical cancer. The effects of RCE-4 on the Bcl-2–Beclin 1 complex were investigated by using the co-immunoprecipitation assay. In addition, autophagy-related genes (ATG) were also analyzed due to their special roles in PCD. The results demonstrated that RCE-4 inhibited the formation of the Bcl-2–Beclin 1 complex in Ca Ski cells via various pathways, and ATG 4B proteins involved in this process served as a key co-factor. Furthermore, based on the above, the sensitivity of RCE-4 to Ca Ski cells was significantly enhanced by inhibiting the expression of the ATG 4B by applying the ATG 4B siRNA plasmid. Full article

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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19 pages, 6121 KiB

Open AccessArticle

MUG Mel3 Cell Lines Reflect Heterogeneity in Melanoma and Represent a Robust Model for Melanoma in Pregnancy

by Silke Schrom, Thomas Hebesberger, Stefanie Angela Wallner, Ines Anders, Erika Richtig, Waltraud Brandl, Birgit Hirschmugl, Mariangela Garofalo, Claudia Bernecker, Peter Schlenke, Karl Kashofer, Christian Wadsack, Ariane Aigelsreiter, Ellen Heitzer, Sabrina Riedl, Dagmar Zweytick, Nadine Kretschmer, Georg Richtig and Beate Rinner

Int. J. Mol. Sci. 2021, 22(21), 11318; https://doi.org/10.3390/ijms222111318 - 20 Oct 2021

Cited by 2 | Viewed by 2314

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

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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11 pages, 1505 KiB

Open AccessCommunication

Polygodial and Ophiobolin A Analogues for Covalent Crosslinking of Anticancer Targets

by Vladimir Maslivetc, Breana Laguera, Sunena Chandra, Ramesh Dasari, Wesley J. Olivier, Jason A. Smith, Alex C. Bissember, Marco Masi, Antonio Evidente, Veronique Mathieu and Alexander Kornienko

Int. J. Mol. Sci. 2021, 22(20), 11256; https://doi.org/10.3390/ijms222011256 - 19 Oct 2021

Cited by 5 | Viewed by 2306

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

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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11 pages, 1261 KiB

Open AccessArticle

Synthesis of Demissidine Analogues from Tigogenin via Imine Intermediates

by Agnieszka Wojtkielewicz, Urszula Kiełczewska, Aneta Baj and Jacek W. Morzycki

Int. J. Mol. Sci. 2021, 22(19), 10879; https://doi.org/10.3390/ijms221910879 - 08 Oct 2021

Cited by 2 | Viewed by 1812

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

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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14 pages, 2343 KiB

Open AccessArticle

The Natural Pigment Violacein Potentially Suppresses the Proliferation and Stemness of Hepatocellular Carcinoma Cells In Vitro

by Yu Jin Kim, Nayeong Yuk, Hee Jeong Shin and Hye Jin Jung

Int. J. Mol. Sci. 2021, 22(19), 10731; https://doi.org/10.3390/ijms221910731 - 03 Oct 2021

Cited by 12 | Viewed by 3294

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

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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13 pages, 1783 KiB

Open AccessArticle

Incomptine A Induces Apoptosis, ROS Production and a Differential Protein Expression on Non-Hodgkin’s Lymphoma Cells

by Emmanuel Pina-Jiménez, Fernando Calzada, Elihú Bautista, Rosa María Ordoñez-Razo, Claudia Velázquez, Elizabeth Barbosa and Normand García-Hernández

Int. J. Mol. Sci. 2021, 22(19), 10516; https://doi.org/10.3390/ijms221910516 - 29 Sep 2021

Cited by 10 | Viewed by 2042

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

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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18 pages, 5028 KiB

Open AccessArticle

Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions

by Haider N. Sultani, Ibrahim Morgan, Hidayat Hussain, Andreas H. Roos, Haleh H. Haeri, Goran N. Kaluđerović, Dariush Hinderberger and Bernhard Westermann

Int. J. Mol. Sci. 2021, 22(13), 7125; https://doi.org/10.3390/ijms22137125 - 01 Jul 2021

Cited by 11 | Viewed by 3187

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

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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Review

Jump to: Editorial, Research

49 pages, 4034 KiB

Open AccessReview

Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies

by Mahshid Deldar Abad Paskeh, Shafagh Asadi, Amirhossein Zabolian, Hossein Saleki, Mohammad Amin Khoshbakht, Sina Sabet, Mohamad Javad Naghdi, Mehrdad Hashemi, Kiavash Hushmandi, Milad Ashrafizadeh, Sepideh Mirzaei, Ali Zarrabi and Gautam Sethi

Int. J. Mol. Sci. 2021, 22(21), 11669; https://doi.org/10.3390/ijms222111669 - 28 Oct 2021

Cited by 27 | Viewed by 4261

Abstract

As a multifactorial disease, treatment of cancer depends on understanding unique mechanisms involved in its progression. The cancer stem cells (CSCs) are responsible for tumor stemness and by enhancing colony formation, proliferation as well as metastasis, and these cells can also mediate resistance [...] Read more.

As a multifactorial disease, treatment of cancer depends on understanding unique mechanisms involved in its progression. The cancer stem cells (CSCs) are responsible for tumor stemness and by enhancing colony formation, proliferation as well as metastasis, and these cells can also mediate resistance to therapy. Furthermore, the presence of CSCs leads to cancer recurrence and therefore their complete eradication can have immense therapeutic benefits. The present review focuses on targeting CSCs by natural products in cancer therapy. The growth and colony formation capacities of CSCs have been reported can be attenuated by the dietary agents. These compounds can induce apoptosis in CSCs and reduce tumor migration and invasion via EMT inhibition. A variety of molecular pathways including STAT3, Wnt/β-catenin, Sonic Hedgehog, Gli1 and NF-κB undergo down-regulation by dietary agents in suppressing CSC features. Upon exposure to natural agents, a significant decrease occurs in levels of CSC markers including CD44, CD133, ALDH1, Oct4 and Nanog to impair cancer stemness. Furthermore, CSC suppression by dietary agents can enhance sensitivity of tumors to chemotherapy and radiotherapy. In addition to in vitro studies, as well as experiments on the different preclinical models have shown capacity of natural products in suppressing cancer stemness. Furthermore, use of nanostructures for improving therapeutic impact of dietary agents is recommended to rapidly translate preclinical findings for clinical use. Full article

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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Open AccessReview

Promising Antiviral Activities of Natural Flavonoids against SARS-CoV-2 Targets: Systematic Review

by Ridhima Kaul, Pradipta Paul, Sanjay Kumar, Dietrich Büsselberg, Vivek Dhar Dwivedi and Ali Chaari

Int. J. Mol. Sci. 2021, 22(20), 11069; https://doi.org/10.3390/ijms222011069 - 14 Oct 2021

Cited by 56 | Viewed by 8747

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

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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24 pages, 2388 KiB

Open AccessReview

Natural Products with Activity against Lung Cancer: A Review Focusing on the Tumor Microenvironment

by Yue Yang, Ning Li, Tian-Ming Wang and Lei Di

Int. J. Mol. Sci. 2021, 22(19), 10827; https://doi.org/10.3390/ijms221910827 - 07 Oct 2021

Cited by 31 | Viewed by 3883

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

(This article belongs to the Special Issue Theme Issue Honoring Prof. Dr. Ludger Wessjohann’s 60th Birthday: Natural Products in Modern Drug Discovery)

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